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/lp/springer-journals/response-variability-in-attention-deficit-hyperactivity-disorder-a-HTS5ecisth
- Publisher
- Springer Journals
- Copyright
- Copyright © 2006 by Russell et al; licensee BioMed Central Ltd.
- Subject
- Biomedicine; Neurosciences; Neurology; Behavioral Therapy; Psychiatry
- eISSN
- 1744-9081
- DOI
- 10.1186/1744-9081-2-30
- pmid
- 16925830
- Publisher site
- See Article on Publisher Site
Abstract
Background: Current concepts of Attention-Deficit/Hyperactivity Disorder (ADHD) emphasize the role of higher-order cognitive functions and reinforcement processes attributed to structural and biochemical anomalies in cortical and limbic neural networks innervated by the monoamines, dopamine, noradrenaline and serotonin. However, these explanations do not account for the ubiquitous findings in ADHD of intra-individual performance variability, particularly on tasks that require continual responses to rapid, externally-paced stimuli. Nor do they consider attention as a temporal process dependent upon a continuous energy supply for efficient and consistent function. A consideration of this feature of intra-individual response variability, which is not unique to ADHD but is also found in other disorders, leads to a new perspective on the causes and potential remedies of specific aspects of ADHD. The hypothesis: We propose that in ADHD, astrocyte function is insufficient, particularly in terms of its formation and supply of lactate. This insufficiency has implications both for performance and development: H1) In rapidly firing neurons there is deficient ATP production, slow restoration of ionic gradients across neuronal membranes and delayed neuronal firing; H2) In oligodendrocytes insufficient lactate supply impairs fatty acid synthesis and myelination of axons during development. These effects occur over vastly different time scales: those due to deficient ATP (H1) occur over milliseconds, whereas those due to deficient myelination (H2) occur over months and years. Collectively the neural outcomes of impaired astrocytic release of lactate manifest behaviourally as inefficient and inconsistent performance (variable response times across the lifespan, especially during activities that require sustained speeded responses and complex information processing). Testing the hypothesis: Multi-level and multi-method approaches are required. These include: 1) Use of dynamic strategies to evaluate cognitive performance under conditions that vary in duration, complexity, speed, and reinforcement; 2) Use of sensitive neuroimaging techniques such as diffusion tensor imaging, magnetic resonance spectroscopy, electroencephalography or magnetoencephalopathy to quantify developmental changes in myelination in ADHD as a potential basis for the delayed maturation of brain function and coordination, and 3) Investigation of the prevalence of genetic markers for factors that regulate energy metabolism (lactate, Page 1 of 25 (page number not for citation purposes) Behavioral and Brain Functions 2006, 2:30 http://www.behavioralandbrainfunctions.com/content/2/1/30 glutamate, glucose transporters, glycogen synthase, glycogen phosphorylase, glycolytic enzymes), release of glutamate from synaptic terminals and glutamate-stimulated lactate production (SNAP25, glutamate receptors, 2+ ), as well as astrocyte function (α , α and β-adrenoceptors, adenosine receptors, neurexins, intracellular Ca 1 2 dopamine D1 receptors) and myelin synthesis (lactate transporter, Lingo-1, Quaking homolog, leukemia inhibitory factor, and Transferrin). Implications of the hypothesis: The hypothesis extends existing theories of ADHD by proposing a physiological basis for specific aspects of the ADHD phenotype – namely frequent, transient and impairing fluctuations in functioning, particularly during performance of speeded, effortful tasks. The immediate effects of deficient ATP production and slow restoration of ionic gradients across membranes of rapidly firing neurons have implications for daily functioning: For individuals with ADHD, performance efficacy would be enhanced if repetitive and lengthy effortful tasks were segmented to reduce concurrent demands for speed and accuracy of response (introduction of breaks into lengthy/effortful activities such as examinations, motorway driving, assembly-line production). Also, variations in task or modality and the use of self- rather than system-paced schedules would be helpful. This would enable energetic demands to be distributed to alternate neural resources, and energy reserves to be re-established. Longer-term effects may manifest as reduction in regional brain volumes since brain areas with the highest energy demand will be most affected by a restricted energy supply and may be reduced in size. Novel forms of therapeutic agent and delivery system could be based on factors that regulate energy production and myelin synthesis. Since the phenomena and our proposed basis for it are not unique to ADHD but also manifests in other disorders, the implications of our hypotheses may be relevant to understanding and remediating these other conditions as well. cytes [14], and thus enables rapid neurotransmission. The 2. Background Attention-Deficit/Hyperactivity Disorder (ADHD) is a presence of receptors for the major brain neurotransmit- highly heritable and heterogeneous condition with a ters on astrocytes adds to the robust evidence for their widespread prevalence [1]. It often persists into adult- direct involvement in neurotransmission [15-18]. Given hood with deleterious effects on educational, social, and that performance variability is not unique to ADHD but occupational outcomes [2,3]. ADHD is defined by persist- rather a common and unifying feature of several disor- ing, developmentally inappropriate, cross-situational, ders, such as Traumatic Brain Injury, Schizophrenia, Nar- impairing levels of inattention, impulsiveness, and hyper- colepsy, Phenylketonuria (PKU), as well as ADHD, we do activity [4]. Our hypothesis focuses on a common observ- not propose such variance as a specific marker of ADHD. able feature of ADHD, marked moment-to-moment Rather we argue that intra-individual response variability fluctuation in task performance [5-9]. Yet this ubiquitous may be an important index of the efficiency of neural sig- phenomenon has been viewed as uninteresting random nalling which, in turn, is dependent on neurobiological noise and ignored in the ADHD research field almost regulation of brain function (e.g. factors that regulate the entirely until recently, when it was proposed as an aetio- energy supply to neurons). Also, we suggest that it may logically important characteristic requiring systematic account for a substantial proportion of the variance in analysis [10]. Behavioural and performance fluctuations performance of executive function tasks such that poor are displayed over multiple time scales, but our primary task performance may not reflect impaired executive func- interest here are with those that occur over seconds, rather tion per se, but rather an admixture of poor neurobiologi- than hours or days. cal regulation of the external physiological environment of rapidly firing neurons as well as slowed processing The genesis of this type of intra-individual performance speed arising from inadequately myelinated neurons, par- variability (variability during continual responding to ticularly those involved in working memory [19]. externally-paced stimuli) remains unknown. We propose that it arises from inefficient and inconsistent neuronal First we summarize the evidence for the transient fluctua- transmission of information, due to a deficient energy tions in task performance of individuals with ADHD, and supply – lactate production – by the major non-neuronal the inadequacy of current explanations to account for the component of the central nervous system (CNS), the short time scales involved. Our hypothesis, introduced astrocyte [11-13]. Astrocytes play a critical role in provid- initially by Todd and Botteron [13], is then elaborated ing energy via lactate to rapidly firing neurons. Astrocytes with evidence for important elements of the theory. can also provide lactate to oligodendrocytes, which is Finally we outline strategies for testing the hypothesis and used as a substrate for myelin synthesis by oligodendro- discuss its theoretical and clinical significance. Page 2 of 25 (page number not for citation purposes) Behavioral and Brain Functions 2006, 2:30 http://www.behavioralandbrainfunctions.com/content/2/1/30 2.1 Transient fluctuations in task performance do not permit examination of potential periodicities 2.1.1 Intra-individual behavioural variability within the moment-to-moment fluctuations in perform- We propose that increased intra-individual behavioural ) / ance. Consecutive variability (CONV = √(∑(RTi - RT i-1 variability in continual responses to rapid, externally- (n - 1)), where I = trial number, n = number of trials, √ = paced stimuli are related to other factors than those caus- square root) provides a measure of local unpredictability ing increased variability in free-operant, non-externally (trial-to-trial variability) as well as controlling overall paced tasks [8,9,20]. The former is timed by objective MRT. Autocorrelations (correlations between consecutive clock time, the latter by behavioural events not necessarily or subsequent observations) measure the extent of linear highly correlated with objective time. We define intra- association between one response and subsequent individual variability as short-term fluctuations in the per- responding, thereby providing insights into the consist- formance of an individual over a time-scale of seconds. It ency and predictability of behaviour [8,25]. Another is differentiated from systematic and longer-lasting time- approach has been to fit trial-by-trial RT data to the ex- related changes in task performance due to practice, learn- Gaussian distribution, which provides parameters that ing, developmental growth, or to remission or progres- may be related to more theoretically based distributions, sion of a clinical condition or disease. This intra- such as the Wald [32]. This method permits determina- individual variability will be the cause of inter-task varia- tion of whether the increase in intra-individual RT varia- bility. While not central in ADHD research, intra-individ- bility in ADHD is a general phenomenon occurring across ual response variability has been used as a primary the whole RT distribution, or reflects a specific variability- dependent variable in research in normal ageing and in producing process, such as attentional lapses, restricted to neurological populations [21-27]. Evidence that individu- the tail at the slow end of the distribution [27]. The ex- als with mild dementia exhibit greater intra-individual Gaussian analysis delivers two measures of variability: variability than both healthy adults and those with arthri- one from the fast, Gaussian portion of the distribution, tis suggests that it reflects neurological compromise rather and one from the slow exponential tail [31]. In normal than deterioration of general health [22,28]. Moreover, development and ageing, age-related change in intra-indi- findings from studies incorporating structural or func- vidual variability throughout childhood affects the distri- tional human brain mapping methods indicate that intra- bution as a whole, whereas in adulthood, differences in individual variability is not simply a sequela of general variability appears to be due to factors influencing prima- brain dysfunction, but is likely related to the functioning rily the slow end of the RT distribution, such as atten- of neural circuits that engage the prefrontal cortex, partic- tional lapses [22,33]. ularly the dorsolateral areas [25,29,30]. Behavioural find- ings indicate that intra-individual response variability is a The fast Fourier transform, which measures the power of strong predictor of success [30], suggesting that poor per- periodic changes at different temporal frequencies, per- formance on control tasks like Go-No-Go, inhibition ver- mits an assessment of periodicity over time [34]. Any peri- sions of continuous performance tests (CPT), and stop- odically recurring patterns of responding within the RT signal task may reflect problems in response variability series are manifest as peaks of power at particular frequen- rather than poor inhibitory control per se. cies. Prior to summarizing the empirical research on intra-indi- 2.1.2 Intra-individual variability in ADHD Significant and reliable differences in the speed and varia- vidual variability in ADHD, a comment is warranted on the various approaches to its measurement. The most bility of responses have been documented between common method of characterizing variability in response ADHD and comparison groups across a wide variety of or reaction times (both denoted here by RT) consists of a neuropsychological tasks. Increased variability is seen in single-point estimate of the standard deviation (SD) tasks requiring continual responses to rapid, externally- around the mean reaction time (MRT) for each individual paced stimuli as well as in "free-operant" tasks without (ISD). This method has the advantage of simplicity, but such a requirement. Recent studies of South African chil- because it aggregates response indices across time inter- dren from 7 ethnic groups and Norwegian children, using vals, it conflates effects due to practice, learning, overall a computerized game-like free-operant task [8,9], showed speed of responding, and randomness, with possible sys- significantly lower predictability of responding in ADHD tematic periodic fluctuations in response times. Most than in non-ADHD groups. Predictability of response importantly, response variability is usually strongly corre- location and timing were measured in terms of variance lated with MRT [31]; computation of an intra-individual explained by autocorrelations. Interestingly, in the free- coefficient of variation (ICV = ISD/MRT) controls to some operant task without externally-paced stimuli, response extent for the individual's overall speed of response. Two location – but not response timing – was a sensitive other measures capitalize to some extent on information behavioural measure. In tasks requiring continual that may be derived from serial analysis of response, but responses to rapid, externally-paced stimuli, however, Page 3 of 25 (page number not for citation purposes) Behavioral and Brain Functions 2006, 2:30 http://www.behavioralandbrainfunctions.com/content/2/1/30 children with ADHD display greater intra-individual vari- around 0.05 Hz, indicative of lapses of attention 2 to 4 ability in response times and are often found to respond times per minute [53]. more slowly and less accurately than their typically devel- oping peers [6]. These performance differences have been Variability is increased at all parts of the distribution [53] found on the stop-signal task [35-38], a variety of CPT which is consistent with Williams et al. [54] who showed [39-41], time perception, time reproduction and motor that that intra-individual response variability in the fast timing tests [42-45], and visuomotor preparation tests tail of the distribution is distinct from that found in the [46]. Notably, a recent psychometric analysis of several slow tail. measures of intra-individual variability (ISD, ICV, CONV) as well as measures of central tendency and shape of the Intra-individual variability in response time has been pro- reaction time distribution derived from children's per- posed as a possible endophenotype with the potential to formance of four different neuropsychological tasks (stop index genetic vulnerability to ADHD [10,55]. Further sup- signal task, CPT, Go-No-Go, n-back working memory port for this proposition comes from two molecular task) yield two important findings [47]. First, measures of genetic studies that report associations between the 10- intra-individual variability best discriminated between repeat risk allele within the dopamine transporter gene the ADHD and control groups; second, intra-individual (DAT1) and response variability in ADHD [56,57]. The variability appeared to be a unitary construct in ADHD dopamine transporter is the main site of action of methyl- (individuals with high variability on one task tended to phenidate, which reduces intra-individual response varia- have high variability on other tasks). bility in ADHD [35,53,58]. Poorer performance on neuropsychological tasks in 2.1.2.1 A theoretical model ADHD is typically interpreted as evidence of executive The above models provide statistics descriptive of the function deficits, an interpretation that is based on slower data. In order to better constrain our hypotheses by data, and less accurate responses averaged across time. Accom- we also develop a model of the cascade of energetic panying group differences in intra-individual response resources that we posit in H1. That supply chain has many variability are typically ignored – or, worse, become a nui- similarities to hydraulic flow through n reservoirs [59], sance parameter that keeps the inferential statistics from with the decay into the last nth state being analogous to achieving significance. For example, the interpretation the repletion of glutamate in the vesicles. Our hypothesis "poor inhibitory control" is commonly based on slower H1 predicts that the decreased efficiency in energy trans- RTs to the stop signal or more commission errors in the port and glutamate restaging, which we posit to be charac- CPT. Yet, it is often intra-individual variability in RT that teristic of ADHD, will cause slower repletion, and entail correlates with the behavioural symptoms of ADHD, not larger values for the time constants that measure the mean the mean of the criterion variable [38,40,48,49]. occupancy times at each energetic stage. To simplify the Response variability correlates more strongly and reliably model in light of available data, we assume equal time- with ratings of ADHD symptoms compared to commis- constants for each stage. This model predicts a gamma dis- sion errors or other outcome measures on the CPT in a tribution of the time required for the energy level at the large epidemiological sample [40] and compared with last stage to reach the threshold necessary to support a stop signal reaction time (i.e. index of inhibitory control) response. in a large twin sample [38] or average response speed in a community sample of typically developing children [48]. The model has two parameters: the number of candidate stages (n), and their average time constants (τ). The Application of the ex-Gaussian model to RT data indicates gamma resembles the familiar ex-Gaussian distribution, that the greater response time variability in individuals and provides a good description of reaction-time data. with ADHD is most evident in the slow tail [50-52]: There Leth-Steensen, Elbaz and Douglas [52] compared the per- appears to be some variability-producing process, such as formance of 17 ADHD boys off medication, with a mean momentary attentional lapses, that affects the slow RTs age of 11 years, with 18 age-matched control boys and ten [50]. Recent evidence from Fourier analysis found that 7 year-old boys, on a four-choice reaction-time task. Four children with ADHD showed increased variability at all warning circles were presented on a screen for 2, 4, or 8 s parts of the RT spectrum [53], consistent with Williams et fore periods, followed by a change in the colour of one to al[54] who showed that intra-individual response varia- yellow. The boys were to press a key corresponding to the bility in the fast tail of the distribution is distinct from that changed stimulus. The authors fit ex-Gaussian densities to found in the slow tail. However, there is significantly the observed distributions, and also reported the mean (50%) more intra-individual variability in reaction time (μ) and variance (σ ) of the RT distributions. From those, of individuals with ADHD at a modal frequency of the parameters of the gamma model may be deduced: n = 2 2 2 μ /σ and τ = σ /μ. This analysis imputed n = 6 stages for Page 4 of 25 (page number not for citation purposes) Behavioral and Brain Functions 2006, 2:30 http://www.behavioralandbrainfunctions.com/content/2/1/30 ADHD, and n = 16 for controls. The model cannot iden- hypothetical map between energy reservoirs and perform- tify precisely which energetic processes correspond to ance. these stages, but does indicate that there is a greater depth of resources available for the control group. As predicted, 2.1.3 Fluctuations in attentional processing and performance the processes are slower for ADHD, with time constants τ Transient fluctuations have also been revealed in recent = 141, 152, and 171 ms for the 2 s, 4 s, and 8 s intervals, studies using innovative methods to capture shifts in compared with τ = 39, 40, and 44 ms for controls. Hold- attentional processing within relatively short time-scales, ing parameters at these stipulated values, the gamma ranging from milliseconds to minutes. For example, rapid model recovered the statistics describing the data, as serial visual presentation (RSVP) paradigms such as the shown in Figure 1. The young control boys had interme- attentional blink design permit evaluation of temporal diate parameters (n = 10 and τ = 40, 117, and 120 ms; characteristics of information processing within a time- their data are omitted from Figure 1 to emphasize the key scale of milliseconds [63,64]. In this paradigm a stream of comparison). The index of skewness of the gamma stimuli is presented briefly (100 ms) in the same location -1/2 depends only on the number of stages, being 2n = 0.50 and in rapid succession (e.g., 10/s) and subjects are for controls and 0.82 for ADHD. This substantial increase required to detect two targets in the stream. When the tar- in skewness is consistent with the differential increase in gets are presented within about 500 ms of one another, long response times for ADHD, and causes the larger var- detection of the second target is impaired – a phenome- iance seen in reaction times for this condition [60]. non termed the "attentional blink". Children and adults According to our model, the increase is explained by the with ADHD and highly impulsive adolescents have been slower replenishment in a cascade of energy reservoirs in found to show a larger and more protracted attentional ADHD individuals compared to controls. blink than their non-ADHD peers, suggesting less efficient attentional processing and/or more rapid depletion of The model is simplistic in that it assumes a common processing resources [64-66]. period (τ) for energetic processes that operate on multiple time-scales, with some processes in parallel, as shown in Transient fluctuations in attentional state over a some- Figure 2. Comparison with other models, such as extreme- what longer time-scale (30 s periods) have been demon- value distributions which also could tell a revealing story strated by means of error analysis on computerized CPT about the latent processes, awaits adequate data. More coupled with an infra-red motion analysis system. Analy- informative trial-by-trial analyses (e.g., [53]) will yield the sis of attentional states over a period of 30-s revealed that fractal patterns of latencies first described by Hurst for children with ADHD exhibit many more shifts in atten- analogous hydraulic systems [61], and found in reaction tion states and spend much less time in an on-task atten- time distributions of normal subjects by Gilden [62]. It tion state than their peers [67]. Fidgetiness, as detected by will require such detailed analyses to further resolve our the motion-analysis system, was found to be related to the percent of time spent in the 'distracted' attentional state, in which the children's awareness of the relevant stimuli was diminished. These measures of attentional state pro- vided more robust indicators of the performance differ- ences between children with ADHD and comparison children than did the traditional time-averaged CPT sum- mary measures of error rates, latency and variability [67]. Fidgetiness, that most public characteristic of ADHD, might be a by-product of fatigue of relevant neuronal cir- cuits, and a search for new ones to engage. 2.1.4 Drug effects on intra-individual variability and attentional fluctuations Reaction time variability is reduced with appropriate monetary reward [45], but such rewards are not differen- Means (open sym b (s = 18 Figure 1 o qua ls) of reaction ) in a 4-choice reaction res, n = 17) and age-matched times bols) and standard deviat for a g time task roup of boys with ADHD control subjec ions (fts (circles, illed sym- n tially effective for children with ADHD. The reason for this Means (open symbols) and standard deviations (filled sym- may be that reinforcers may be less effective for tasks bols) of reaction times for a group of boys with ADHD requiring continual responses to rapid, externally-paced (squares, n = 17) and age-matched control subjects (circles, n stimuli than for subject-paced (free-operant) responding = 18) in a 4-choice reaction time task. The data are from [68]. The reason for this is probably that reinforcers work Leth-Steensen et al. [52]. The lines through the data derive from a series latency mechanism described in the text. on free-operant behaviour, but not on instructed behav- iour typical in tasks requiring continual responses to Page 5 of 25 (page number not for citation purposes) Behavioral and Brain Functions 2006, 2:30 http://www.behavioralandbrainfunctions.com/content/2/1/30 A n Figure 2 e scheme illustr nts contributin ag to hypotheses 1 a ting a glutamatergic neuron (left) nd 2 (H1 and H2 a glial c ) ell (astrocyte) and a small blood vessel (right) and the major compo- A scheme illustrating a glutamatergic neuron (left) a glial cell (astrocyte) and a small blood vessel (right) and the major compo- nents contributing to hypotheses 1 and 2 (H1 and H2). Neural activity triggers release of the neurotransmitter glutamate that is taken up into the astrocyte (via GLAST and GLT-1 transporters), and stimulates the breakdown of glycogen, the uptake of glucose, and glycolysis, to produce lactate. Rapid neuronal firing is sustained by the energy provided by the astrocyte-neuron lactate shuttle. Energy demands are high during rapid (burst) and maintained rates of neuronal firing. H1: At times of increased neuronal demand, deficient lactate results in decreased neuronal conversion of lactate to acetyl CoA, decreased ATP forma- + + tion, deficient ATPase function, delayed restoration of ion gradients, elevated extracellular K , deficient Na -dependent trans- port of glutamate into astrocytes that is required to drive glycolysis and lactate release by the astrocytes. The result is that situationally appropriate firing rates are achieved only episodically. Methylphenidate treatment results in an increase of the extracellular levels of the catecholamines, NA (and DA) that stimulate glycolysis and release of lactate from the astrocytes. This is followed by glycogen replenishment, thereby correcting the energy deficiency, and restoring appropriate firing rates. H2: A deficient supply of lactate for oligodendrocytes in the developing nervous system slows and reduces the synthesis of fatty acids required for the synthesis of myelin. Poorly myelinated axons would transmit action potentials more slowly, accounting for inefficient integration (coherence) between brain regions and for slow reaction times. A number of neurotrans- mitter receptors present on astrocytes are not illustrated (e.g. muscarinic, α , DA D3, D4, D5 and receptors for several neu- ropeptides). Page 6 of 25 (page number not for citation purposes) Behavioral and Brain Functions 2006, 2:30 http://www.behavioralandbrainfunctions.com/content/2/1/30 rapid, externally-paced stimuli (cf., [68]). Methylpheni- time variability and other manifestations of transient fluc- date medication improves accuracy, speeds reaction time, tuations in performance, which arise in the context of the and reduces reaction time variability in individuals with need for continuous rapid neuronal firing, reflect the ADHD [35,58]. Moreover, methylphenidate has been effects of transient depletion of neuronal energy on the shown to improve time on-task, with concomitant efficiency of information processing. decreases in the number of shifts in attention as the task progressed [67]. Such treatment effects suggest that the 3. The hypothesis increased availability of extra-neuronal catecholamines In this section we highlight the strengths and limitations arising from the blockade of their uptake by methylpheni- of Todd and Botteron's Energy-Deficiency Model (section date could lead to increased activity of noradrenaline at β- 3.1), present a brief background on astrocytes and their adrenoceptors and possibly also dopamine acting at D1 role in the development and function of the CNS (section receptors found on astrocytes [15,69]. A key fact is that 3.2), formulate the hypotheses (H1 and H2: section 3.3), stimulation of α - and β-adrenoceptors on astrocytes and provide a detailed summary of evidence supporting enhances glycolysis and lactate production [69]. the hypotheses (section 3.4). Dopamine acting on D1 receptors may have similar effects, but these are not well documented. 3.1 Energy-deficiency model According to Todd and Botteron [13], the genesis of the 2.1.5 Existing explanations and their limitations behavioural symptoms of ADHD is linked directly to At present, various tasks used to measure different aspects impairments of the astrocyte-neuron lactate/energy-shut- of executive function usually have moderately heavy cog- tle that is based on the astrocytic uptake of glucose from nitive demands and share requirements for continuous blood capillaries, its utilization (conversion to lactate) speeded responding to computer- or experimenter-pro- and storage as glycogen [76]. Since acute amphetamine duced stimuli, rather than being self-paced. Experimenter- treatment of young adults has been reported to stimulate paced measures of working memory are substantially bet- glucose uptake in the frontal lobes [77], Todd and Bot- ter predictors of reading letter span, continuous operation teron hypothesized that reduced catecholaminergic input span, literacy and mathematics scores than are more tradi- (in ADHD) leads to a decrease in astrocyte-mediated neu- tional, subject-paced measures [70]. We believe they pro- ronal energy metabolism and impaired frontal function. vide better diagnostics of ADHD because, like stress tests for cardiac function, they most directly challenge the sub- Todd and Botteron's model links catecholaminergic activ- jects' short-term reserves of energy, and that is a major ity to the regulation of neuronal energy metabolism. But resource compromised in ADHD. it does not make explicit how a decreased neuronal energy supply mediated by hypofunctioning catecholamines Slowing of MRT and increasing RT variability over time might alter either cognitive performance based on frontal has been postulated to reflect mental fatigue, 'resource lobe function or account for ADHD symptomatology in depletion', motivational deficits, fluctuations in executive general. In contrast, our hypothesis addresses a specific control, or underlying neurobiological disturbances (e.g., aspect of the clinical presentation, – namely, moment-to- motor timing deficits), which are caused by the need for moment fluctuations in task performance that are often continuous speeded responding to high-demand tasks also manifest in general behaviour – and we refine and [6,20,71-75]. Most of these models cannot account for the extend the biochemical bases that underlie this hypo- moment-to-moment fluctuations in response accuracy thesis. characteristic of ADHD. 3.2 Astrocyte and oligodendrocyte function in the central nervous system (CNS) The dynamic developmental theory of ADHD [8,9,20] explains intra-individual behavioural variability as defi- The CNS comprises two main types of cells: neurons that cient acquisition of stimulus control of long chains of are directly involved in information processing, and glial behaviour. This deficiency is rooted in reduced efficacy of cells (astrocytes, oligodendrocytes and microglia) which reinforcers ("rewards") combined with poorer extinction play a major role in the development and mature function ("unlearning") of inefficient behaviour. The dynamic of the CNS. Astrocytes are responsible for maintaining the developmental theory addresses free-operant behaviour environment of cells in the CNS: they provide nutrients without time constraints. However, neither the dynamic and modulate the release and uptake of glutamate, elec- + + developmental theory of ADHD, nor other theories and trolytes (Na /K ) and other by-products of neural activity explanations account for the intra-individual perform- [78]. In addition, astrocytes play an important role in neu- ance variability of ADHD on tasks that require continual ral signalling. They have receptors for neurotransmitters responses to rapid, externally-paced stimuli. The present such as glutamate, GABA, acetylcholine and the monoam- paper addresses this aspect by postulating that reaction ines as well as for other neuromodulators including neu- Page 7 of 25 (page number not for citation purposes) Behavioral and Brain Functions 2006, 2:30 http://www.behavioralandbrainfunctions.com/content/2/1/30 ropeptides, cytokines and steroid hormones [15-18,79- Neuronal activity is tightly coupled to glucose utilization 84]. They can modulate the excitability of neurons via [91]. Neural activity triggers oxidative metabolism (to 2+ levels initiated by stimulation of oscillations of Ca produce ATP) within neurons followed by breakdown of metabotropic glutamate receptors [15,85-90]. energy stores (glycogen in astrocytes) and uptake of glu- cose from blood capillaries into astrocytes to produce lac- Oligodendrocytes are responsible for forming myelin, a tate [91]. Rapid neuronal firing, however, is sustained by membranous sheath that is wound spirally around axons, the astrocyte-neuron lactate shuttle [92]. Lactate is the providing electrical insulation that leads to a more than essential energy source for rapidly firing neurons. It is a 10-fold increase in the speed of signal transmission occur- more efficient fuel than glucose because it is metabolized ring in unmyelinated axons [11]. to form ATP more rapidly and, unlike glucose, does not require ATP for its metabolism [76]. It is imperative for 3.3 Statement of the hypothesis neurons to make use of the most efficient energy supplies Lactate production by astrocytes is insufficient during when rapid neural processing is required and demands for brief periods of increased demand in ADHD. This hypo- energy are high, and the brain has evolved ways to do so thesis has two consequences (Figure 2). H1) The inability [93]. The neurotransmitter glutamate (released by the of astrocytes to provide an adequate supply of lactate to majority of excitatory neurons in the CNS) stimulates gly- rapidly firing neurons results in a localized and transient colysis (glucose utilization and lactate production) in deficiency in ATP production, impaired restoration of astrocytes and release of lactate into the extracellular fluid ionic gradients across neuronal membranes and slowed [91,94]. An inadequate supply of lactate during periods of neuronal firing. This leads to inconsistent performance of rapid neuronal firing, when local energy demand is high, demanding cognitive tasks; H2) Insufficient provision of briefly impairs neuronal function, particularly during the lactate for oligodendrocyte function in the longer term latter part of a train of neural impulses and shortly there- gives rise to deficient fatty acid synthesis and delayed or after, causing an extended refractory period. This reduced myelination of axons. In turn this leads to less increased latency to new information is measured in the efficient transmission and longer reaction times. The attentional blink paradigm (section 2.1.3). Compromised hypothesis refers to two effects over very different time energy supply, as hypothesized for ADHD, should impair scales: The effects on rapidly firing neurons occur over response inhibition or alternation at these times. milliseconds (H1), whereas the effects of reduced lactate supply for oligodendrocytes when demands are high dur- Periods of rapid neuronal firing will be followed by slow ing development takes place over months and years (H2). unsynchronized firing exerting less demand on energy Collectively the neural outcomes of astrocyte dysfunction resources, allowing replenishment of energy reserves and would manifest behaviourally as inefficient and/or incon- restoration of function. Energy reserves will depend on sistent performance (i.e. slow and/or variable response the prior history of neural and astrocyte activity. Brief peri- times across the lifespan, particularly during tasks that ods of energy insufficiency followed by periods of normal require continuous speeded responses and complex infor- supply are proposed to account for the variability of mation processing). behavioural response seen in ADHD when performing complex tasks that require speed and accuracy. 3.4 The hypothesis – discussion 3.4.1 H1: Impaired astrocyte function limits energy (lactate) supply 3.4.1.1 Impaired maintenance of ion gradients across the neuronal to rapidly firing neurons membrane The ionic composition of the cell cytoplasm is very differ- Decreased availability of lactate to produce energy in the ent from extracellular ion concentrations. In the neuron form of ATP would impair the function of membrane- + + 2+ the ionic gradients across the membrane constitute a store associated Na /K ATPase and Ca ATPase pumps, result- + + 2+ of potential energy that can drive the influx of Na and ing in elevated extracellular K and decreased Ca and + + efflux of K ions to generate an action potential, and the Na concentrations. Consistent with this hypothesis, 2+ influx of Ca ions to trigger neurotransmitter release and ADHD children were reported to have decreased urinary 2+ 2+ + + to generate Ca waves in and between both neurons and excretion of Ca , Na and phosphate, but not K ions glial cells. To maintain repeated firing over an extended [95]. Failure to maintain homeostasis of inorganic ions time, neurons require energy to restore the trans-mem- will alter electrochemical gradients across neuronal and + + 2+ brane gradients of Na , K and Ca ions. Neurons gener- glial cell membranes. As the resting membrane potential ate the necessary energy in the form of ATP; this drives the of neurons is dominated by the K concentration gradient + + + membrane-associated Na /K ATPase to pump Na out of across the membrane, failure to reduce elevated extracel- + + the cell and K back into the cell. ATP is also required by lular K concentrations following neural activity will alter 2+ 2+ Ca ATPase to pump Ca out of the cell or into intracel- membrane potentials, cause depolarization to last longer lular stores (Figure 2). than required, and thus impair neuronal function. Raised Page 8 of 25 (page number not for citation purposes) Behavioral and Brain Functions 2006, 2:30 http://www.behavioralandbrainfunctions.com/content/2/1/30 + + K /reduced Na gradients are likely to have widespread Glucocorticoid hormones also modulate the supply of effects in different parts of the brain, promoting for exam- energy [113,114]. Glucocorticoids inhibit glucose trans- ple monoamine release (e.g. dopamine [96]) and altering port into neurons and astrocytes and inhibit glycogen syn- the conformation of transporters, thus affecting monoam- thesis stimulated by noradrenergic activity [115]. Thus, ine uptake (e.g. dopamine [97] 5-HT [98]). glial activity may be down-regulated by increased hypoth- alamo-pituitary-adrenal activity in situations perceived as 3.4.1.2 Impaired uptake and removal of extracellular glutamate stressful (e.g. expressed emotion in the family of ADHD Astrocytes normally maintain low extracellular levels of children or the challenge provided by cognitive tasks pre- glutamate and K [78]. Glutamate transport into astro- sented to the children). High levels of glucocorticoids act- cytes is driven by the influx of Na along its electrochemi- ing on astrocytes would impair glycogen replenishment, cal gradient. But the low membrane potential resulting deplete energy reserves, and reduce lactate transport. from the astrocytes being less able to maintain low extra- Behaviourally, this will give rise to fatigue and predispose cellular K concentrations in the ADHD condition will to psychological problems, as has been proposed for other diminish the electromotive drive for Na influx and disorders such as Parkinsonism and major depression thereby hamper removal of glutamate from the extracellu- [116]. lar fluid [93,99,100]. Failure to maintain low extracellular glutamate levels will impair glutamate neurotransmitter Cytokines, small proteins that support communication function, neuroplasticity, learning and memory, and between cells of the immune system, can be produced by could lead to excitotoxicity and cell death, reflected as and influence the function of astrocytes (e.g. TNF-alpha, reduced CNS gray matter. (Small reductions in grey matter IL-1, IL-6 [117]). Reduced stimulation of β-adrenoceptors are reported for subjects with ADHD [101-103]). leads not only to decreased glycogenolysis but also to impaired production of several growth factors (e.g. nerve 3.4.1.3 Impaired neuromodulator regulation of lactate formation growth factor (NGF), basic fibroblast growth factor (basic Several neurotransmitters can potentially modulate lac- FGF), transforming growth factor-beta1 (TGF-beta1) tate production in astrocytes, with the majority of evi- along with increased production of nitric oxide and the dence supporting a role for noradrenaline acting on α -, pro-inflammatory cytokines [118,119]. Cytokine expo- α - and β-adrenoceptors [88,104-106]. This is important sure can lead to an overproduction of nitric oxide and its in view of widely accepted explanations of ADHD symp- metabolites that diffuse out and damage mitochondria toms in terms of catecholamine function [107], psychos- and the energy supply in nearby cells (including neurons timulant effects on glucose utilization (section 3.1) and [120]). TNF-alpha and IL-1 can fundamentally perturb the efficacy as medication [108]. Glial receptors for dopamine energy metabolism of astrocytes promoting the uptake of (D1–5) [15,88] and serotonin (5-HT2) [109] have also glucose without either storing it as glycogen or releasing been reported but their effects on lactate production in lactate [121]. This disruption can therefore not only astrocytes have not been well documented. impair short-term demands for energy, but also the long- term requirements for development (see hypothesis H2, Extracellular lactate decreases immediately after neuronal section 3.4.3), that in the worst case can lead to apoptosis activation, but rises again after a short delay [110]. Nor- of the oligodendrocyte [118]. Other cytokines (e.g. the mally within milliseconds of glial β- or α -adrenoceptor calcium-binding S100B) also regulate energy metabolism, activation noradrenaline induces the breakdown of glyco- promote neuronal survival and regeneration [122]. gen to glucose (glycogenolysis) to supply the needed lac- Dopamine also stimulates release of growth factors tate [69,105,111,112]. This is followed by a phase of (including NGF, glial-derived nerve growth factor, GDNF glycogen re-synthesis in the astrocytes that can last several and brain-derived nerve growth factor, BDNF) and there- hours [112]. Failure to adequately replenish glycogen fore plays a crucial role in development of the brain and stores in the astrocytes would reduce the availability of maturation of the nervous system [84]. energy substrates required for subsequent or sustained neuronal activity. Therapeutic agents (e.g. methylpheni- 3.4.2 Preliminary evidence: impaired energy supply during rapid neuronal firing in ADHD date, amphetamine, atomoxetine, desipramine, modafinil) block the noradrenaline transporter and This section first considers the limited direct neuroimag- increase extracellular concentrations of noradrenaline ing evidence of altered energy utilization in the CNS of which stimulates glycolysis and lactate production in people with ADHD that could potentially derive from astrocytes. Although evidence strongly supports a role for deficient astrocyte function [116]. We then discuss elec- noradrenaline, both dopamine and serotonin are known troencephalographic (EEG) recordings indicating ineffi- to modulate cAMP levels in astrocytes and could therefore cient communication within and between neuron clusters also play a role [15,109]. that could be attributed to impaired energy supplies. Page 9 of 25 (page number not for citation purposes) Behavioral and Brain Functions 2006, 2:30 http://www.behavioralandbrainfunctions.com/content/2/1/30 Energy utilization in the brain associated with the cogni- born very prematurely and given the diagnosis of ADHD, tive challenge of CPT performance was measured by posi- compared to those who had a similarly low birth weight tron emission tomography (PET) and deoxyglucose in 25 without the ADHD diagnosis [132]. Methylphenidate adults with childhood onset of ADHD [123]. The authors treatment decreased variability both of the P3 component reported decreases in utilization in 30 of 60 regions ana- [133,134] and the response times recorded [135,136]. lysed, and a global reduction of >8%. The largest decreases The number of responses that were too early (premature, were registered in adjacent regions of the superior frontal, impulsive) or too late were reduced with psychostimulant premotor, and somatosensory cortices. Methylphenidate treatment [135,137]. Effective therapeutic drugs blocked in healthy volunteers has been shown to increase glucose dopamine and noradrenaline transporters and increased utilization in these and other brain regions (e.g. cerebel- extracellular levels of catecholamines permitting activa- lum), perhaps by elevating extracellular noradrenaline tion of β-adrenoceptors (and/or D1 receptors) on astro- concentrations. Decreased glucose utilization in ADHD cytes to stimulate lactate production. may result from inadequate noradrenergic stimulation of astrocytes. But decreased glucose utilization in striatum 3.4.3 H2. Impaired oligodendrocyte function impairs axon myelination and differences following acute vs. chronic methylpheni- date treatment are results that warn against making simple In the human brain the myelination of axons – a principle generalizations about the effects of stimulants on energy function of the oligodendrocytes – starts in utero and con- utilization [124]. tinues through the first 3–4 decades of life [138]. The increase of white matter during development puts high Some EEG measures indicative of ADHD may reflect demands on metabolism. Myelin starts to form before impaired immediate energy supply from astrocytes (H-1) birth with much being laid down in the first two years of and others impaired myelination (H-2, section 3.4.3/4) life. Myelination is prominent in the prefrontal cortex, deriving from a longer-term lactate deficiency. In either and of course in the major fibre tracts, especially the cor- case the presence or absence of effort to overcome the pus callosum – with levels of "adult functionality" inefficiency should be visible in terms of the amplitude of achieved normally during adolescence [139,140]. event-related potential (ERP) components in the EEG rep- Impaired myelin synthesis as a result of intermittently resenting the stages of information processing, and defi- insufficient lactate production by astrocytes would have a cient levels of 'activation' in the ERP latencies. detrimental effect on the coordinated myelination of axons during development, and lead to impaired commu- The contingent negative variation (CNV) is an excitatory, nication between brain regions and poor integration of slow, negative-going waveform that occurs in the second information in these target brain structures. before a stimulus. The CNV is usually considered to index anticipatory and preparatory processes to a stimulus that Oligodendrocytes normally oxidise glucose and lactate at may require a response. It has been reported to be reduced far higher rates than either neurons or astrocytes [14,141]. in amplitude in people with ADHD [125-127], although Glucose is metabolised in the pentose phosphate pathway this was not replicated in two further reports [128,129]. to produce NADPH and in the glycolytic pathway to pro- The extent to which the reduction of CNV reflects reduced duce lactate, both of which are used to synthesize lipids: effort in or motivation for preparation is secondary to the lactate is the preferred substrate for fatty acid synthesis point at issue here, namely that subjects with ADHD are and myelin formation. As oligodendrocytes are the high- poorly prepared for the stimulus. This may be due to est lactate and glucose consumers in the developing brain, impaired learning, or poor association of actions with any deficiency in the supply of lactate would impair lipid delayed outcomes in previous experiences, as suggested by synthesis and retard myelination of axons. Impaired mye- Sagvolden et al. [20], and this is non-adaptive to the lination reduces the speed of conduction of action poten- demands of the situation. The P3 component elicited by a tials in individual neurons and could account for slow rare or meaningful stimulus represents updating of work- reaction times. Axons that are not properly insulated by ing memory-like templates of its associations. The ampli- the myelin sheath would be less efficient at conducting tude is reduced in most studies of ADHD. It has been action potentials and require more energy resources than argued that reduced effort makes a contribution to this normal. Partial myelination of fibre pathways would also effect [130,131]. These are two of several ERP markers contribute to impaired integration of information in tar- reflecting inefficient information processing in ADHD. get regions and provide a further source of response vari- We propose that insufficient energy reserves underlie this ability. deficiency. Myelination is a sensitive indicator of functional brain Variable ERP latencies are widely reported, especially for maturation. Across at least the first two decades of devel- the P3. This variability is evident in 8–9 year-old children opment myelination consists of a broad increase in over- Page 10 of 25 (page number not for citation purposes) Behavioral and Brain Functions 2006, 2:30 http://www.behavioralandbrainfunctions.com/content/2/1/30 all white matter density as well as a more region-specific peduncle (left cerebellum and parieto-occipital region). progression, proceeding from posterior to more anterior Ashtari and colleagues report that the lower the cerebellar regions, [142-145]. In magnetic resonance spectroscopy FA, the more severe were the ratings of symptoms of inat- (MRS) and diffusion tensor imaging (DTI) studies, matu- tention [151]. These first findings point to a link between ration of relatively restricted regions of white matter has white matter anomalies and the symptomatology of been found to correlate with the development of cognitive ADHD. functions such as working memory capacity (left frontal regions), reading ability (left temporal lobe) and even Such findings are extended by H-MRS measures of neu- with IQ (bilateral association areas [144,146]. In a study ronal metabolism in the brains of subjects with ADHD. of 100 children with evidence of delayed development With this method creatine, choline, taurine, inositol, but otherwise normal MR-scans, Pujol and colleagues NAA, glutamate and lactate can be detected and meas- [143] were able to show a reduction of myelination (in ured. Unfortunately there have been scant attempts to part asymmetric) equivalent to normally developing chil- report on the last two. As yet creatine, choline (and their dren who were some 3 years younger. Also, at the other phospho-derivatives) – regarded as indicators of lipid end of the lifespan, white matter damage due to axonal metabolism and membrane integrity – have also not been loss that occurs in normal ageing has been found to corre- studied in ADHD. The easiest metabolite to measure is late with working memory performance, even after con- NAA. NAA is found in neurons, not in glia, and is regarded trolling for age [19]. This suggests that working memory as a marker of neuronal density, function, viability and performance may be particularly dependent on complex perhaps functional connectivity [152]. It is synthesised by networks, which in turn depend upon white matter con- the enzyme NAA transferase in neuronal mitochondria nections. These studies conclude that there is a positive from acetyl coenzyme A (acetyl Co-A) and aspartate, and relationship between the density and organization of used by oligodendrocytes to produce acetyl groups for the myelinated fibres and the efficiency (maturity) of cogni- synthesis of myelin lipids [153,154]. During development tive function [144]. NAA levels increase (as choline levels fall) and reflect increased synthesis (or decreased utilization) in the for- 3.4.4 Preliminary evidence of altered myelination in ADHD mation of myelin [155,156]. High NAA concentrations 3.4.4.1 Neuroimaging correlate with increased ADP [157,158] as acetyl CoA lev- Evidence for impaired and/or delayed myelination els required for ATP synthesis are depleted. Decreases of derives from MR measures of white matter density and the NAA levels reflecting neuronal dysfunction are associated integrity of myelinated neuronal pathways indexed by with neuronal loss in certain parts of the brain in many DTI and MRS measures of metabolites (e.g. N-acetyl- major psychiatric illnesses [159]. aspartate, NAA). Support for the functional impairment of these pathways comes from EEG recordings (section Increased NAA levels are reported for the right frontal lobe 3.4.4.2). [160] and fibres entering/leaving left frontal regions (cen- trum semi-ovale [161]) of ADHD subjects compared to Seven of the 8 anatomical MRI studies report decreased healthy and autistic comparison groups. But group differ- total white matter volumes in children and adolescents ences were not found in 2 studies of the right frontal lobe with ADHD [102,103,147-150]. In the largest MRI study [162,163] and decreases were reported in small studies for that scanned over 150 boys with ADHD on at least two the left frontal [164] and right lenticular regions [165]. separate occasions, the reduction in white matter volume However Yeo et al. [162] noted that the smaller right fron- was substantial (a 10% reduction) compared to those tal volume for their 17 ADHD children correlated with who had been treated with stimulant medication or had NAA and choline measures, and that NAA levels in turn no diagnosis [103]. Indeed, one study linked smaller related to performance on a sustained attention task. Else- white matter volumes with slower processing speed, as where, intriguingly, raised frontal glutamate concentra- indexed by the speed of colour-naming [150]. These tions were noted, particularly on the right [160,163]. As a results implicate a contribution of delayed myelination to cautionary note, it should be pointed out that animal ADHD cognition. work has shown that methylphenidate treatment can lead to increased cortical levels of NAA [166]. Further, the DTI provides a measure (fractional anisotropy, FA) of the results of these 6 ADHD studies must be regarded as pre- coherence and integrity of the biochemical microstructure liminary as they each represent very small subject groups, of myelinated pathways. An initial study comparing a and the range of brain regions they could sample was very group of 18 children with ADHD with 15 matched con- restricted. Nonetheless it should be noted that all the trols recorded a reduced FA in the right cerebral peduncle/ studies recorded changes, and unusually some subjects anterior limb of the internal capsule (right neostriatum show raised metabolite levels (NAA, choline, glutamate). and premotor cortex), and in the left middle cerebellar These results point to changed patterns and rates of mye- Page 11 of 25 (page number not for citation purposes) Behavioral and Brain Functions 2006, 2:30 http://www.behavioralandbrainfunctions.com/content/2/1/30 lin synthesis (and breakdown) that may reflect intermit- elevated slow-wave coherences and reduced fast-wave tently insufficient supplies of lactate. The result is an coherences between hemispheres, although within hemi- overall decrease of white matter for a given age-class, as spheres the coherence in the theta band is reduced, espe- described above. cially over frontal regions [176-178]. This is most easily explained by unusual if not delayed development of the 3.4.4.2 Neurophysiology large white matter tracts connecting brain regions. At We propose that the functional consequences of the short distances between signals the increased coherence at impaired/delayed developmental laying down of the slow wave frequencies in children with ADHD is viewed myelin sheath can be seen in three types of EEG measure: as consistent with a delay in the pruning back of over-pro- evoked potential (EP) latencies, the topographic distribu- duced synapses and local connections [179]. As would be tion of the power spectrum in the quantitative EEG, and expected such long-term alterations remain unaffected by in the coherence of the EEG waveforms between brain short-term methylphenidate treatment [180]. regions. 3.5 Supportive evidence from related disorders We propose that a disturbed lactate shuttle in ADHD EPs representing sensory information ascending in the auditory nerve [167] and the brain stem appear at longer accounts for brief transient impairments in rapid neuro- than normal latencies (e.g., components III and V). nal firing and delayed myelination: Together they result in Indeed, the transmission times from components I to III variable responses. These impairments may account for and I to V are reported to be increased in subjects with similar phenomena in other neurodevelopmental disor- ADHD [168]. The latency of the steady state visual EP in ders. We do not regard our hypothesis as specific to the frontal cortex of ADHD children is markedly delayed ADHD – for example, individuals with schizophrenia [169]. Indeed, in their report of a delayed velocity index have been found to respond more slowly and variably on for EPs in ADHD, Ucles et al [170] proposed not only that attentional and cognitive tasks [181,182] – nor do we sug- abnormal myelination in the cortico-spinal path could be gest that it occurs in all psychiatric disorders. In the fol- responsible, but that the result could be indicative of a lowing sections we select two disorders, PKU and much more widespread problem. narcolepsy, to illustrate the presence of phenomena that appear to model the situation that pertains to ADHD. A large proportion of patients with ADHD (or narcolepsy, see 3.5.1 below) demonstrate an increased ratio of relative 3.5.1 Parallel pathological conditions: Phenylketonuria (PKU) theta to alpha or beta power in the EEG, especially over PKU results from high concentrations of phenylalanine anterior brain regions [171,172]. One explanation of the (Phe), that arise from an inability to convert it into tyro- dominant lower firing frequencies could lie with the sine, and which inhibit transport across the blood brain reduced lactate availability required to sustain rapidly fir- barrier of neutral amino acids such as tyrosine and tryp- ing neurons. There is usually a marked normalization of tophan necessary for the synthesis of the three principle this balance between oscillation frequencies after methyl- monoamine transmitters. If children are placed on Phe- phenidate treatment [173]. In the unmedicated sample free diet early enough, microcephaly, mental retardation there is a positive correlation between P2, N2 and P3 ERP and motor problems can be avoided, although sub-clini- latencies, widely reported to be delayed [137] and cal symptoms may remain, particularly in the cognitive increased theta power [174,175]. A plausible reason for domain [183,184]. Children with PKU (off-diet) are rated this shift in balance between oscillation frequencies lies in by parents and teachers as more distractible, hyperactive, a decreased representation of the faster frequencies owing and impulsive than healthy controls [185], with many to deficient neuronal energy supply (H1) and/or reduced symptoms similar to ADHD (e.g. restlessness, fidgeting, myelination in brain stem reticular sources active in gen- concentration difficulty, short attention span, low frustra- erating some of these rhythms [170] which is consistent tion tolerance [186]). Realmuto et al. [187] noted that 9/ with our hypothesis H2. 13 of their subjects either manifested or had a history of comorbidity with ADHD. Prenatal exposure was associ- A more direct measure of the coupling of activity between ated with a higher likelihood of expressing hyperactive/ brain regions can be estimated by EEG coherence of wave- impulsive symptoms and postnatal exposure was associ- form between recording sites. Coherence can be conceptu- ated with a higher likelihood of expressing inattentive alised as the correlation in the time domain between 2 symptoms [188]. Indeed, a considerable proportion of signals in a given frequency band. EEG coherence nor- people with treated PKU take psychostimulant medica- mally develops systematically with age in a non-linear tion for their attentional problems (e.g. 26% of a sample fashion. There is evidence of development in longer-range of 38 school-aged children with PKU [189]). inter-hemispheric coherences which are not apparent in boys with ADHD. Furthermore, boys with ADHD show Page 12 of 25 (page number not for citation purposes) Behavioral and Brain Functions 2006, 2:30 http://www.behavioralandbrainfunctions.com/content/2/1/30 Cognitive impairments of individuals with PKU like those narcolepsy-related deficits in attentional and executive with ADHD include variable reaction times, sustained function which place high demands on inhibition and attention, working memory, executive function, planning, task management, but not on simple tasks of memory and learning, tests of colour-naming, arithmetic, verbal abili- attention [214,215]. The pattern of findings was thought ties and academic performance [187,190-199]. Inter- to be indicative of a depletion of available cognitive hemispheric interactions, as measured by slowed transfer processing resources because of the need for continuous times [200], and a lack of the across-hemisphere advan- allocation of resources to monitoring. tage in performing a name-identity task [183], are affected in comparison to neurologically intact children. Neuro- Like ADHD, hypoarousal (sleepiness) is induced in situa- physiological studies report slow latencies for several early tions of low stimulation, such as reading or boring repet- EPs [201], the later P3 component and slower more vari- itive tasks [112,216-218]. Similarly, children with ADHD able motor reaction times [194,195,202]. In the EEG slow or narcolepsy appear to use motor overactivity and fidget- (theta) rhythms are characteristic of individuals with iness to counteract their drowsiness [218-220]. It is inter- PKU. Indeed their high theta/alpha ratio (recalling esting to speculate how a deficiency in energy supply ADHD) was sensitive to treatment reducing the levels of might contribute to the other symptoms of ADHD, such Phe [203,204]. as hyperactivity. Depression of sensory modules could certainly lead to a suboptimal level of stimulation, induc- Functionally, these features reflect delayed myelination, ing sensation-seeking behaviour, with motor, vocal, and low monoamine levels, and impaired energy availability. other activities displacing the contextually "appropriate" Impaired myelination is the primary neuropathological behaviours, which through local energy deficiency can no feature of treated or untreated people with PKU: A delay is longer provide the necessary arousal. Derangements of typical of the younger ages and diffuse demyelination is calcium-dependent protein phosphatase and kinase activ- reported at older ages [205-208]. The finding of low HVA ity impair working memory [221]. These and other impli- levels (dopamine metabolite) in the CSF [209] confirms cations of the energetics hypothesis require further the second feature, low dopamine levels. Importantly, consideration, lying beyond the scope of this paper. changes of dopamine in the rodent model go hand in Lastly, as in ADHD analyses, EEG rhythms show the ratio hand with the depletion and restoration of Phe levels of theta to alpha or beta power in narcolepsy to be higher [210]. Noradrenaline and serotonin would also be than normal [172]. Narcolepsy has been attributed to expected to be affected. The third feature was addressed in depletion of the transmitter hypocretin, a hypothalamic 11 young adults with PKU using phosphate MRS. Pietz et neuropeptide that regulates energy metabolism and al. [204] describe changes of cerebral energy metabolism dopamine activity in certain brain regions [222-224]. that could underlie reduced transmission speed, myelina- Modafinil, the drug normally used to treat narcolepsy, is tion and catecholamine availability [205]. Among 11 effective in treating ADHD and can inhibit dopamine re- measures taken at baseline, only ADP was significantly uptake [220,225-228]. It is also an α -adrenoceptor ago- elevated, and inorganic phosphate decreased. Phe loading nist and can therefore facilitate β-adrenoceptor-stimu- then decreased phosphocreatine and ATP levels while fur- lated lactate production in astrocytes [229,230]. Thus, the ther increasing ADP. This is consistent with Phe inhibition mechanism of treatment could be the same in both disor- of pyruvate kinase and the concurrent conversion of ADP ders. This highlights the similarities between the disorders to ATP [211]. Impaired pyruvate synthesis would reduce that could reflect common underlying disturbances. lactate production and the ability of astrocytes to meet the energy requirements of sustained rapid neural firing and a 4. Testing the hypotheses shortage of lactate would also impair the ability of oli- The fundamental tenet of our hypotheses (H-1 and H-2) godendrocytes to synthesize myelin. – to be tested – is that a deficient energy supply to rapidly firing neurons (the lactate shuttle) underlies moment-to- 3.5.2 Parallel pathological conditions: narcolepsy moment fluctuations in response speed and accuracy Narcolepsy is a neurological disorder characterized by (astrocyte mechanisms) and, in the long-term, episodes of excessive daytime sleepiness [212]. Some of the neuropsy- lactate deficiency during development delays axon myeli- chological characteristics of narcolepsy are strikingly sim- nation (oligodendrocyte function). These two links need ilar to those seen in ADHD and children with ADHD have to be demonstrated (section 4.1). an increased tendency to daytime sleepiness [213]. Indi- viduals with narcolepsy have slower reaction times and The consequences of these disturbances are proposed to more within-task variability of performance than control lie with a) decreased neural activity when sustained rapid subjects on a variety of attentional tasks ranging from firing is required (neurophysiological level), b) delayed those sensitive to arousal and sustained attention, to the and variable cohesion between the components of the executive control of attention [214]. Recent studies report neural circuitry responsible for integration of information Page 13 of 25 (page number not for citation purposes) Behavioral and Brain Functions 2006, 2:30 http://www.behavioralandbrainfunctions.com/content/2/1/30 and selection/organization of appropriate response (psy- tions and extracellular calcium waves generated by neuro- chophysiology), and c) the poorly coordinated and intra- transmitter stimulated glia. These calcium signals individual variability of performance typical of individu- stimulate glutamate release, modulate neuronal excitabil- als with ADHD. More evidence is required (section 4.2). ity and carbohydrate metabolism [86,89]. Changes in cal- cium concentration can be monitored by new contrast 4.1 Is there an energy deficiency? substances being developed for MRI investigations. These There are several points in the energy cycle where dysfunc- techniques, and recent applications of 2-photon optical tion could occur. The present hypothesis focuses on one calcium imaging in animals, could also address the role of specific aspect: The provision of adequate amounts of the dopamine D1 and D2 receptors [233] as well as metabo- more efficient metabolic fuel, lactate (rather than glu- tropic glutamate receptors and their modulation by α - cose), to rapidly firing neurons (e.g. glutamate trans- adrenoceptors in the stimulation of calcium responses in porter, mitochondria, monoaminergic regulation of astrocytes [85,234,235]. A third example is the need for astrocyte function: section 4.1.1). Identification of envi- cross-sectional if not longitudinal MRS data on myo- ronmental and/or genetic origins of the lactate deficiency inositol. This is suggested to be a marker of the integrity of would contribute to an understanding of intra-individual glia and glial transport mechanisms, but the signal has variability in performance of high energy-demanding proved difficult to separate from that for the large tasks (section 4.1.2). Factors that impair myelination may amounts of glycine present that also resonate at 3.6 ppm contribute to slow responsiveness and are also reviewed [236]. Whereas increased levels of myo-inositol are (section 4.1.2). claimed to reflect gliosis that would not be expected in ADHD, decreased levels, as reported for major depressive 4.1.1. The performance of energetic compartments disorder, may reflect glial loss or altered glial metabolism There is a need for more precise measures of the dynamics [237]. Indeed a functional decrease may apply to ADHD. within and between the major compartments of energy A preliminary report on 15 subjects with ADHD found an production, storage and utilization through studies using increased glutamate/myo-inositol ratio [238], that would labelling, stimulation and inhibition of the various con- be consistent with either increased extracellular glutamate stituents in animal models of ADHD and tissue culture concentrations or an inadequate supply of myo-inositol. (e.g. delineation of the quantitative relationship between neuronal firing rate and lactate utilization, intra/extracel- 4.1.2 Origins of a putative energy and lipid deficiency lular glutamate flow, mitochondrial function (ATP/ADP The principle claim of our hypothesis, that lactate produc- ratio and oxygen consumption), effects of lactate restric- tion and availability is impaired, may be difficult to meas- tion on ionic gradients, function of regulatory factors (e.g. ure directly in human subjects, but may be best tested neurotransmitter/neuropeptide receptors, particularly with a pharmacological challenge in animal models of noradrenergic α -, α - and β-adrenoceptors), effect of ADHD such as the spontaneously hypertensive rat (SHR) 1 2 impaired lactate production on myelin synthesis (and [239,240] and poor (and impulsive) performers on the 5- accumulation of NAA), influence of NAA availability on choice serial reaction time task that show low 2-deoxyglu- acetyl-group incorporation into myelin). Regional differ- cose uptake (index of brain glucose uptake) in the cingu- ences in measures of effects of transient energy deficiency late and ventrolateral orbital cortices during performance are important to note, since the hypothesis does not pre- of the visuospatial task [241]. Lactate production should dict that all parts of the brain will be affected equally. be recorded at baseline, during performance of the task, Greater effects (e.g. reduced size) should be observed in and after methylphenidate, atomoxetine or venlafaxin those brain areas that contain or form part of rapidly fir- treatment (transport inhibitors of the three monoam- ing neural circuits that transiently deplete local energy ines). The effect of pretreatment with monoamine recep- reserves and hinder synapse formation. tor antagonists could also be investigated. The link between performance, energy availability and at least Measures of some of these effects are becoming techni- some of these treatments should be established. Other cally feasible for human studies, in vivo, with MRS. For cognitive tests that make use of dynamic strategies example, changes in glutamate production (tricarboxylic (change in contingency) can be used to evaluate possible acid cycle), lactate synthesis (glycolysis) and glutamine correlation between changes in lactate production/utiliza- synthesis have been demonstrated in neurological tion and performance speed/accuracy. patients using labelled carbon ( C) MRS [231,232]. Fur- ther data on the energy metabolites ATP, ADP, inorganic Glutamate availability for uptake into astrocytes and stim- phosphate, phosphocreatine and creatine obtained from ulation of lactate production requires special attention. more conventional proton and phosphate MRS studies Impaired release would reduce astrocytic lactate synthesis. would also be useful (cf. section 3.5.1). A second example The impairment could lie with SNAP-25, a protein impor- is based on the changes of intracellular calcium oscilla- tant for the release of the transmitter. There is some evi- Page 14 of 25 (page number not for citation purposes) Behavioral and Brain Functions 2006, 2:30 http://www.behavioralandbrainfunctions.com/content/2/1/30 dence for an association between polymorphisms of the dles that are [254] or in ADHD are not showing normal SNAP-25 gene and ADHD [242,243]. A potential relation- developmental increases of anisotropy studied with DTI. ship to energy production should be investigated. Lactate synthesis is dependent on glutamate uptake into astro- Of the numerous potential genetic sources of the modifi- cytes. Problems with glutamate transport could give rise to cation of energy availability, we would select those that deficient lactate synthesis. Metabotropic glutamate recep- regulate lactate metabolism (lactate, glutamate and glu- tor function and the glutamate/aspartate transporter cose transporters, glycogen synthase, glycogen phosphor- (GLAST) have been suggested to play a role the develop- ylase, glycolytic enzymes), factors that regulate glutamate ment of fatigue [78,244]. To test this hypothesis, gluta- release from synaptic terminals and hence glutamate- mate metabolism could be measured in astrocytes of stimulated lactate production (e.g. SNAP25, vesicle trans- animal models of ADHD using an experimental setup that porter, metabotropic glutamate receptors, adenosine A1 simulates the role of neurons (glutamate producers and receptors, neurexins, factors that regulate intracellular 2+ glutamine consumers) by the addition of glutaminase to Ca ), and astrocyte function (e.g. noradrenergic α , α 1 2 the culture medium [245]. A steady supply of glutamate and β-adrenoceptors, dopamine D1 receptors). Mito- can be imposed at the expense of glutamine, and the stress chondrial function should also be considered, as impair- intensity manipulated by changing the glutaminase con- ment of gene transcription can occur through the centration [246]. The extracellular concentration of gluta- accumulation of mitochondrial DNA mutations [255]. mate will provide information on the efficiency of flux One potential candidate is Ant1, a mitochondrial ATP/ through the glutamate transporter and glutamine syn- ADP exchanger that facilitates efflux of ATP out of the thetase system in restoring the extracellular concentration mitochondria and glutamate uptake into astrocytes [256]. of glutamate to a low level [247]. This will provide a meas- Metabotropic glutamate receptors are of special interest as 2+ ure of the glutamate drive of lactate formation. stimulation can produce marked Ca oscillations. Its expression represents a glial sensor of the extracellular More quantification of developmental changes in myeli- glutamate concentration that can be used to acutely regu- nation in ADHD, using sensitive neuroimaging tech- late excitatory transmission [257]. niques such as DTI, MRS, EEG or MEG would be informative. More simply, for indications of impaired Likewise, there are many genetic influences on lipid syn- white matter generation blood samples should be taken thesis and myelin formation of potential relevance to our from healthy children and those with ADHD to investi- hypothesis on oligodendrocyte function in ADHD. We gate lipid availability (serum fatty acid levels and the select but one for attention. Lingo-1 is expressed in oli- nature of red blood corpuscle membranes). This approach godendrocytes and is critical for CNS myelin formation. has been useful in showing changes in patients with schiz- Treatment of neuron and oligodendrocyte cell culture ophrenia and depression (e.g. reduced polyunsaturated with soluble Lingo-1 (a transmembrane protein binding fatty acids like arachidonic and docosahexaenoic acid to the Nogo-66 receptor/p75 signaling complex) led to [246,247], decreased linoleic acid [248], less high-density highly developed and differentiated axons [258,259]. In lipoprotein levels [249]). An early report on hyperactive animal studies it appears that its up-regulation may be a children suggested there were slightly decreased levels of characteristic of activity-induced neural plasticity poly-unsaturated, but increased levels of saturated fatty responses [260]. Thus, its impaired expression could be a acids [250]. Chen et al. [251] found decreased nervonic feature of several developmental disorders. We would also acid, linoleic acid, arachidonic acid, and docosahexaenoic advocate the initiation of microarray studies of gene acid in red blood cell membranes of children with ADHD expression in samples taken from subjects with ADHD. while plasma gamma-linolenic acid and red blood cell This large scale profiling technique applied to patients oleic acid were increased. Irmisch noted a potential rela- with schizophrenia has already shown a surprising tionship with stress experienced by their subjects [250]. As number of genes related to energy metabolism, oli- glucocorticoids modulate membrane stability and the godendrocyte function and myelin formation that are adrenal hormone dehydroepiandrosterone influences associated with psychopathology [261]. lipid synthesis, both steroids should be monitored in the recommended study [252] (section 3.4.1.3). The availa- 4.1 Neurophysiological and behavioural consequences of bility of these fatty acids (particularly of the omega series), an energy deficiency as well as marked prostaglandin synthesis (e.g. cyclooxy- Neuroimaging techniques reflecting glucose or oxygen genase) around puberty are crucial determinants of syn- utilization would be well-suited to examine the effect of apse modification, pruning and maturation processes cognitive challenges on glycogen, glucose or lactate utili- [253] that may be delayed in ADHD. These studies would zation (e.g. PET with deoxyglucose, near-infra-red spec- usefully supplement further delineation of the fibre bun- troscopy of oxygenated/deoxygenated haemoglobin [262,263]). To what extent do task manipulations (event- Page 15 of 25 (page number not for citation purposes) Behavioral and Brain Functions 2006, 2:30 http://www.behavioralandbrainfunctions.com/content/2/1/30 rate, delayed reinforcement and difficulty) elicit differen- this implication of the hypothesis, numerous studies have tial responsiveness according to these measures in within- found reduced brain volume in people with ADHD, par- subject designs with symptomatic and asymptomatic ticularly prefrontal cortex, cerebellum, corpus callosum, individuals? and basal ganglia, areas of the brain engaged in informa- tion processing and planning/selecting the appropriate Similar task manipulations should be used during EEG behavioural response [102,103,147,270]. monitoring of sustained neuronal firing and connectivity (EP latencies, theta/beta ratios and the coherence between The hypothesis H1 implies that people with ADHD may sites of signal processing). Do people with ADHD show develop strategies to overcome their inability to fully uti- an early onset of fatigue or feel that they exert undue effort lize the more efficient lactate shuttle during periods of to overcome the deficiencies across a period of task per- high energy demand, i.e. extended high frequency neuro- formance? Skin conductance records would provide an nal firing. In order to avoid catastrophic depletion of independent reference for changes in the level of activa- localized energy reserves, a strategy may have evolved dur- tion. However, analyses should carefully consider issues ing development to avoid prolonged high-frequency fir- that could mask clear-cut associations such as the different ing of neural circuits by switching to other neural circuits types of oscillation pattern and the sub-diagnosis often that produce behaviours that may help to complete the encountered in an ADHD population [264,265]. Baseline task. When required to focus and concentrate on perform- measures should then be compared with the effects of ing a specific task, their behaviour is automatically medication and carbohydrate loading. switched to other circuits. The advantage of this strategy may be that they explore the environment more actively One test of energy deficiency would be based on the lac- and appear to learn more quickly initially, but they fail to tate and glucose dependency of the neurophysiological learn new rules when the contingency changes because of spike activity underlying LTP [266], the basis of short- their inability to stay on task. This may cause the individ- term working memories often poorly expressed in ADHD ual with ADHD to appear easily distracted, because of rap- (section 2.1). Animal work has shown that LTP, engen- idly switching from one task to another to avoid highly dered in models of ischemic conditions, is amplified by localized depletion of energy reserves. Evidence to sup- dopamine D1 action on the AMPA (but not the NMDA) port this suggestion is provided by clinical studies. In both component of LTP [267]. Would ADHD subjects with a Norwegian and South African populations of children demonstrable lactate shuttle impairment show improved with ADHD, Aase, Meyer and Sagvolden [8,9,271] dem- working memory following psychostimulant induced onstrated increased intra-individual variability of spatial dopamine D1 stimulation of AMPA function? location of motor responses, independent of accuracy of performance and time on task (greater spatial variability A behavioural approach could also be applied. Under but not greater temporal variability because there were no high cognitive demand (e.g. the incompatible conditions external time demands placed on participants), suggesting of asynchronous flanker tasks) energy requirements are that sensory-motor reflexes were not as efficient as in con- high and stored resources limited. Mental effort and trols, possibly because of impaired energy supply to rap- energy mobilization may be measured via blood glucose idly firing neurons in cortico-striatal and/or cortico- levels and cardiovascular function [268]. Even though the cerebellar circuits. Impaired maintenance of high neuro- measures are relatively simple, they are yet likely to be nal firing rates due to suboptimal ATP production would associated with the variability of performance over time impair learning at all levels of neural circuits involved in and be capable of modification by agents that modify memory formation, including prefrontal cortex, striatum, monoamine transporter function. Support for this predic- cerebellum, and parietal cortex. Variability of spatial loca- tion derives from a report on two cases of spino-cerebellar tion would engage different neural circuits and may reflect ataxia. The authors describe a strong association between a strategy developed to overcome the problem of insuffi- PET measures of decreased glucose utilization, SPECT cient lactate reserves to meet demands of prolonged rapid measures of reduced dopamine transporter binding in the neuronal firing. Variability persists into adulthood putamen and poor performance on tests of executive func- [272,273]. The apparent remission of symptoms in many tion [269]. adults may be due to their elaboration of a set of redun- dant processing elements, and the neural procedures for 5 Implications of the hypothesis their seamless engagement, which provide alternative 5.1 Implications for basic research task-relevant procedures lacking in children. Although it is not possible to state which brain areas will be affected by restricted energy (lactate) supply, those The hypothesis H1 implies that myelinated and unmyeli- with the highest energy demands are more likely to be nated axons will be affected differently. Non-myelinated affected and may be reduced in size [93]. In support of axons are less efficient than myelinated axons and we pre- Page 16 of 25 (page number not for citation purposes) Behavioral and Brain Functions 2006, 2:30 http://www.behavioralandbrainfunctions.com/content/2/1/30 dict that they may be more vulnerable to the lactate defi- vation' as described by Sergeant and van der Meere ciency. Interestingly this would target non-myelinated [274,275]. nigrostriatal, mesocortical and mesolimbic dopamine projections, among others, which would affect the devel- Barkley (1997) considers symptoms of ADHD to arise opment of their target structures including striatum, pre- from the disruption of neurocognitive control. Like Bar- frontal cortex and hippocampus. Compromised kley we have selected top-down, executive processes for dopamine neuronal firing could account for decreased special but not exclusive consideration. We emphasise dopamine function in target areas as proposed by intra-individual variability in the control of the mainte- Sagvolden et al [20] in the dynamic developmental theory nance or switching of set appropriate to adaptive plan- of ADHD. Drugs used to treat ADHD, such as methylphe- ning, and behavioural organization towards reasonable nidate, block the dopamine transporter and can thereby goals. Barkley, however, views these brain-behaviour rela- enhance the dopamine signal without requiring increased tions to be mediated fully by inhibitory processes. Our firing of dopamine neurons. hypothesis is not so restrictive, and thereby questions the centrality of inhibitory processes to ADHD. What Barkley A further critical implication of the hypothesis H1 is that sees as inhibition we see as a failure of activation, for therapeutic drugs should directly or indirectly stimulate which we provide a specific mechanism. lactate production by astrocytes. Our hypothesis overlaps with the explanations offered by 5.2 Implications for theories of ADHD Sonuga-Barke [278] and Sagvolden et al. [20]. Sonuga- The current hypothesis extends existing theories of ADHD Barke's dual pathway theory invokes a role for the mesocor- by proposing a physiological basis for specific aspects of tical dopamine system in modulating (deficient) dorsal the ADHD phenotype – namely frequent, transient and fronto-striatal glutamatergic mediation of some executive impairing fluctuations in functioning, particularly during functions. It also envisages a role for the mesolimbic performance of speeded, effortful tasks. We briefly point dopamine system in the anomalously functioning reward to the interfaces and overlaps. and motivation-influencing circuits of the more ventral frontal-accumbens glutamatergic system [107]. The mes- One proposal attributes many features of ADHD to prob- olimbic role is often associated with the preference of lems with the regulation of 'state' that affects the alloca- ADHD subjects for immediate rather than delayed tion of 'energy' and 'effort' [274,275]. Based on the rewards. This relates to the dynamic developmental the- "cognitive-energetic" model of Sanders [276] they define ory of Sagvolden et al., which concentrates on the registra- state regulation as the allocation of extra effort to defend tion of reinforcement and related motivational performance in the presence of stressors such as high pres- consequences, in particular, a mesolimbic impairment of entation rates of stimuli. Whereas CNS activation nor- the "efficiency with which the contingency between mally increases with event-rates, long inter-event intervals present action and future rewards is signalled". In ADHD engender a sub-optimal hypoactivation in people with research there is widespread agreement that there is a ADHD, who then are unable to recruit the necessary effort reduction in the control by future rewards of current to adjust appropriately to the demands of the situation. behaviour, and an increase in the extent to which they are Activation can be viewed as a state of readiness in selec- discounted (i.e., a steeper delay of reward gradient). tively targeting possible outcomes of behaviour: The mon- Sagvolden et al. also extend their theory to impaired func- itoring of input, endogenous interactions and feedback tion of the ascending nigrostriatal and mesocortical are involved. Effort is viewed as a process necessary for dopamine pathways. coupling and re-coupling input-information, neuronal modules and activational processes [277]. Our hypothesis Both theories are driven by interpretations of the relative is broadly consistent with this 'state-regulation' theory, success of the psychostimulants in terms of dopamine but elaborates details of its potential physiological basis, function as a neurotransmitter, and the need to explain and that in turn is specifically directed to account for responsivity to reinforcement in ADHD in a wider moti- intra-individual variability of performance on sustained vational context. To a degree the explanations are success- demand. The distinction with our formulation lies with a) ful. But we would shift emphasis in our interpretation. our emphasis on coping with high energy demands rather The first shift is clearly from a neurotransmitter interpre- than a state of hypoactivation at low event-rates, and b) tation of psychostimulant function to the additional role our prediction that the consequences of impaired lactate of glial stimulation. The second shift concerns the empha- shuttle function lie with reduced rapid neuronal firing sis on the role of delay periods. Our hypothesis views when that is required, and the delayed development of these as requiring the operation of attentional and work- myelination. We do not predict a generalized 'state of acti- ing memory components of executive function. Typically such delays require consistent firing of prefrontal neurons Page 17 of 25 (page number not for citation purposes) Behavioral and Brain Functions 2006, 2:30 http://www.behavioralandbrainfunctions.com/content/2/1/30 with high demands on energy resources [279]]. To a is capable of delivering the requisites to where they are degree our emphasis on impaired function under high needed. In the longer term it may prove more feasible to demands is consistent with Sonuga-Barke's description of modify the expression of genes demonstrated to be essen- impaired efficiency of mesocortical dopamine control of tial in the regulation of astrocyte function, lactate produc- fronto-striatal circuits, and Sagvolden's description of the tion, glutamate transport and myelin synthesis [261]. difficulty for children with ADHD to comply with (the Several novel forms of therapeutic agent and delivery sys- demanding) shallow reinforcement gradients. According tem based on the components of the energy cycle and the to our hypothesis, the reinforcement contingency is not so synthesis of myelin could be tested. much a causal factor in ADHD, as it is an occasion in which the mechanisms we have outlined are likely to be 6 Abbreviations operative. People with ADHD will tend to go "off-task" Acetyl CoA acetyl coenzyme A independent of the reinforcement lost because the effort to remain "on-task" requires energy resources that are no ADHD attention-deficit hyperactivity disorder longer available to them. ADP/ATP adenosine di-/tri-phosphate 5.3 Implications for ADHD in the clinic Impaired performance is expressed mainly in tasks of high AMPA alpha-amino-3-hydroxy-5-methyl-4-isoxazolepro- temporal and/or cognitive demand and will be less appar- pionic acid ent in self-paced tasks of low complexity. Proposals for 2+ modifying current treatment methods can be made at the Ca calcium ions behavioural and the biochemical level. Segmenting tasks to reduce concurrent demands for speed and accuracy of CNS central nervous system responding would be helpful in situations that place high and prolonged demands on neural activity (function). CNV contingent negative variation One possibility is to introduce frequent variation into the nature of the task or its modality in order to allow for a re- CPT continuous performance test distribution of the energetic demands to alternate neural processing circuitry. A second possibility is to introduce DTI diffusion tensor imaging frequent breaks into ongoing, lengthy and demanding activities such as school exams, assembly lines and motor- EEG electroencephalogram way driving. Both strategies would permit energetic demands to be distributed to alternate resources and the EP evoked potential re-establishment of depleted energy reserves. A third method is the institution of self-paced rather than system- ERP event-related potential paced scheduling of the required activity. Each strategy would reduce concurrent demands for both the speed and FA fractional anisotropy accuracy of performance during continuous and complex information processing tasks. Also, if speed and accuracy GLAST glutamate/aspartate transporter are required in a complex task, a third possibility is to reduce the cognitive demands by segmenting the task into GLT-1 glutamate transporter smaller and simpler steps, with breaks between steps. Glu glutamate Investigations of potential therapeutic agents that target the energetic system rather than neurotransmitter func- H-MRS proton magnetic resonance spectroscopy tion may yield additional improvements in treatment beyond the positive modulation of the energy balance ISD individual standard deviation noted for monoaminergic drugs in current use. One aim could be to stimulate creatine kinase function, and thus to K potassium ions increase the availability of phosphocreatine, and the re- synthesis of ATP. Increasing creatine levels would have the MRI magnetic resonance imaging additional advantage of being neuroprotective [280]. While there is clearly a need to restore carbohydrate and MRS magnetic resonance spectroscopy energy reserves and to ensure an adequate supply of omega fatty acids and other elements essential for myelin MRT mean reaction time synthesis, it is equivocal whether dietary supplementation Page 18 of 25 (page number not for citation purposes) Behavioral and Brain Functions 2006, 2:30 http://www.behavioralandbrainfunctions.com/content/2/1/30 12. Ostrow LW, Sachs F: Mechanosensation and endothelin in Na sodium ions astrocytes--hypothetical roles in CNS pathophysiology. Brain Res Brain Res Rev 2005, 48:488-508. NAA N-acetyl-aspartate 13. Todd RD, Botteron KN: Is attention-deficit/hyperactivity disor- der an energy deficiency syndrome? Biol Psychiatry 2001, 50:151-158. NMDA N-methyl-d-aspartate 14. Sanchez-Abarca LI, Tabernero A, Medina JM: Oligodendrocytes use lactate as a source of energy and as a precursor of lipids. Glia 2001, 36:321-329. Phe phenylalanine 15. 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Behavioral and Brain Functions – Springer Journals
Published: Aug 23, 2006