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Evidence exists for the association between attention-deficit hyperactivity disorder (ADHD), or hyperkinetic disorder (HKD), and possible structural,1-12 functional13-20 and neurotransmitter21-27 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 and Professor Philip Asherson


Having watched these two videos on “ADHD and the brain”, would you use them in consultation with your patients to demonstrate that ADHD may be a life-long disease?

Structural

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 abnormalities4,5
  • Reduced total brain volume and volume of some brain structures1,6-8
  • Cortical differences
    • Delayed cortical maturation in children/adolescents9-11
    • Reduced cortical thickness in adults.1,12

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).10 Delays were most prominent in prefrontal regions, which are important for control of cognitive processes, including attention and motor planning (Figures).

Figure: Cortical maturation in patients with and without ADHD. Reproduced with kind permission from Shaw P et al. Proc Natl Acad Sci U S A 2007; 104: 19649-19654.10

Cortical maturation in patients with and without ADHD

Figure: Rate of cortical maturation in patients with and without ADHD. Reproduced with kind permission from Shaw P et al. Proc Natl Acad Sci U S A 2007; 104: 19649-19654.10

Rate of cortical maturation in patients with and without ADHD

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).12

Figure: Grey matter density and cortical thickness in patients with ADHD. Reproduced with kind permission from Proal E et al. Arch Gen Psychiatry 2011; 68: 1122-1134.1

Grey matter density and cortical thickness in patients with and without ADHD

By using an online version of the ADHD symptoms criteria detailed in the Diagnostic and Statistical Manual of Mental Disorders – 4th Edition (DSM-IV), and by taking MRI scans to calculate total brain volumes, structural abnormalities in the brain associated with self-reported ADHD symptoms in healthy adults (aged 18–35 years; n=652) were investigated. A significant association between the number of self-reported ADHD symptoms and total brain volume was found, such that healthy adults who reported ≥6 symptoms had a lower brain volume than those who reported ≤3 symptoms of ADHD. This study suggests that self-reported ADHD symptoms in healthy adults may have neurobiological underpinnings.8

Figure: Total brain volume was associated with total number of self-reported ADHD symptoms (p=0.014 in healthy adults). Reproduced with kind permission from Hoogman M et al. PLoS One 2012; 7: e31273.8

Total brain volume was associated with total number of self-reported ADHD symptoms (p=0.014 in healthy adults)

Functional

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 from Purper-Ouakil D et al. Pediatr Res 2011; 69: 69R-79R.13

Functional abnormalities in the ADHD brain

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.12,14-20

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

Figure: Meta-analysis of 16 functional MRI studies: patterns of activation differ significantly between networks (p<0.0001). Reproduced with kind permission from Cortese S et al. Am J Psychiatry 2012; 169: 1038-1055.14

Meta-analysis of functional MRI studies: patterns of activation

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 ADHD.13
  • 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 healthy controls, in particular:

  • Over-activation (reduced suppression) of the default mode network during task performance.19,20
  • Under-activation of fronto-striatal and fronto-parietal circuits, and other frontal brain region.14-18
  • Under-activation of systems involved in executive function and attention.12,14

Neurotransmitter alterations

Catecholamine signalling systems may be disrupted in the ADHD brain.

There are alterations in activity and communication between different regions and networks of the ADHD brain,28-31 and there is evidence to suggest that disruptions in the relay of messages between neurons by the chemicals dopamine and noradrenaline (in animal studies) also contribute to the neurobiology of ADHD.21,22,32

Maturation of certain dopaminergic neural pathways appears to be delayed in children and adolescents with ADHD.33

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.22,34,35

In rats, interference with the noradrenaline system impacts on:21,23

  • Impulsivity
  • Attentional accuracy
  • Response control.

Established ADHD treatments are known to interact with the dopamine and noradrenaline systems.24

Emerging evidence suggests possible roles for other signalling systems

Polymorphisms in the serotonin transporter gene have been associated with differential response to ADHD treatment36 and the presence of comorbid conduct disorder in children and adolescents with HKD.25

In adults with ADHD, there is emerging evidence that deficiencies in glutamate signalling may play a role in modulating neurotransmitter release in some brain regions.26,27

  1. 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.
  2. 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.
  3. 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.
  4. Davenport ND, Karatekin C, White T, et al. Differential fractional anisotropy abnormalities in adolescents with ADHD or schizophrenia. Psychiatry Res 2010; 181: 193-198.
  5. 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.
  6. 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.
  7. 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.
  8. 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.
  9. 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.
  10. 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.
  11. 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.
  12. 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.
  13. Purper-Ouakil D, Ramoz N, Lepagnol-Bestel AM, et al. Neurobiology of attention deficit/hyperactivity disorder. Pediatr Res 2011; 69: 69R-76R.
  14. 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.
  15. 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.
  16. 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.
  17. 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.
  18. 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.
  19. 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.
  20. 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.
  21. 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.
  22. 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.
  23. 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.
  24. Del Campo N, Chamberlain SR, Sahakian BJ, et al. The roles of dopamine and noradrenaline in the pathophysiology and treatment of attention-deficit/hyperactivity disorder. Biol Psychiatry 2011; 69: e145-157.
  25. 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.
  26. 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.
  27. 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.
  28. Cocchi L, Bramati IE, Zalesky A, et al. Altered functional brain connectivity in a non-clinical sample of young adults with attention-deficit/hyperactivity disorder. J Neurosci 2012; 32: 17753-17761.
  29. Hoekzema E, Carmona S, Ramos-Quiroga JA, et al. An independent components and functional connectivity analysis of resting state fMRI data points to neural network dysregulation in adult ADHD. Hum Brain Mapp 2014; 35: 1261-1272.
  30. Mattfeld AT, Gabrieli JD, Biederman J, et al. Brain differences between persistent and remitted attention deficit hyperactivity disorder. Brain 2014; 137: 2423-2428.
  31. McCarthy H, Skokauskas N, Mulligan A, et al. Attention network hypoconnectivity with default and affective network hyperconnectivity in adults diagnosed with attention-deficit/hyperactivity disorder in childhood. JAMA Psychiatry 2013; 70: 1329-1337.
  32. 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.
  33. 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.
  34. 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.
  35. Volkow ND, Wang GJ, Kollins SH, et al. Evaluating dopamine reward pathway in ADHD: clinical implications. JAMA 2009; 302: 1084-1091.
  36. 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.
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