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hyperactivity disorder an energy deficiency syndrome?
REVIEW Is Attention-Deficit/Hyperactivity Disorder an Energy Deficiency Syndrome? Richard D. Todd and Kelly N. Botteron Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable yet clinically heterogeneous syndrome associated with hypocatecholamine function in subcortical and prefrontal cortical regions and clinical response to medications that enhance catecholamine function. The goal of this article is to present a hypothesis about the etiology of ADHD by synthesizing these findings with recent experiments indicating that activity-dependent neuronal energy consumption is regulated by cortical astrocytes. The scientific literature was searched from 1966 to the present using MEDLINE and relevant key words. Inattention and impulsivity may be related to hypofunctionality of catecholamine projection pathways to prefrontal cortical areas, resulting in decreased neuronal energy availability. This may be mediated by astrocyte catecholamine receptors that normally regulate energy availability during neuronal activation. At least some forms of ADHD may be viewed as cortical, energy-deficit syndromes secondary to catecholamine-mediated hypofunctionality of astrocyte glucose and glycogen metabolism, which provides activity-dependent energy to cortical neurons. Several tests of this hypothesis are proposed. Biol Psychiatry 2001;50: 151–158 © 2001 Society of Biological Psychiatry Key Words: ADHD, catecholamines, astrocytes, prefrontal cortex, lactate, glycogenolysis
Introduction
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ecent scientific articles and reviews have suggested that attention-deficit/hyperactivity disorder (ADHD) is composed of a number of more or less independent, highly heritable syndromes characterized by differing combinations of problems in attention, impulsivity, hyperactivity, and comorbidity (Faraone 2000; Faraone and Biederman 1998; Faraone et al 2000; Hudziak and Todd 1993; Todd 2000a, 200b). Speculation has also focused on the possible involvement of noradrenergic mechanisms in ADHD in addition to the more traditional dopaminergic hypothesis (Biederman and Spencer 2000). Though it has been known for several decades that catecholamines, such
From the Departments of Psychiatry (RDT, KNB), Genetics (RDT), and Radiology (KNB), Washington University School of Medicine, St. Louis, Missouri. Address reprint requests to Richard D. Todd, PhD, MD, Washington University School of Medicine, Department of Psychiatry and Genetics, 660 So. Euclid Avenue, Campus Box 8134, St. Louis, MO 63110. Received January 18, 2001; revised April 11, 2001; accepted April 16, 2001.
© 2001 Society of Biological Psychiatry
as dopamine and noradrenaline, influence brain energy metabolism in both cortical and subcortical regions, the molecular and cellular pathways involved in these effects have only recently been partially elucidated (Magistretti and Pellerin 1999; Magistretti et al 1993, 1999; Pellerin et al 1998). The purpose of this article is to review what is known about the control of neuronal activity– dependent brain energy metabolism in light of current hypotheses of catecholamine hypoactivity in ADHD. It will be argued that the noradrenergic and dopaminergic theories of the genesis of ADHD symptomatology can be directly linked to known components of the astrocyte–neuronal lactate energy shuttle and the storage of astrocyte glycogen. These proposed linkages offer several specific experimental tests for the hypothesis that at least some types of ADHD may be linked to specific problems in neuronal energy metabolism.
Methods A MEDLINE literature search for the period of 1966 to week 4 of December 2000 was completed using combinations of the key words ADHD, genetics, energy metabolism, glycogenesis, glycogenolysis, astrocytes, glia, catecholamines, dopamine, noradrenaline, magnetic resonance imaging (MRI), functional magnetic resonance imaging (fMRI), and positron emission tomography (PET). These studies were combined with others known to the authors, and the results were integrated into a hypothesis relating clinical symptomatology to catecholamine regulation of neuronal energy metabolism. The studies referenced here are not comprehensive but reflect a representative series of review and original articles.
Results Catecholaminergic Hypotheses of ADHD and the Prefrontal Cortex Recent review articles (Arnsten 2000, Barkley 2000; Biederman and Spencer 2000; Faraone 2000; Todd 2000a, 2000b; Todd and O’Malley 2001) have documented the structural, neurochemical, and hereditary bases of ADHD. A consensus has developed that a primary mechanism related to ADHD symptomatology is hypofunctionality of 0006-3223/01/$20.00 PII S0006-3223(01)01173-8
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catecholaminergic pathways projecting to prefrontal cortical areas. A variety of studies in animals and in nonADHD individuals are consistent with both dopamine and noradrenaline having prominent effects on cognitive activities mediated by the prefrontal cortex (Arnsten 1998). Whether such functional hypoactivity in ADHD represents decreased activity or efficacy of these pathways or less responsivity of the targets of these pathways is unclear. What is clear, however, is that individuals with ADHD show consistently impaired performance on tests of prefrontal cortical function. Recent structural imaging studies are consistent with ADHD subjects having structural differences in subcortical–prefrontal circuits. These differences have consistently included decreased and/or altered lateralization of basal ganglia structures, such as the caudate and reduced right prefrontal lobe volume (Castellanos et al 1996; Filipek et al 1997). Several recent studies have demonstrated that changes in right prefrontal–subcortical circuits correlate significantly with neuropsychological measures of sustained attention (Semrud-Clikeman et al 2000) and impulsivity (Casey et al 1997). These differences are consistent with models of selective and sustained attention (Posner and Raichle 1994). Perhaps the most compelling lines of evidence that catecholaminergic mechanisms are involved in ADHD are pharmacological challenge studies in animals and pharmacological treatment studies in humans. As recently reviewed by Biederman and Spencer (2000), manipulation of noradrenergic and dopaminergic systems results in alterations of prefrontal cortex–related behaviors and in improvement in ADHD symptoms. Given that the observed clinical heterogeneity of ADHD is also associated with marked heterogeneity in comorbidity profiles, family clustering, longitudinal course, and possible genetic heterogeneity (reviewed in Faraone 2000; Faraone et al 2000; Hudziak and Todd 1993; Todd 2000a, 2000b), it is entirely plausible that dopaminergic and noradrenergic mechanisms may operate to different extents in different patients and different familial subtypes of ADHD.
Regulation of Activity-Dependent Neuronal Energy Metabolism by Catecholamines The primary source of energy for the brain is blood-borne glucose and to a lesser extent its intracellular counterpart glycogen. Stimulated by a desire to link studies of neuronal activity to parameters of functional brain imaging, such as deoxyglucose uptake by PET or changes in hemoglobin oxygenation by fMRI, a variety of studies over the last decade have begun to establish the molecular and cellular mechanisms of neuronal energy metabolism in response to activation. This literature has a long-
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standing link to catecholamines, because it has been demonstrated as early as the 1970s that amphetamine, which causes the release of cerebral catecholamines, is a potent glycogenolytic agent (Hutchins and Rogers 1970, 1973; Rogers and Hutchins 1972). More recent studies also demonstrate that acute dextroamphetamine challenge increases cortical glucose uptake in many brain regions in humans (Ernst et al 1997b). Our current understanding of the regulation of neuronal activity– dependent energy metabolism has been greatly revised to include the central role of cortical astrocytes in the regulation of neuronal energy homeostasis via glycogenesis and glycogenolysis (Magistretti et al 1993, 1999). Cortical astrocytes are positioned between capillaries and cortical neurons. Their foot processes closely surround capillaries and synaptic clefts (Figure 1). This architectural arrangement makes the astrocyte a natural partner in the regulation of neurotransmission as well as energy homeostasis. Astrocytes have active transport mechanisms for neurotransmitters, such as glutamate, dopamine, and noradrenaline, and serve an important role in the termination of neurotransmitter activity via uptake of neurotransmitters released within the synapse. Astrocytes also take up glucose from blood capillaries and convert this to lactate for immediate use by neurons or convert and retain it as glycogen for long-term storage. These same astrocytes also have receptors for a variety of neurotransmitters, including catecholamines, which play active roles in adjusting energy availability to neurons through the regulation of glycogenolysis and glycogen synthesis in the astrocytes. These astrocyte receptor–mediated roles include both short-term effects and longer-term effects on glucose availability through activation of transcriptional and translational mechanisms by modulation of second messengers, such as cyclic adenosine monophosphate (cAMP). Our current understanding of several of these mechanisms will be briefly reviewed here and is schematically outlined in Figure 1. The interested reader is referred to several recent review articles for more comprehensive details (Magistretti and Pellerin 1999; Magistretti et al 1993, 1999; Pellerin et al 1998). During neuronal activation, glutamate, an excitatory neurotransmitter, is released by about 90% of cortical neurons and diffuses across the synaptic cleft to interact with postsynaptic receptors. The released glutamate is rapidly removed from the synapse by glutamate transporters primarily located on surrounding astrocytes. Following uptake into the astrocyte, glutamate is converted to glutamine, which is subsequently released by the astrocytes and taken up by the presynaptic neurons, where it is converted back to glutamate and repackaged in synaptic vesicles (the so-called glutamate– glutamine cycle). The uptake and metabolism of glutamate to glutamine requires
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Figure 1. Simplified schematic of the interactions of astrocytes and neurons in the regulation of activity-dependent neuronal energy metabolism. The capillary (red), astrocyte (yellow) and synaptic (green: presynaptic; blue: postsynaptic) compartments are shown along with the proposed glutamate– glutamine cycle (glu– gln), the lactate shuttle, and adenosine triphosphate (ATP) production sites. Sites on the astrocyte for the glutamate transporter (blue), sodiumpotassium-ATPase (orange) and catecholamine receptors (red) are indicated. Stochiometries for the different processes are not shown. cAMP, cyclic adenosine monophosphate. The figure is a synthesis and modification of diagrams from several sources (Magistretti and Pellerin 1999; Magistretti et al 1993, 1999; Pellerin et al 1998).
adenosine triphosphate (ATP). Because there is no direct ATP exchange mechanism between cells, both astrocytes and neurons must generate their own energy. The source of this energy is ultimately glucose supplied by the blood. Glucose metabolism within the astrocyte is closely linked to neuronal activation and glutamate reuptake (by the astrocyte). Capillary glucose is taken up by astrocytes, where it is immediately metabolized to lactate or converted and stored as glycogen. Lactate is the common end product of astrocytic glucose metabolism, whether glucose is immediately used following transport from the blood or following release from glycogen stores. Lactate is transferred via a lactate shuttle from the astrocyte to the neuron. Once in the neuron, the lactate serves as an energy source. Thus, astrocytes are hypothesized to be the primary source of lactate for neuronal activity– dependent energy production via coupling of the glutamate– glutamine cycle to the lactate shuttle. Recent studies on the stoichiometry of this energy coupling suggest that one glucose molecule is consumed for each glutamate molecule cycled (Magistretti et al 1999). As described above, it has been known for 30 years or more that regional brain metabolism can be impacted by the release of brain catecholamines. Both dopamine and noradrenaline result in the immediate release of glucose from glycogen stores (Hutchins and Rogers 1970, 1973; Rogers and Hutchins 1972). A series of studies have demonstrated the presence of both dopamine and noradrenergic receptors on astrocytes and that stimulation of these receptors result in increases in intracellular cyclic AMP in cortical and striatal astrocytes (see, for example,
Hansson et al 1984). The receptors appear to be principally of the D1-like (Hansson and Ro¨nnba¨ck 1988; Hansson et al 1984; Hosli and Hosli 1986; Zanassi et al 1999) and  subtypes (Sorg and Magistretti 1991) for dopamine and noradrenaline, respectively. For noradrenaline, which has been more widely studied, acute application of transmitter on cultured astrocytes results in immediate decreases in glycogen stores. The functional result of this is an increase in intracellular concentrations of glucose and increased production of lactate. Hence, stimulation of these receptors can result in increased energy access for neurons via the astrocyte–neuron lactate shuttle. Though not studied in the same detail, application of dopamine also results in immediate decreases in glycogen stores and hence may also increase available neuronal energy. Interestingly, the immediate reduction in glycogen stores following catecholamine receptor stimulation, which is principally cAMP– dependent, is followed by a long period of increased glycogen synthesis. Hence, catecholaminergic stimulation results in both increased energy availability at short time periods and long-term increases in energy storage. Though most energy for brain activity is derived from blood glucose, such astrocyte glycogen stores may be important in short-term matching of energy needs and lactate supplies. This latter effect of catecholamine receptor stimulation on increased glycogen storage requires gene transcription and translation and may be related to changes in the amount of and activity of glycogen synthesis enzymes. For example, in cultured cortical astrocytes, noradrenaline pulses as short as a few minutes increase glycogenesis for up to 24 hours (Sorg
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and Magistretti 1992). This effect is dependent on protein synthesis and can be mimicked by the cAMP analog dibutyryl-cAMP. The long-term effect on glycogenesis is independent of the initial glycogenolysis, per se, because glycogenolytic agents that do not act via increasing cAMP do not result in increases in glycogen synthesis. As in hepatocytes, increases in astrocyte cAMP result in induction of the CCAAT/enhancer binding protein (C/EBP) family of transcription factors with subsequent increased production of energy metabolism–related enzymes (Cardinaux and Magistretti 1996). No similar studies of the long-term effects of dopamine on astrocyte glycogen synthesis or on the activation of energy metabolism related transcription factors have been published. Dopamine release does increase cAMP levels in striatal and cortical astrocytes, however, suggesting it may have effects similar to noradrenaline on these mechanisms.
ADHD as an Energy Deficiency Syndrome: A Hypothesis As described above, a leading hypothesis for the genesis of ADHD is a functional hypoactivity of catecholamine projection pathways to the prefrontal cortex. The reported elevations of dopamine transporter concentrations in unmedicated ADHD individuals (Dougherty et al 1999; Krause et al 2000) and their normalization following treatment (Krause et al 2000) suggest that this hypofunctionality represents a decrease in catecholamine release at synapses and that successful stimulant treatment operates through normalization of synaptic concentrations of catecholamines. It is unclear whether this reflects abnormalities of dopamine alone or whether there is a more widespread catecholamine deficiency. How does this hypofunctionality interfere with the normal functioning of the prefrontal cortex? One possibility would be through dysregulation of cortical transmission secondary to decreased stimulation of postsynaptic catecholamine receptors. An alternative hypothesis, however, is that decreased catecholamine input results in decreased astrocyte-mediated neuronal energy metabolism following neuronal activation. In this case, prefrontal cortical dysfunction is due to decreased energy availability for neurons by interference with astrocyte-mediated processes. This might include both the regulation of the immediate uptake and conversion of glucose to lactate and the long-term regulation of glycogen levels in astrocytes.
Discussion How can such an energy deficiency state be linked to previous studies of structural and functional brain imaging and candidate gene studies of ADHD? Similarly, how can
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such a hypothesis be tested either in experimental systems or individuals with ADHD?
Can an Energy Deficiency State Explain Structural Brain Changes in ADHD? Developmentally, a catecholamine-mediated energy deficiency state might contribute to the observed prefrontal– subcortical structural brain differences described above. In particular, dopamine is known to affect cortical maturation and the arborization of dopamine receptor– expressing neurons (see, for example, Swarzenski et al 1994; Todd 1992). Dopamine D1-like receptor stimulation decreases neurite growth, whereas D2-like receptor stimulation increases outgrowth and branching in developing neurons. The interaction of these effects with astrocyte development and lactate transfer are unknown. Decreased energy availability could result in reductions of both target region size and number of catecholaminergic synapses by interfering with activity-dependent synapse formation and stabilization (reviewed in Todd et al 1995).
Do Functional Imaging Studies of ADHD Support an Energy Deficiency Hypothesis? Given the established tight couplings between cerebral blood flow, cerebral glucose metabolism, and astrocyte function, if ADHD were associated with a prefrontal cortical energy deficiency state, then functional imaging measures of cerebral blood flow and regional glucose metabolism should show lower rates in subjects with ADHD than in control individuals. It should be noted under the above hypothesis, however, that this would not necessarily effect resting state energy metabolism but only that associated with neuronal activation. Hence, studies of regional brain metabolism and regional brain blood flow in resting states may not contribute to this analysis. Similarly, the reliance of radioactivity-based studies, such as xenon inhalation or 18F-fluoro-deoxyglucose uptake, are greatly restricted in children and adolescents due to concerns over safety of radiation exposure. Hence, most radiation-based functional imaging studies are restricted to adult populations. Functional MRI is appropriate for the study of child and adolescent age groups and, because it relies on activation paradigms, is well suited to the testing of these hypotheses. Given these caveats, some early studies using the inhalation of xenon (Lou et al 1984, 1989, 1990) did find lower cerebral blood flow primarily in subcortical areas in hyperactive children. These hyperactive children did not necessarily meet modern criteria for ADHD. More recently, Gustafsson et al (2000), using single photon emission computed tomography (SPECT), reported an inverse relationship between severity of ADHD symptoms
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and blood flow in right frontal regions in ADHD children. Zametkin et al (1990) also found low prefrontal regional brain metabolism as well as decreased metabolism in a number of subcortical structures in adults with ADHD. Initial PET studies of adolescents seem to confirm the results of adult studies (i.e., showing decreased regional glucose utilization; Ernst et al 1994; Zametkin et al 1993); however, subsequent studies in larger groups using auditory continuous performance activation tasks could not replicate these findings (Ernst et al 1997a). Further studies have suggested that part of the problem with the replication of regional glucose metabolism studies of ADHD is the presence of age-, gender-, and diagnosis-specific findings (Ernst et al 1998a). Despite attempts to statistically control for these effects, current SPECT and PET studies suffer from tremendous individual variations in reported measures, poor regional identifications of metabolic signals and the use of overlapping groups of patients between studies. Three fMRI studies of ADHD individuals have been published (Bush et al 1999; Rubia et al 1999; Vaidya et al 1998). All used small groups of ADHD individuals (n ⱕ 10) and matched control subjects but differed in diagnostic assessments and activation paradigms and in the gender and age composition of the groups studied. In the studies of Bush et al (1999) and Rubia et al (1999), adolescent and adult ADHD patients demonstrated less prefrontal and less anterior cingulate cortical activation than normal control subjects. In contrast, Vaidya et al (1998) found no difference or increased cortical activation in 8 –13-year-old ADHD patients on two different tasks. Variable results were reported for subcortical regions in the three studies. The studies of Bush et al (1999) and Rubia et al (1999) are compatible with prefrontal deficits in energy utilization in ADHD. Overall, current functional imaging studies do not offer convincing evidence for or against the hypothesis of ADHD being secondary to an energy deficiency state in prefrontal cortical regions following neuronal activation. Whether the varied results of these studies are due to sampling or methodological issues or are related to phenotypic heterogeneity in ADHD is unresolved. This later possibility is important, because the clinical characteristics of participants in most imaging studies are poorly documented. Twin studies suggest that phenotypically distinct ADHD cases may have independent familial forms of illness (Todd 2000a, 2000b).
Do Candidate Gene Studies of Catecholamine Pathways Support an Energy Deficiency Hypothesis? As reviewed above, a variety of twin and family studies suggest that ADHD is highly heritable. Though it needs to
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be appreciated that there are current controversies regarding what is familial about ADHD and whether the genetic components are better modeled as discrete or continuum disorders (Todd 2000a, 2000b), a variety of groups have begun candidate gene studies of ADHD. In particular, the response to stimulants in ADHD has promoted an investigation of catecholamine pathway enzymes, receptors, and transporters. As discussed above, these pathways are particularly relevant to a developmental disorder such as ADHD, because over- or under-stimulation of different dopamine receptors can result in markedly different cell morphologies (see, for example, Swarzenski et al 1994) and may affect regional brain volumes. The strongest current evidence for association of ADHD with catecholamine pathway genes is for the dopamine D4 receptor gene (reviewed in Faraone et al, in press) and for the dopamine transporter gene (reviewed by Barr et al 2000a). Other partially replicated findings include an association with the D5 receptor gene (Barr et al 2000b) and noradrenaline pathway genes (Comings et al 1999, 2000). The hypothesis elucidated above would predict hypofunctionality of catecholamine projection pathway genes at the sites of neural transmitter synthesis, release, re-uptake, or receptor action on astrocytes. Of course this could be linked to transfer of information from the astrocyte surface to the intercellular pathways as well. Such receptor effects on astrocytes would be most likely of the dopamine D1 (DRD1 and DRD5) or -adrenergic types. Overall, current results from candidate gene studies are compatible with both dopamine and norepinephrine pathways being involved in the genetic liability to ADHD, but the current data are inconclusive. It is of course possible that multiple different defects in these pathways could result in a common mechanism of dysregulation of energy metabolism during neuronal activation. Similarly, allelic variation in the same catecholamine pathway genes may contribute to the observed phenotypic heterogeneity of ADHD by causing different degrees of physiologic dysfunction.
Testable Predictions of the Energy Deficiency Hypothesis The hypothesis that some forms of ADHD are secondary to catecholamine-induced deficiencies in neuronal activation–associated astrocyte energy metabolism can be tested at several levels. These include model systems of molecular mechanisms, functional energy studies of ADHD individuals, and a broader concept of candidate gene studies for linkage disequilibrium analysis. As discussed above, the majority of studies focusing on a possible relationship of astrocytes to neuronal energy homeostasis have focused on vasoactive intestinal peptide (VIP) and noradrenaline; however, current evidence sug-
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gests that dopamine may have equivalent effects on glycogenesis and glycogenolysis via astrocyte dopamine D1-like, receptor-mediated effects. The effects of dopamine on astrocyte glycogen content have been well established, as has the presence of D1-like dopamine receptors that increase cAMP levels. What are lacking are experiments directly testing whether dopamine receptor activation leads to changes in astrocyte glycogen synthesis and glycogenolysis, as well as studies of receptor-mediated effects on gene transcription. These studies are straightforward, using established methods (see, for example, Sorg and Magistretti 1992; Zanassi et al 1999). The limitations of current PET and xenon-inhalation studies of regional brain metabolism suggest that major efforts should be made to expand fMRI paradigms in the investigation of ADHD children. Functional MRI allows improved regional anatomical assignment of changes in hemoglobin oxygenation and hence has improved ability to test specific anatomical hypotheses. Such functional approaches should include quantitative structural measures of the brain areas being studied As outlined above, only results from small samples have been published to date. Such studies also need to include better phenotypic characterization of participants and their biological relatives, to help control for clinical and genetic heterogeneity. The previous PET studies have also demonstrated large individual differences in regional brain metabolism and significant age, gender, and diagnostic effects. Functional MRI studies might be better accomplished using sibling control subjects, who do or do not have ADHD, or using concordant and discordant twin pairs, which are naturally controlled on a variety of potentially confounding factors, such as age, gender, and background genotype. The broadening of catecholamine pathway candidate gene hypotheses to include energy metabolic pathways suggest a host of other reasonable targets for linkage disequilibrium and association studies. These would include not only astrocyte-associated glucose uptake proteins and glycogen cycle enzymes but also transcription factors turned on by stimulating astrocytes with dopamine or norepinephrine. Testing of ensembles of candidate genes as proposed by Comings et al (2000) may be appropriate, given the likely oligogenic nature of the genetic contributions of ADHD. A final test of this hypothesis would be to measure regional brain glycogen levels in ADHD individuals. Currently this is technically difficult, owing to the small MR spectroscopy signal of glycogen. Higher field strength (7–10 Tesla) magnets are available in some centers that could make these types of regional chemical determinations. In summary, current data are compatible with ADHD representing a syndrome of hypofunctionality of catechol-
amine projection pathways to prefrontal cortical areas. At the same time, it has recently been hypothesized that neuronal activation–induced energy metabolism is largely controlled by astrocytes. One mechanism for the translation of catecholamine hypofunction of projection pathways into decreased function of prefrontal cortical areas is that a disruption of astrocyte-mediated neuronal energy transfer results in decreased and disorganized neuronal function in these areas. This hypothesis is amenable to a variety of experimental tests. Though we have focused on ADHD in this article, we note that abnormalities of prefrontal cortical functioning have also been reported for other disorders, such as schizophrenia and mood disorders. Reconceptualizations of these disorders as possible energy deficiency syndromes would suggest that experimental approaches similar to those outlined above may be broadly useful. Financial support for National Institutes of Health Dr. Richard D. Todd is from Grants MH52813 and MH31302; support for Dr. Kelly N. Botteron is from Grant MH01292.
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Sorg O, Magistretti PJ (1992): Vasoactive intestinal peptide and noradrenaline exert long-term control on glycogen levels in astrocytes: Blockade by protein synthesis inhibition. J Neurosci 12:4923– 4931. Swarzenski BC, Tang L, Oh YJ, O’Malley KL, Todd RD (1994): Morphogenic potentials of D2, D3 and D4 dopamine receptors revealed in transfected neuronal cell lines. Proc Natl Acad Sci U S A 91:649 – 653. Todd RD (1992): Neural development is regulated by classical neurotransmitters: Dopamine D2 receptor stimulation enhances neurite outgrowth. Biol Psychiatry 31:794 – 807. Todd RD (2000a) Genetics of attention deficit/hyperactivity disorder: Are we ready for molecular genetic studies? Am J Med Genet 96:241–243. Todd RD (2000b): Genetics of childhood disorders: XXI. ADHD, part 5: A behavioral genetic perspective. J Am Acad Child Adolesc Psychiatry 39:1271–1274. Todd RD, O’Malley KL (2001): The dopamine DRD4 receptor gene: Are duplications distracting? Trends Pharmaco Sci 22:55–56. Todd RD, Swarzenski B, Visconti P, Giovanardi-Rossi P (1995):
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Structural and functional development of the human brain. In: Cicchetti D, Cohen D, editors. Developmental Psychopathology, Vol. 1: Theory and Methods. New York: John Wiley & Sons, 161–194. Vaidya CJ, Austin G, Kirkorian G, Ridlehuber HW, Desmond JE, Glover GH, et al (1998): Selective effects of methylphenidate in attention deficit hyperactivity disorder: A functional magnetic resonance study. Proc Natl Acad Sci U S A 95:14494 –14499. Zametkin AJ, Liebenauer LL, Fitzgerald GA, King AC, Minkunas DV, Herscovitch P, et al (1993): Brain metabolism in teenagers with attention-deficit hyperactivity disorder. Arch of Gen Psychiatry 50:333–340. Zametkin AJ, Nordahl TE, Gross M, King AC, Semple WE, Rumsey J, et al (1990): Cerebral glucose metabolism in adults with hyperactivity of childhood. N Engl J Med 323:1361– 1366. Zanassi P, Paolillo M, Montecucco A, Avvedimento EV, Schinelli S (1999): Pharmacological and molecular evidence for dopamine D1 receptor expression by striatal astrocytes in culture. J Neurosci Res 58:544 –552.
Introduction
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ecent scientific articles and reviews have suggested that attention-deficit/hyperactivity disorder (ADHD) is composed of a number of more or less independent, highly heritable syndromes characterized by differing combinations of problems in attention, impulsivity, hyperactivity, and comorbidity (Faraone 2000; Faraone and Biederman 1998; Faraone et al 2000; Hudziak and Todd 1993; Todd 2000a, 200b). Speculation has also focused on the possible involvement of noradrenergic mechanisms in ADHD in addition to the more traditional dopaminergic hypothesis (Biederman and Spencer 2000). Though it has been known for several decades that catecholamines, such
From the Departments of Psychiatry (RDT, KNB), Genetics (RDT), and Radiology (KNB), Washington University School of Medicine, St. Louis, Missouri. Address reprint requests to Richard D. Todd, PhD, MD, Washington University School of Medicine, Department of Psychiatry and Genetics, 660 So. Euclid Avenue, Campus Box 8134, St. Louis, MO 63110. Received January 18, 2001; revised April 11, 2001; accepted April 16, 2001.
© 2001 Society of Biological Psychiatry
as dopamine and noradrenaline, influence brain energy metabolism in both cortical and subcortical regions, the molecular and cellular pathways involved in these effects have only recently been partially elucidated (Magistretti and Pellerin 1999; Magistretti et al 1993, 1999; Pellerin et al 1998). The purpose of this article is to review what is known about the control of neuronal activity– dependent brain energy metabolism in light of current hypotheses of catecholamine hypoactivity in ADHD. It will be argued that the noradrenergic and dopaminergic theories of the genesis of ADHD symptomatology can be directly linked to known components of the astrocyte–neuronal lactate energy shuttle and the storage of astrocyte glycogen. These proposed linkages offer several specific experimental tests for the hypothesis that at least some types of ADHD may be linked to specific problems in neuronal energy metabolism.
Methods A MEDLINE literature search for the period of 1966 to week 4 of December 2000 was completed using combinations of the key words ADHD, genetics, energy metabolism, glycogenesis, glycogenolysis, astrocytes, glia, catecholamines, dopamine, noradrenaline, magnetic resonance imaging (MRI), functional magnetic resonance imaging (fMRI), and positron emission tomography (PET). These studies were combined with others known to the authors, and the results were integrated into a hypothesis relating clinical symptomatology to catecholamine regulation of neuronal energy metabolism. The studies referenced here are not comprehensive but reflect a representative series of review and original articles.
Results Catecholaminergic Hypotheses of ADHD and the Prefrontal Cortex Recent review articles (Arnsten 2000, Barkley 2000; Biederman and Spencer 2000; Faraone 2000; Todd 2000a, 2000b; Todd and O’Malley 2001) have documented the structural, neurochemical, and hereditary bases of ADHD. A consensus has developed that a primary mechanism related to ADHD symptomatology is hypofunctionality of 0006-3223/01/$20.00 PII S0006-3223(01)01173-8
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catecholaminergic pathways projecting to prefrontal cortical areas. A variety of studies in animals and in nonADHD individuals are consistent with both dopamine and noradrenaline having prominent effects on cognitive activities mediated by the prefrontal cortex (Arnsten 1998). Whether such functional hypoactivity in ADHD represents decreased activity or efficacy of these pathways or less responsivity of the targets of these pathways is unclear. What is clear, however, is that individuals with ADHD show consistently impaired performance on tests of prefrontal cortical function. Recent structural imaging studies are consistent with ADHD subjects having structural differences in subcortical–prefrontal circuits. These differences have consistently included decreased and/or altered lateralization of basal ganglia structures, such as the caudate and reduced right prefrontal lobe volume (Castellanos et al 1996; Filipek et al 1997). Several recent studies have demonstrated that changes in right prefrontal–subcortical circuits correlate significantly with neuropsychological measures of sustained attention (Semrud-Clikeman et al 2000) and impulsivity (Casey et al 1997). These differences are consistent with models of selective and sustained attention (Posner and Raichle 1994). Perhaps the most compelling lines of evidence that catecholaminergic mechanisms are involved in ADHD are pharmacological challenge studies in animals and pharmacological treatment studies in humans. As recently reviewed by Biederman and Spencer (2000), manipulation of noradrenergic and dopaminergic systems results in alterations of prefrontal cortex–related behaviors and in improvement in ADHD symptoms. Given that the observed clinical heterogeneity of ADHD is also associated with marked heterogeneity in comorbidity profiles, family clustering, longitudinal course, and possible genetic heterogeneity (reviewed in Faraone 2000; Faraone et al 2000; Hudziak and Todd 1993; Todd 2000a, 2000b), it is entirely plausible that dopaminergic and noradrenergic mechanisms may operate to different extents in different patients and different familial subtypes of ADHD.
Regulation of Activity-Dependent Neuronal Energy Metabolism by Catecholamines The primary source of energy for the brain is blood-borne glucose and to a lesser extent its intracellular counterpart glycogen. Stimulated by a desire to link studies of neuronal activity to parameters of functional brain imaging, such as deoxyglucose uptake by PET or changes in hemoglobin oxygenation by fMRI, a variety of studies over the last decade have begun to establish the molecular and cellular mechanisms of neuronal energy metabolism in response to activation. This literature has a long-
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standing link to catecholamines, because it has been demonstrated as early as the 1970s that amphetamine, which causes the release of cerebral catecholamines, is a potent glycogenolytic agent (Hutchins and Rogers 1970, 1973; Rogers and Hutchins 1972). More recent studies also demonstrate that acute dextroamphetamine challenge increases cortical glucose uptake in many brain regions in humans (Ernst et al 1997b). Our current understanding of the regulation of neuronal activity– dependent energy metabolism has been greatly revised to include the central role of cortical astrocytes in the regulation of neuronal energy homeostasis via glycogenesis and glycogenolysis (Magistretti et al 1993, 1999). Cortical astrocytes are positioned between capillaries and cortical neurons. Their foot processes closely surround capillaries and synaptic clefts (Figure 1). This architectural arrangement makes the astrocyte a natural partner in the regulation of neurotransmission as well as energy homeostasis. Astrocytes have active transport mechanisms for neurotransmitters, such as glutamate, dopamine, and noradrenaline, and serve an important role in the termination of neurotransmitter activity via uptake of neurotransmitters released within the synapse. Astrocytes also take up glucose from blood capillaries and convert this to lactate for immediate use by neurons or convert and retain it as glycogen for long-term storage. These same astrocytes also have receptors for a variety of neurotransmitters, including catecholamines, which play active roles in adjusting energy availability to neurons through the regulation of glycogenolysis and glycogen synthesis in the astrocytes. These astrocyte receptor–mediated roles include both short-term effects and longer-term effects on glucose availability through activation of transcriptional and translational mechanisms by modulation of second messengers, such as cyclic adenosine monophosphate (cAMP). Our current understanding of several of these mechanisms will be briefly reviewed here and is schematically outlined in Figure 1. The interested reader is referred to several recent review articles for more comprehensive details (Magistretti and Pellerin 1999; Magistretti et al 1993, 1999; Pellerin et al 1998). During neuronal activation, glutamate, an excitatory neurotransmitter, is released by about 90% of cortical neurons and diffuses across the synaptic cleft to interact with postsynaptic receptors. The released glutamate is rapidly removed from the synapse by glutamate transporters primarily located on surrounding astrocytes. Following uptake into the astrocyte, glutamate is converted to glutamine, which is subsequently released by the astrocytes and taken up by the presynaptic neurons, where it is converted back to glutamate and repackaged in synaptic vesicles (the so-called glutamate– glutamine cycle). The uptake and metabolism of glutamate to glutamine requires
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Figure 1. Simplified schematic of the interactions of astrocytes and neurons in the regulation of activity-dependent neuronal energy metabolism. The capillary (red), astrocyte (yellow) and synaptic (green: presynaptic; blue: postsynaptic) compartments are shown along with the proposed glutamate– glutamine cycle (glu– gln), the lactate shuttle, and adenosine triphosphate (ATP) production sites. Sites on the astrocyte for the glutamate transporter (blue), sodiumpotassium-ATPase (orange) and catecholamine receptors (red) are indicated. Stochiometries for the different processes are not shown. cAMP, cyclic adenosine monophosphate. The figure is a synthesis and modification of diagrams from several sources (Magistretti and Pellerin 1999; Magistretti et al 1993, 1999; Pellerin et al 1998).
adenosine triphosphate (ATP). Because there is no direct ATP exchange mechanism between cells, both astrocytes and neurons must generate their own energy. The source of this energy is ultimately glucose supplied by the blood. Glucose metabolism within the astrocyte is closely linked to neuronal activation and glutamate reuptake (by the astrocyte). Capillary glucose is taken up by astrocytes, where it is immediately metabolized to lactate or converted and stored as glycogen. Lactate is the common end product of astrocytic glucose metabolism, whether glucose is immediately used following transport from the blood or following release from glycogen stores. Lactate is transferred via a lactate shuttle from the astrocyte to the neuron. Once in the neuron, the lactate serves as an energy source. Thus, astrocytes are hypothesized to be the primary source of lactate for neuronal activity– dependent energy production via coupling of the glutamate– glutamine cycle to the lactate shuttle. Recent studies on the stoichiometry of this energy coupling suggest that one glucose molecule is consumed for each glutamate molecule cycled (Magistretti et al 1999). As described above, it has been known for 30 years or more that regional brain metabolism can be impacted by the release of brain catecholamines. Both dopamine and noradrenaline result in the immediate release of glucose from glycogen stores (Hutchins and Rogers 1970, 1973; Rogers and Hutchins 1972). A series of studies have demonstrated the presence of both dopamine and noradrenergic receptors on astrocytes and that stimulation of these receptors result in increases in intracellular cyclic AMP in cortical and striatal astrocytes (see, for example,
Hansson et al 1984). The receptors appear to be principally of the D1-like (Hansson and Ro¨nnba¨ck 1988; Hansson et al 1984; Hosli and Hosli 1986; Zanassi et al 1999) and  subtypes (Sorg and Magistretti 1991) for dopamine and noradrenaline, respectively. For noradrenaline, which has been more widely studied, acute application of transmitter on cultured astrocytes results in immediate decreases in glycogen stores. The functional result of this is an increase in intracellular concentrations of glucose and increased production of lactate. Hence, stimulation of these receptors can result in increased energy access for neurons via the astrocyte–neuron lactate shuttle. Though not studied in the same detail, application of dopamine also results in immediate decreases in glycogen stores and hence may also increase available neuronal energy. Interestingly, the immediate reduction in glycogen stores following catecholamine receptor stimulation, which is principally cAMP– dependent, is followed by a long period of increased glycogen synthesis. Hence, catecholaminergic stimulation results in both increased energy availability at short time periods and long-term increases in energy storage. Though most energy for brain activity is derived from blood glucose, such astrocyte glycogen stores may be important in short-term matching of energy needs and lactate supplies. This latter effect of catecholamine receptor stimulation on increased glycogen storage requires gene transcription and translation and may be related to changes in the amount of and activity of glycogen synthesis enzymes. For example, in cultured cortical astrocytes, noradrenaline pulses as short as a few minutes increase glycogenesis for up to 24 hours (Sorg
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and Magistretti 1992). This effect is dependent on protein synthesis and can be mimicked by the cAMP analog dibutyryl-cAMP. The long-term effect on glycogenesis is independent of the initial glycogenolysis, per se, because glycogenolytic agents that do not act via increasing cAMP do not result in increases in glycogen synthesis. As in hepatocytes, increases in astrocyte cAMP result in induction of the CCAAT/enhancer binding protein (C/EBP) family of transcription factors with subsequent increased production of energy metabolism–related enzymes (Cardinaux and Magistretti 1996). No similar studies of the long-term effects of dopamine on astrocyte glycogen synthesis or on the activation of energy metabolism related transcription factors have been published. Dopamine release does increase cAMP levels in striatal and cortical astrocytes, however, suggesting it may have effects similar to noradrenaline on these mechanisms.
ADHD as an Energy Deficiency Syndrome: A Hypothesis As described above, a leading hypothesis for the genesis of ADHD is a functional hypoactivity of catecholamine projection pathways to the prefrontal cortex. The reported elevations of dopamine transporter concentrations in unmedicated ADHD individuals (Dougherty et al 1999; Krause et al 2000) and their normalization following treatment (Krause et al 2000) suggest that this hypofunctionality represents a decrease in catecholamine release at synapses and that successful stimulant treatment operates through normalization of synaptic concentrations of catecholamines. It is unclear whether this reflects abnormalities of dopamine alone or whether there is a more widespread catecholamine deficiency. How does this hypofunctionality interfere with the normal functioning of the prefrontal cortex? One possibility would be through dysregulation of cortical transmission secondary to decreased stimulation of postsynaptic catecholamine receptors. An alternative hypothesis, however, is that decreased catecholamine input results in decreased astrocyte-mediated neuronal energy metabolism following neuronal activation. In this case, prefrontal cortical dysfunction is due to decreased energy availability for neurons by interference with astrocyte-mediated processes. This might include both the regulation of the immediate uptake and conversion of glucose to lactate and the long-term regulation of glycogen levels in astrocytes.
Discussion How can such an energy deficiency state be linked to previous studies of structural and functional brain imaging and candidate gene studies of ADHD? Similarly, how can
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such a hypothesis be tested either in experimental systems or individuals with ADHD?
Can an Energy Deficiency State Explain Structural Brain Changes in ADHD? Developmentally, a catecholamine-mediated energy deficiency state might contribute to the observed prefrontal– subcortical structural brain differences described above. In particular, dopamine is known to affect cortical maturation and the arborization of dopamine receptor– expressing neurons (see, for example, Swarzenski et al 1994; Todd 1992). Dopamine D1-like receptor stimulation decreases neurite growth, whereas D2-like receptor stimulation increases outgrowth and branching in developing neurons. The interaction of these effects with astrocyte development and lactate transfer are unknown. Decreased energy availability could result in reductions of both target region size and number of catecholaminergic synapses by interfering with activity-dependent synapse formation and stabilization (reviewed in Todd et al 1995).
Do Functional Imaging Studies of ADHD Support an Energy Deficiency Hypothesis? Given the established tight couplings between cerebral blood flow, cerebral glucose metabolism, and astrocyte function, if ADHD were associated with a prefrontal cortical energy deficiency state, then functional imaging measures of cerebral blood flow and regional glucose metabolism should show lower rates in subjects with ADHD than in control individuals. It should be noted under the above hypothesis, however, that this would not necessarily effect resting state energy metabolism but only that associated with neuronal activation. Hence, studies of regional brain metabolism and regional brain blood flow in resting states may not contribute to this analysis. Similarly, the reliance of radioactivity-based studies, such as xenon inhalation or 18F-fluoro-deoxyglucose uptake, are greatly restricted in children and adolescents due to concerns over safety of radiation exposure. Hence, most radiation-based functional imaging studies are restricted to adult populations. Functional MRI is appropriate for the study of child and adolescent age groups and, because it relies on activation paradigms, is well suited to the testing of these hypotheses. Given these caveats, some early studies using the inhalation of xenon (Lou et al 1984, 1989, 1990) did find lower cerebral blood flow primarily in subcortical areas in hyperactive children. These hyperactive children did not necessarily meet modern criteria for ADHD. More recently, Gustafsson et al (2000), using single photon emission computed tomography (SPECT), reported an inverse relationship between severity of ADHD symptoms
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and blood flow in right frontal regions in ADHD children. Zametkin et al (1990) also found low prefrontal regional brain metabolism as well as decreased metabolism in a number of subcortical structures in adults with ADHD. Initial PET studies of adolescents seem to confirm the results of adult studies (i.e., showing decreased regional glucose utilization; Ernst et al 1994; Zametkin et al 1993); however, subsequent studies in larger groups using auditory continuous performance activation tasks could not replicate these findings (Ernst et al 1997a). Further studies have suggested that part of the problem with the replication of regional glucose metabolism studies of ADHD is the presence of age-, gender-, and diagnosis-specific findings (Ernst et al 1998a). Despite attempts to statistically control for these effects, current SPECT and PET studies suffer from tremendous individual variations in reported measures, poor regional identifications of metabolic signals and the use of overlapping groups of patients between studies. Three fMRI studies of ADHD individuals have been published (Bush et al 1999; Rubia et al 1999; Vaidya et al 1998). All used small groups of ADHD individuals (n ⱕ 10) and matched control subjects but differed in diagnostic assessments and activation paradigms and in the gender and age composition of the groups studied. In the studies of Bush et al (1999) and Rubia et al (1999), adolescent and adult ADHD patients demonstrated less prefrontal and less anterior cingulate cortical activation than normal control subjects. In contrast, Vaidya et al (1998) found no difference or increased cortical activation in 8 –13-year-old ADHD patients on two different tasks. Variable results were reported for subcortical regions in the three studies. The studies of Bush et al (1999) and Rubia et al (1999) are compatible with prefrontal deficits in energy utilization in ADHD. Overall, current functional imaging studies do not offer convincing evidence for or against the hypothesis of ADHD being secondary to an energy deficiency state in prefrontal cortical regions following neuronal activation. Whether the varied results of these studies are due to sampling or methodological issues or are related to phenotypic heterogeneity in ADHD is unresolved. This later possibility is important, because the clinical characteristics of participants in most imaging studies are poorly documented. Twin studies suggest that phenotypically distinct ADHD cases may have independent familial forms of illness (Todd 2000a, 2000b).
Do Candidate Gene Studies of Catecholamine Pathways Support an Energy Deficiency Hypothesis? As reviewed above, a variety of twin and family studies suggest that ADHD is highly heritable. Though it needs to
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be appreciated that there are current controversies regarding what is familial about ADHD and whether the genetic components are better modeled as discrete or continuum disorders (Todd 2000a, 2000b), a variety of groups have begun candidate gene studies of ADHD. In particular, the response to stimulants in ADHD has promoted an investigation of catecholamine pathway enzymes, receptors, and transporters. As discussed above, these pathways are particularly relevant to a developmental disorder such as ADHD, because over- or under-stimulation of different dopamine receptors can result in markedly different cell morphologies (see, for example, Swarzenski et al 1994) and may affect regional brain volumes. The strongest current evidence for association of ADHD with catecholamine pathway genes is for the dopamine D4 receptor gene (reviewed in Faraone et al, in press) and for the dopamine transporter gene (reviewed by Barr et al 2000a). Other partially replicated findings include an association with the D5 receptor gene (Barr et al 2000b) and noradrenaline pathway genes (Comings et al 1999, 2000). The hypothesis elucidated above would predict hypofunctionality of catecholamine projection pathway genes at the sites of neural transmitter synthesis, release, re-uptake, or receptor action on astrocytes. Of course this could be linked to transfer of information from the astrocyte surface to the intercellular pathways as well. Such receptor effects on astrocytes would be most likely of the dopamine D1 (DRD1 and DRD5) or -adrenergic types. Overall, current results from candidate gene studies are compatible with both dopamine and norepinephrine pathways being involved in the genetic liability to ADHD, but the current data are inconclusive. It is of course possible that multiple different defects in these pathways could result in a common mechanism of dysregulation of energy metabolism during neuronal activation. Similarly, allelic variation in the same catecholamine pathway genes may contribute to the observed phenotypic heterogeneity of ADHD by causing different degrees of physiologic dysfunction.
Testable Predictions of the Energy Deficiency Hypothesis The hypothesis that some forms of ADHD are secondary to catecholamine-induced deficiencies in neuronal activation–associated astrocyte energy metabolism can be tested at several levels. These include model systems of molecular mechanisms, functional energy studies of ADHD individuals, and a broader concept of candidate gene studies for linkage disequilibrium analysis. As discussed above, the majority of studies focusing on a possible relationship of astrocytes to neuronal energy homeostasis have focused on vasoactive intestinal peptide (VIP) and noradrenaline; however, current evidence sug-
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gests that dopamine may have equivalent effects on glycogenesis and glycogenolysis via astrocyte dopamine D1-like, receptor-mediated effects. The effects of dopamine on astrocyte glycogen content have been well established, as has the presence of D1-like dopamine receptors that increase cAMP levels. What are lacking are experiments directly testing whether dopamine receptor activation leads to changes in astrocyte glycogen synthesis and glycogenolysis, as well as studies of receptor-mediated effects on gene transcription. These studies are straightforward, using established methods (see, for example, Sorg and Magistretti 1992; Zanassi et al 1999). The limitations of current PET and xenon-inhalation studies of regional brain metabolism suggest that major efforts should be made to expand fMRI paradigms in the investigation of ADHD children. Functional MRI allows improved regional anatomical assignment of changes in hemoglobin oxygenation and hence has improved ability to test specific anatomical hypotheses. Such functional approaches should include quantitative structural measures of the brain areas being studied As outlined above, only results from small samples have been published to date. Such studies also need to include better phenotypic characterization of participants and their biological relatives, to help control for clinical and genetic heterogeneity. The previous PET studies have also demonstrated large individual differences in regional brain metabolism and significant age, gender, and diagnostic effects. Functional MRI studies might be better accomplished using sibling control subjects, who do or do not have ADHD, or using concordant and discordant twin pairs, which are naturally controlled on a variety of potentially confounding factors, such as age, gender, and background genotype. The broadening of catecholamine pathway candidate gene hypotheses to include energy metabolic pathways suggest a host of other reasonable targets for linkage disequilibrium and association studies. These would include not only astrocyte-associated glucose uptake proteins and glycogen cycle enzymes but also transcription factors turned on by stimulating astrocytes with dopamine or norepinephrine. Testing of ensembles of candidate genes as proposed by Comings et al (2000) may be appropriate, given the likely oligogenic nature of the genetic contributions of ADHD. A final test of this hypothesis would be to measure regional brain glycogen levels in ADHD individuals. Currently this is technically difficult, owing to the small MR spectroscopy signal of glycogen. Higher field strength (7–10 Tesla) magnets are available in some centers that could make these types of regional chemical determinations. In summary, current data are compatible with ADHD representing a syndrome of hypofunctionality of catechol-
amine projection pathways to prefrontal cortical areas. At the same time, it has recently been hypothesized that neuronal activation–induced energy metabolism is largely controlled by astrocytes. One mechanism for the translation of catecholamine hypofunction of projection pathways into decreased function of prefrontal cortical areas is that a disruption of astrocyte-mediated neuronal energy transfer results in decreased and disorganized neuronal function in these areas. This hypothesis is amenable to a variety of experimental tests. Though we have focused on ADHD in this article, we note that abnormalities of prefrontal cortical functioning have also been reported for other disorders, such as schizophrenia and mood disorders. Reconceptualizations of these disorders as possible energy deficiency syndromes would suggest that experimental approaches similar to those outlined above may be broadly useful. Financial support for National Institutes of Health Dr. Richard D. Todd is from Grants MH52813 and MH31302; support for Dr. Kelly N. Botteron is from Grant MH01292.
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