Evidence exists for the association between attention-deficit hyperactivity disorder (ADHD) and possible structural,1-12 functional11,13-20 and neurotransmitter21-30 alterations in various regions of the brain in children, adolescents and adults with ADHD.
Childhood/Adolescent ADHD and the brain by Dr Mitul Mehta
Adult ADHD and the brain by Dr Mitul Mehta
Imaging studies suggest that ADHD is typically associated with some structural abnormalities in the brain.
The following structural abnormalities have been observed in children/adolescents and adults with ADHD versus healthy controls:
- Lower grey matter density1-3
- White matter abnormalities4,12
- Reduced total brain volume and volume of some brain structures1,5-7
- Cortical differences
- Delayed cortical maturation in children/adolescents8-10
- Reduced cortical thickness in adults.1,11
In a prospective magnetic resonance imaging (MRI) study, children and adolescents with ADHD (n=223) exhibited delays in cortical maturation versus typically developing controls (n=223).9 Delays were most prominent in prefrontal regions (Figures).
Cortical maturation in patients with and without ADHD. Reproduced with kind permission.9
Rate of cortical maturation in patients with and without ADHD. Reproduced with kind permission.9
A prospective follow-up study, which compared MRI brain scans of adults with ADHD and adults without ADHD (n=59 and n=80, respectively), found that adults with ADHD had significantly lower mean surface-wide cortical thickness and regional grey matter density (p<0.001) compared with adults without ADHD.1
The bilateral dorsal network was affected by these structural changes (found in the parietal, temporal and posterior frontal regions), and the researchers concluded that this supported previous evidence of the involvement of this region in attention functioning (Figure).1
These findings support the work of the first study of cortical thickness in adults with ADHD, which compared MRI scans of adults with ADHD with scans of adults without ADHD (n=24 and n=18, respectively) and found that adults with ADHD had significant thinning in the cortical neural network associated with attention, which primarily involved the right frontal and parietal lobes, compared with adults without ADHD (p=0.034).11
Grey matter density and cortical thickness in patients with ADHD. Reproduced with kind permission.1
Regions of the brain that have been implicated in ADHD correspond to brain networks (e.g. involving frontal regions, or supporting executive function and attention) (Figure).13
Figure: Functional abnormalities in the ADHD brain. Reproduced with kind permission.13
Neurobiological correlates of adult ADHD
Functional neuroimaging studies have identified under- or over-activation of some brain networks in adults with ADHD compared with healthy controls.14-16
One meta-analysis of 16 functional MRI studies of adults with and without ADHD demonstrated that the patterns of under- and over-activation differed significantly between these groups of patients. Networks under-activated in ADHD were almost exclusively located in the frontoparietal network, whereas over-activated regions were found in the visual, dorsal attention and default mode networks.14
Furthermore, the overall distribution of under- and over-activation differed significantly between networks, indicating that the pathology of ADHD may be based upon the interrelationships between networks.14
Meta-analysis of 16 functional MRI studies: patterns of activation differ significantly between networks (p<0.0001). Reproduced with kind permission.14
Techniques such as functional MRI and diffusion tensor imaging are providing insights into the possible dysfunction of these neural networks in ADHD.
Different models have been proposed to describe how dysfunction of particular networks may lead to symptoms of ADHD:
- Impairments in prefrontal-striatal networks may contribute to the inattention observed in ADHD13
- Impairments in frontal-limbic networks may be linked to symptoms of hyperactivity.13
Functional neuroimaging studies have identified under- or over-activation of some brain networks in ADHD versus control subjects, in particular:
- Over-activation (reduced suppression) of the default mode network during task performance19,20
- Under-activation of fronto-striatal and fronto-parietal circuits, and other frontal brain regions14-18
- Under-activation of systems involved in executive function and attention.11,14
Catecholamine signalling systems may be disrupted in the ADHD brain.21-24
Maturation of certain dopaminergic neural pathways appears to be delayed in children and adolescents with ADHD.24
Levels of available dopamine receptor and transporter molecules are typically lower in some parts of the brain in adults with ADHD than in healthy controls.21-23
In rats, interference with the noradrenaline system impacts on:28,29
- Attentional accuracy
- Response control.
Established ADHD treatments are known to interact with the dopamine and noradrenaline systems.14,21,31-66
Emerging evidence suggests possible roles for other signalling systems
Polymorphisms in the serotonin transporter gene have been associated with differential response to ADHD treatment27 and the presence of comorbid conduct disorder in children and adolescents with hyperkinetic disorder.30
In adults with ADHD, deficiencies in glutamate signalling may play a role in modulating neurotransmitter release in some brain regions.25,26
- Proal E, Reiss PT, Klein RG, et al. Brain gray matter deficits at 33-year follow-up in adults with attention-deficit/hyperactivity disorder established in childhood. Arch Gen Psychiatry 2011; 68: 1122-1134.
- Nakao T, Radua J, Rubia K, et al. Gray matter volume abnormalities in ADHD: voxel-based meta-analysis exploring the effects of age and stimulant medication. Am J Psychiatry 2011; 168: 1154-1163.
- Ellison-Wright I, Ellison-Wright Z, Bullmore E. Structural brain change in Attention Deficit Hyperactivity Disorder identified by meta-analysis. BMC Psychiatry 2008; 8: 51.
- Davenport ND, Karatekin C, White T, et al. Differential fractional anisotropy abnormalities in adolescents with ADHD or schizophrenia. Psychiatry Res 2010; 181: 193-198.
- Valera EM, Faraone SV, Murray KE, et al. Meta-analysis of structural imaging findings in attention-deficit/hyperactivity disorder. Biol Psychiatry 2007; 61: 1361-1369.
- Ivanov I, Bansal R, Hao X, et al. Morphological abnormalities of the thalamus in youths with attention deficit hyperactivity disorder. Am J Psychiatry 2010; 167: 397-408.
- Hoogman M, Rijpkema M, Janss L, et al. Current self-reported symptoms of attention deficit/hyperactivity disorder are associated with total brain volume in healthy adults. PLoS One 2012; 7: e31273.
- Shaw P, Lerch J, Greenstein D, et al. Longitudinal mapping of cortical thickness and clinical outcome in children and adolescents with attention-deficit/hyperactivity disorder. Arch Gen Psychiatry 2006; 63: 540-549.
- Shaw P, Eckstrand K, Sharp W, et al. Attention-deficit/hyperactivity disorder is characterized by a delay in cortical maturation. Proc Natl Acad Sci U S A 2007; 104: 19649-19654.
- Shaw P, Malek M, Watson B, et al. Development of cortical surface area and gyrification in attention-deficit/hyperactivity disorder. Biol Psychiatry 2012; 72: 191-197.
- Makris N, Biederman J, Valera EM, et al. Cortical thinning of the attention and executive function networks in adults with attention-deficit/hyperactivity disorder. Cereb Cortex 2007; 17: 1364-1375.
- Shaw P, Sudre G, Wharton A, et al. White matter microstructure and the variable adult outcome of childhood attention deficit hyperactivity disorder. Neuropsychopharmacology 2015; 40: 746-754.
- Purper-Ouakil D, Ramoz N, Lepagnol-Bestel AM, et al. Neurobiology of attention deficit/hyperactivity disorder. Pediatr Res 2011; 69: 69R-76R.
- Cortese S, Kelly C, Chabernaud C, et al. Toward systems neuroscience of ADHD: a meta-analysis of 55 fMRI studies. Am J Psychiatry 2012; 169: 1038-1055.
- Morein-Zamir S, Dodds C, van Hartevelt TJ, et al. Hypoactivation in right inferior frontal cortex is specifically associated with motor response inhibition in adult ADHD. Hum Brain Mapp 2014; 35: 5141-5152.
- Karch S, Voelker JM, Thalmeier T, et al. Deficits during Voluntary Selection in Adult Patients with ADHD: New Insights from Single-Trial Coupling of Simultaneous EEG/fMRI. Front Psychiatry 2014; 5: 41.
- Dickstein SG, Bannon K, Castellanos FX, et al. The neural correlates of attention deficit hyperactivity disorder: an ALE meta-analysis. J Child Psychol Psychiatry 2006; 47: 1051-1062.
- Cubillo A, Halari R, Giampietro V, et al. Fronto-striatal underactivation during interference inhibition and attention allocation in grown up children with attention deficit/hyperactivity disorder and persistent symptoms. Psychiatry Res 2011; 193: 17-27.
- Peterson BS, Potenza MN, Wang Z, et al. An FMRI study of the effects of psychostimulants on default-mode processing during Stroop task performance in youths with ADHD. Am J Psychiatry 2009; 166: 1286-1294.
- Liddle EB, Hollis C, Batty MJ, et al. Task-related default mode network modulation and inhibitory control in ADHD: effects of motivation and methylphenidate. J Child Psychol Psychiatry 2011; 52: 761-771.
- Volkow ND, Wang GJ, Newcorn J, et al. Brain dopamine transporter levels in treatment and drug naive adults with ADHD. Neuroimage 2007; 34: 1182-1190.
- Volkow ND, Wang GJ, Newcorn J, et al. Depressed dopamine activity in caudate and preliminary evidence of limbic involvement in adults with attention-deficit/hyperactivity disorder. Arch Gen Psychiatry 2007; 64: 932-940.
- Volkow ND, Wang GJ, Kollins SH, et al. Evaluating dopamine reward pathway in ADHD: clinical implications. JAMA 2009; 302: 1084-1091.
- Tomasi D, Volkow ND. Functional connectivity of substantia nigra and ventral tegmental area: maturation during adolescence and effects of ADHD. Cereb Cortex 2014; 24: 935-944.
- Maltezos S, Horder J, Coghlan S, et al. Glutamate/glutamine and neuronal integrity in adults with ADHD: a proton MRS study. Transl Psychiatry 2014; 4: e373.
- Perlov E, Philipsen A, Hesslinger B, et al. Reduced cingulate glutamate/glutamine-to-creatine ratios in adult patients with attention deficit/hyperactivity disorder — a magnet resonance spectroscopy study. J Psychiatr Res 2007; 41: 934-941.
- Thakur GA, Grizenko N, Sengupta SM, et al. The 5-HTTLPR polymorphism of the serotonin transporter gene and short term behavioral response to methylphenidate in children with ADHD. BMC Psychiatry 2010; 10: 50.
- Economidou D, Theobald DE, Robbins TW, et al. Norepinephrine and dopamine modulate impulsivity on the five-choice serial reaction time task through opponent actions in the shell and core sub-regions of the nucleus accumbens. Neuropsychopharmacology 2012; 37: 2057-2066.
- Liu YP, Lin YL, Chuang CH, et al. Alpha adrenergic modulation on effects of norepinephrine transporter inhibitor reboxetine in five-choice serial reaction time task. J Biomed Sci 2009; 16: 72.
- Seeger G, Schloss P, Schmidt MH. Functional polymorphism within the promotor of the serotonin transporter gene is associated with severe hyperkinetic disorders. Mol Psychiatry 2001; 6: 235-238.
- Heal DJ, Cheetham SC, Smith SL. The neuropharmacology of ADHD drugs in vivo: insights on efficacy and safety. Neuropharmacology 2009; 57: 608-618.
- Han DD, Gu HH. Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs. BMC Pharmacol 2006; 6: 6.
- Volkow ND, Wang GJ, Fowler JS, et al. Dopamine transporter occupancies in the human brain induced by therapeutic doses of oral methylphenidate. Am J Psychiatry 1998; 155: 1325-1331.
- Hannestad J, Gallezot JD, Planeta-Wilson B, et al. Clinically relevant doses of methylphenidate significantly occupy norepinephrine transporters in humans in vivo. Biol Psychiatry 2010; 68: 854-860.
- Crunelle CL, van den Brink W, Dom G, et al. Dopamine transporter occupancy by methylphenidate and impulsivity in adult ADHD. Br J Psychiatry 2014; 204: 486-487.
- Somkuwar SS, Kantak KM, Dwoskin LP. Effect of methylphenidate treatment during adolescence on norepinephrine transporter function in orbitofrontal cortex in a rat model of attention deficit hyperactivity disorder. J Neurosci Methods 2015; 252: 55-63.
- Volkow ND, Wang G, Fowler JS, et al. Therapeutic doses of oral methylphenidate signficantly increase extracellular dopamine in the human brain. J Neurosci 2001; 21: RC121.
- Volkow ND, Wang GJ, Tomasi D, et al. Methylphenidate-elicited dopamine increases in ventral striatum are associated with long-term symptom improvement in adults with attention deficit hyperactivity disorder. J Neurosci 2012; 32: 841-849.
- Berridge CW, Devilbiss DM, Andrzejewski ME, et al. Methylphenidate preferentially increases catecholamine neurotransmission within the prefrontal cortex at low doses that enhance cognitive function. Biol Psychiatry 2006; 60: 1111-1120.
- Wall SC, Gu H, Rudnick G. Biogenic amine flux mediated by cloned transporters stably expressed in cultured cell lines: amphetamine specificity for inhibition and efflux. Mol Pharmacol 1995; 47: 544-550.
- Kahlig KM, Galli A. Regulation of dopamine transporter function and plasma membrane expression by dopamine, amphetamine, and cocaine. Eur J Pharmacol 2003; 479: 153-158.
- Schiffer WK, Volkow ND, Fowler JS, et al. Therapeutic doses of amphetamine or methylphenidate differentially increase synaptic and extracellular dopamine. Synapse 2006; 59: 243-251.
- Zhu MY, Shamburger S, Li J, et al. Regulation of the human norepinephrine transporter by cocaine and amphetamine. J Pharmacol Exp Ther 2000; 295: 951-959.
- Avelar AJ, Juliano SA, Garris PA. Amphetamine augments vesicular dopamine release in the dorsal and ventral striatum through different mechanisms. J Neurochem 2013; 125: 373-385.
- Easton N, Steward C, Marshall F, et al. Effects of amphetamine isomers, methylphenidate and atomoxetine on synaptosomal and synaptic vesicle accumulation and release of dopamine and noradrenaline in vitro in the rat brain. Neuropharmacology 2007; 52: 405-414.
- Johnson LA, Furman CA, Zhang M, et al. Rapid delivery of the dopamine transporter to the plasmalemmal membrane upon amphetamine stimulation. Neuropharmacology 2005; 49: 750-758.
- Kahlig KM, Binda F, Khoshbouei H, et al. Amphetamine induces dopamine efflux through a dopamine transporter channel. Proc Natl Acad Sci U S A 2005; 102: 3495-3500.
- Sulzer D, Chen TK, Lau YY, et al. Amphetamine redistributes dopamine from synaptic vesicles to the cytosol and promotes reverse transport. J Neurosci 1995; 15: 4102-4108.
- Partilla JS, Dempsey AG, Nagpal AS, et al. Interaction of amphetamines and related compounds at the vesicular monoamine transporter. J Pharmacol Exp Ther 2006; 319: 237-246.
- Teng L, Crooks PA, Dwoskin LP. Lobeline displaces [3H]dihydrotetrabenazine binding and releases [3H]dopamine from rat striatal synaptic vesicles: comparison with d-amphetamine. J Neurochem 1998; 71: 258-265.
- Wallace LJ. Effects of amphetamine on subcellular distribution of dopamine and DOPAC. Synapse 2012; 66: 592-607.
- Johnson LA, Guptaroy B, Lund D, et al. Regulation of amphetamine-stimulated dopamine efflux by protein kinase C beta. J Biol Chem 2005; 280: 10914-10919.
- Jones SR, Gainetdinov RR, Wightman RM, et al. Mechanisms of amphetamine action revealed in mice lacking the dopamine transporter. J Neurosci 1998; 18: 1979-1986.
- Bymaster FP, Katner JS, Nelson DL, et al. Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: a potential mechanism for efficacy in attention deficit / hyperactivity disorder. Neuropsychopharmacology 2002; 27: 699-711.
- Swanson CJ, Perry KW, Koch-Krueger S, et al. Effect of the attention deficit/hyperactivity disorder drug atomoxetine on extracellular concentrations of norepinephrine and dopamine in several brain regions of the rat. Neuropharmacology 2006; 50: 755-760.
- Wang M, Ramos BP, Paspalas CD, et al. Alpha2A-adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex. Cell 2007; 129: 397-410.
- Yi F, Liu SS, Luo F, et al. Signaling mechanism underlying alpha2A -adrenergic suppression of excitatory synaptic transmission in the medial prefrontal cortex of rats. Eur J Neurosci 2013; 38: 2364-2373.
- Ji XH, Ji JZ, Zhang H, et al. Stimulation of alpha2-adrenoceptors suppresses excitatory synaptic transmission in the medial prefrontal cortex of rat. Neuropsychopharmacology 2008; 33: 2263-2271.
- Grijalba B, Callado LF, Javier MJ, et al. Alpha 2-adrenoceptor subtypes in the human brain: a pharmacological delineation of [3H]RX-821002 binding to membranes and tissue sections. Eur J Pharmacol 1996; 310: 83-93.
- Kawaura K, Karasawa J, Chaki S, et al. Stimulation of postsynapse adrenergic alpha2A receptor improves attention/cognition performance in an animal model of attention deficit hyperactivity disorder. Behav Brain Res 2014; 270: 349-356.
- Uhlen S, Wikberg JE. Delineation of rat kidney alpha 2A- and alpha 2B-adrenoceptors with [3H]RX821002 radioligand binding: computer modelling reveals that guanfacine is an alpha 2A-selective compound. Eur J Pharmacol 1991; 202: 235-243.
- Coupry I, Lachaud V, Podevin RA, et al. Different affinities of alpha 2-agonists for imidazoline and alpha 2-adrenergic receptors. Am J Hypertens 1989; 2: 468-470.
- George MS, Abbott LF, Siegelbaum SA. HCN hyperpolarization-activated cation channels inhibit EPSPs by interactions with M-type K(+) channels. Nat Neurosci 2009; 12: 577-584.
- Ren WW, Liu Y, Li BM. Stimulation of α(2A)-adrenoceptors promotes the maturation of dendritic spines in cultured neurons of the medial prefrontal cortex. Mol Cell Neurosci 2012; 49: 205-216.
- Hu J, Vidovic M, Chen MM, et al. Activation of alpha 2A adrenoceptors alters dendritic spine development and the expression of spinophilin in cultured cortical neurones. Brain Res 2008; 1199: 37-45.
- Song ZM, Abou-Zeid O, Fang YY. alpha2a adrenoceptors regulate phosphorylation of microtubule-associated protein-2 in cultured cortical neurons. Neuroscience 2004; 123: 405-418.