Neuroimaging studies have associated various structural,1-6 functional,7,8 electrical activity9 and chemical10,11 correlates with attention-deficit hyperactivity disorder (ADHD) in children, adolescents and adults.
Brain imaging studies have associated structural abnormalities with ADHD in children and adolescents,1-6,12,13 including:
- Delayed cortical development12,13
- Cortical thinning, and reductions in the volume of grey and white matter5,6,12
- Reductions in the volume of several regions of the brain, including: the posterior inferior vermis; splenium of the corpus callosum; total and right cerebral volume; right caudate; right global pallidus; right anterior frontal region; cerebellum; temporal lobe; and pulvinar2,3,14,15 (Figure).
Regions of the brain implicated in ADHD in children and adolescents1-6,8,13,15,16
Brain abnormalities associated with ADHD in children and adolescents may persist into adulthood.17-21 MRI studies in adults have yielded similar evidence as described above with regards to reduction in the volume of several regions of the brain, cortical thickness, and grey matter;19,20 particularly in the frontal cortex of the brain, compared with controls;18-21 as well as structural abnormalities in connecting brain cells within networks that regulate attention and emotion.22
Brain structures implicated in ADHD correspond to brain networks, including some involving frontal regions, and some that support executive function and attention (Figure).23
Functional circuits involved in the pathophysiology of ADHD as identified in a review of the neurobiology of ADHD23
Activation abnormalities are associated with ADHD in children, adolescents and adults,24,25 with meta-analyses demonstrating significant activation reductions in various frontal regions of the brain including the anterior cingulate; dorsolateral prefrontal and inferior prefrontal cortices; and related regions including the basal ganglia, thalamus, and areas of parietal cortex.8
Furthermore, atypical functional network connectivity in the default mode network (a network of brain regions that are active during resting) has been observed in children and adolescents with ADHD.26
In addition, there is some evidence that patterns of under- and over-activation of certain regions of the brain differ between children and adolescents versus adults, as indicated by a meta-analysis of 55 fMRI studies which compared children, adolescents and adults with ADHD with healthy controls (Table).7
|Activation patterns in the brain as indicated by a meta-analysis of 55 fMRI studies7|
|Age group||Regions associated with over-activation||Regions associated with under-activation|
|Children and adolescents||
A meta-analysis of worldwide studies reported that quantitative electroencephalography (EEG; the recording of electrical activity along the scalp) may be used to identify changes in brain electrical activity. An increase in the theta/beta (two EEG frequency bands) ratio was observed in all studies included in the review.27 Further research is required to substantiate EEG findings for use as a biomarker in ADHD diagnosis.28 Individual EEG patterns associated with ADHD are under early investigation for utility in personalising neurofeedback protocols — computer-assisted training to self-regulate brainwave activity — as non-pharmacological treatment options for ADHD.29
Delayed maturation of certain dopaminergic neural pathways has been observed in children and adolescents with ADHD,30 as well as an imbalance in the levels of both dopamine and noradrenaline in the brains of children, adolescents and adults with ADHD compared with healthy controls.10,11,31,32 Dopamine and noradrenaline have been implicated in influencing impulsivity,10 and dopamine in influencing inattention.11
Emerging evidence also suggests possible roles for other signalling systems in the neurobiology of ADHD. Deficiencies in glutamate signalling in some regions of the brain may have a modulatory role in adults with ADHD.33,34 Furthermore, polymorphisms in the serotonin transporter gene have been associated with differential response to ADHD treatment,35 and the presence of comorbid conduct disorder in children and adolescents with hyperkinetic disorder (an alternative description of ADHD).36
- Davenport ND, Karatekin C, White T, et al. Differential fractional anisotropy abnormalities in adolescents with ADHD or schizophrenia. Psychiatry Res 2010; 181: 193-198.
- 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.
- Kobel M, Bechtel N, Specht K, et al. Structural and functional imaging approaches in attention deficit/hyperactivity disorder: does the temporal lobe play a key role? Psychiatry Res 2010; 183: 230-236.
- 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.
- 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.
- Pavuluri MN, Yang S, Kamineni K, et al. Diffusion tensor imaging study of white matter fiber tracts in pediatric bipolar disorder and attention-deficit/hyperactivity disorder. Biol Psychiatry 2009; 65: 586-593.
- 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.
- 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.
- Quintana H, Snyder SM, Purnell W, et al. Comparison of a standard psychiatric evaluation to rating scales and EEG in the differential diagnosis of attention-deficit/hyperactivity disorder. Psychiatry Res 2007; 152: 211-222.
- 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.
- Volkow ND, Wang GJ, Kollins SH, et al. Evaluating dopamine reward pathway in ADHD: clinical implications. JAMA 2009; 302: 1084-1091.
- 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, Malek M, Watson B, et al. Development of cortical surface area and gyrification in attention-deficit/hyperactivity disorder. Biol Psychiatry 2012; 72: 191-197.
- Castellanos FX, Giedd JN, Marsh WL, et al. Quantitative brain magnetic resonance imaging in attention-deficit hyperactivity disorder. Arch Gen Psychiatry 1996; 53: 607-616.
- Valera EM, Faraone S, Murray KE, et al. Meta-analysis of structural imaging findings in attention-deficit/hyperactivity disorder. Biol Psychiatry 2007; 61: 1369.
- Snell RS. Clinical Neuroanatomy for Medical Students in: Nervous system - anatomy and histology. Third edition. USA: 1992.
- Hart H, Radua J, Nakao T, et al. Meta-analysis of functional magnetic resonance imaging studies of inhibition and attention in attention-deficit/hyperactivity disorder: exploring task-specific, stimulant medication, and age effects. JAMA Psychiatry 2013; 70: 185-198.
- 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.
- 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.
- Makris N, Liang L, Biederman J, et al. Toward Defining the Neural Substrates of ADHD: A Controlled Structural MRI Study in Medication-Naive Adults. J Atten Disord 2013.
- 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.
- Shaw P, Sudre G, Wharton A, et al. White Matter Microstructure and the Variable Adult Outcome of Childhood Attention Deficit Hyperactivity Disorder. Neuropsychopharmacology 2014.
- Purper-Ouakil D, Ramoz N, Lepagnol-Bestel AM, et al. Neurobiology of attention deficit/hyperactivity disorder. Pediatr Res 2011; 69: 69R-76R.
- Wang X, Jiao Y, Tang T, et al. Altered regional homogeneity patterns in adults with attention-deficit hyperactivity disorder. Eur J Radiol 2013; 82: 1552-1557.
- 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.
- Fair DA, Posner J, Nagel BJ, et al. Atypical default network connectivity in youth with attention-deficit/hyperactivity disorder. Biol Psychiatry 2010; 68: 1084-1091.
- Snyder SM, Hall JR. A meta-analysis of quantitative EEG power associated with attention-deficit hyperactivity disorder. J Clin Neurophysiol 2006; 23: 440-455.
- Loo SK, Makeig S. Clinical utility of EEG in attention-deficit/hyperactivity disorder: a research update. Neurotherapeutics 2012; 9: 569-587.
- Arns M, Drinkenburg W, Leon KJ. The effects of QEEG-informed neurofeedback in ADHD: an open-label pilot study. Appl Psychophysiol Biofeedback 2012; 37: 171-180.
- 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.
- del Campo N, Fryer TD, Hong YT, et al. A positron emission tomography study of nigro-striatal dopaminergic mechanisms underlying attention: implications for ADHD and its treatment. Brain 2013; 136: 3252-3270.
- 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.
- Maltezos S, Horder J, Coghlan S, et al. Glutamate/glutamine and neuronal integrity in adults with ADHD: a proton MRS study. Trans Psychiatr 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 behavioural response to methylphenidate in children with ADHD. BMS Psychiatry 2010; 10: 50.
- Seeger G, Schloss P, Schmidt MH. Functional polymorphism within the promoter of the serotonin transporter gene is associated with severe hyperkinetic disorders. Mol Psychiatr 2001; 6: 235-238.