ADHD

Clinical picture (children and adolescents)

• Core domains: inattention (difficulty sustaining attention, forgetfulness, disorganization), hyperactivity and impulsivity (restlessness, difficulty waiting one's turn, interrupting). Symptoms begin before age 12, appear in more than one setting (home, school) and impair functioning. A
• Prevalence: about 3.4% of children and adolescents worldwide (Polanczyk et al., 2015); 5.3% in an earlier meta-regression (Polanczyk et al., 2007). The difference between estimates comes largely from diagnostic criteria and methods, not from country. A
• Sex: diagnosed more often in boys; the gap is larger in clinical than in community samples. In girls, a quieter, mainly inattentive presentation can delay diagnosis (Faraone et al., 2021). B
• Across development: hyperactivity decreases with age, while inattention and inner restlessness persist longer. In a substantial share of those diagnosed in childhood, symptoms continue to affect functioning in adulthood (Faraone et al., 2021). A
• Common co-occurring conditions: oppositional defiant disorder, specific learning disorder, anxiety disorders, tic disorders, autism spectrum disorder, developmental coordination disorder; in adolescence, substance use and accidents. A

Circuits and networks

• Dorsolateral Prefrontal Cortex (dorsolateral prefrontal cortex): working memory, planning and top-down attentional control; the delay in cortical maturation is most marked in frontal regions (Shaw et al., 2007). B
• Anterior Cingulate Cortex (anterior cingulate cortex): error monitoring and conflict detection; its connectivity with the DMN is altered during attentional fluctuations (Castellanos et al., 2008). B
• Caudate Nucleus, Putamen (striatum) and Nucleus Accumbens (nucleus accumbens): fronto-striatal loops and reward/motivation. In ENIGMA, accumbens (d = −0.15), caudate (d = −0.11) and putamen (d = −0.14) volumes were smaller; differences were clearer in children (Hoogman et al., 2017). A
• Amygdala and Hippocampus: in ENIGMA, amygdala (d = −0.19) and hippocampus (d = −0.11) volumes were smaller; linked to difficulties in emotion regulation (Hoogman et al., 2017). A
• Ventral Tegmental Area and Substantia Nigra (midbrain dopamine nuclei): sources of mesolimbic and nigrostriatal dopamine; the system targeted by medication.
• Locus Coeruleus (locus coeruleus): source of noradrenaline; tunes arousal and attention.
• Cerebellum: timing and motor control; fronto-cerebellar loops.
• Inferior Parietal Lobule and Superior Parietal Lobule (parietal cortex): posterior nodes of the attention networks.
• Networks: the Frontoparietal control network (frontoparietal control) and Dorsal attention network (dorsal attention) networks do not engage enough during tasks; the Default mode network (DMN) (default mode) is not silenced enough during tasks and causes lapses of attention (the "default mode interference" hypothesis; Sonuga-Barke and Castellanos, 2007). This is at the level of a hypothesis. C

Neurotransmitter systems

• Dopamine (dopamine): reward processing and motivation; in unmedicated adults, dopamine transporter and D2/D3 receptor binding in the reward pathway were low and related to inattention (Volkow et al., 2009). The association is moderate to weak. B
• Noradrenaline (noradrenaline): α2A receptors in the prefrontal cortex are needed for working memory and attention; atomoxetine and guanfacine target this system. B
• Heritability is high: 74% on average in twin studies (Faraone and Larsson, 2019). Individual genetic variants have very small effects; risk comes from the sum of many genes. A

Imaging and neurobiological findings

• ENIGMA-ADHD (1,713 with ADHD, 1,529 controls): accumbens, amygdala, caudate, hippocampus, putamen and intracranial volume smaller; effect sizes small (d = −0.10 to −0.19), largest in the amygdala. Differences were clear under age 15 and not significant in adults. Medication use and comorbid diagnoses did not change the results (Hoogman et al., 2017). A
• These are group-level differences; brain imaging cannot diagnose ADHD in an individual. A

Developmental course

• The cortex matures in the normal order (back to front) but is delayed by about 3 years on average; the delay is greatest in frontal regions. The motor cortex matures slightly earlier (Shaw et al., 2007; 446 children, 824 MRI scans). B
• This finding supports seeing ADHD as a maturational delay rather than a permanent "impairment"; however, the delay cannot be detected in a single person's scan. B

Treatment and the systems it targets

• Preschool (under 5): parent training programs are first line; medication is considered only with a second specialist opinion (NICE NG87). A
• Behavioral interventions (parent training, classroom adjustments): small to moderate effects on symptoms and co-occurring oppositional problems; the effect is largest for raters closest to treatment; 21 studies, more than 2,200 children (Groenman et al., 2022). B
• Medication (children and adolescents): methylphenidate is first choice in the short term; amphetamines in adults. Network meta-analysis of 133 double-blind trials (Cortese et al., 2018). Long-term data are limited. A
  • Methylphenidate: blocks the dopamine and noradrenaline transporters (DAT, NET); raises dopamine and noradrenaline in the striatum and prefrontal cortex. A
  • Amphetamines: besides blocking transporters, also increase dopamine and noradrenaline release. A
  • Atomoxetine: selective noradrenaline reuptake inhibitor; also raises dopamine in the prefrontal cortex. B
  • Guanfacine and clonidine: α2A adrenergic receptor agonists; strengthen signal transmission in the prefrontal cortex. B

Link to the book (The Green Walnut on the Couch)

• In the book (translated from the Turkish original):
  • SEEKING system, clinical: "anhedonia, depression, addiction, ADHD, mania, and excessive attribution of meaning in psychosis".
  • PLAY system, clinical: "ADHD, social play in autism, traumatic play, depression".
  • Mesolimbic dopamine pathway, where it appears in the book: "the neuroanatomy of SEEKING, the mechanism of action of methylphenidate (blocking dopamine and noradrenaline reuptake through DAT/NET blockade), hypoactivation of this pathway in depression, ADHD hypotheses (Chapters 7–8)."
  • The book also covers: the chronic low tonic dopamine hypothesis in ADHD (Chapter 7), delayed cortical maturation in ADHD (Chapter 7), attention regulation and the ACC in ADHD (Chapter 7).

In the atlas

Regions

Core structures in bold.

Networks

Neurotransmitter pathways

Panksepp systems

References

1. Castellanos FX et al. (2008). Cingulate-precuneus interactions: a new locus of dysfunction in adult attention-deficit/hyperactivity disorder. Biological Psychiatry, 63(3), 332–337. Search PubMed
2. Cortese S et al. (2018). Comparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta-analysis. Lancet Psychiatry, 5(9), 727–738. Search PubMed
3. Faraone SV, Larsson H (2019). Genetics of attention deficit hyperactivity disorder. Molecular Psychiatry, 24(4), 562–575. PMCID: PMC6477889. Search PubMed
4. Faraone SV et al. (2021). The World Federation of ADHD International Consensus Statement: 208 evidence-based conclusions about the disorder. Neuroscience & Biobehavioral Reviews, 128, 789–818. DOI: 10.1016/j.neubiorev.2021.01.022.
5. Groenman AP et al. (2022). An individual participant data meta-analysis: behavioral treatments for children and adolescents with attention-deficit/hyperactivity disorder. JAACAP, 61(2), 144–158. DOI: 10.1016/j.jaac.2021.02.024.
6. Hoogman M et al. (2017). Subcortical brain volume differences in participants with attention deficit hyperactivity disorder in children and adults: a cross-sectional mega-analysis. Lancet Psychiatry, 4(4), 310–319. Search PubMed
7. NICE (2018, with updates). Attention deficit hyperactivity disorder: diagnosis and management (NG87). Search PubMed
8. Panksepp J, Burgdorf J, Turner C, Gordon N (2003). Modeling ADHD-type arousal with unilateral frontal cortex damage in rats and beneficial effects of play therapy. Brain and Cognition, 52(1), 97–105. Search PubMed
9. Polanczyk G et al. (2007). The worldwide prevalence of ADHD: a systematic review and metaregression analysis. American Journal of Psychiatry, 164(6), 942–948. Search PubMed
10. Polanczyk GV et al. (2015). Annual research review: A meta-analysis of the worldwide prevalence of mental disorders in children and adolescents. Journal of Child Psychology and Psychiatry, 56(3), 345–365. Search PubMed
11. Shaw P et al. (2007). Attention-deficit/hyperactivity disorder is characterized by a delay in cortical maturation. PNAS, 104(49), 19649–19654. PMCID: PMC2148352. Search PubMed
12. Sonuga-Barke EJS, Castellanos FX (2007). Spontaneous attentional fluctuations in impaired states and pathological conditions: a neurobiological hypothesis. Neuroscience & Biobehavioral Reviews, 31(7), 977–986. Search PubMed
13. Volkow ND et al. (2009). Evaluating dopamine reward pathway in ADHD: clinical implications. JAMA, 302(10), 1084–1091. PMCID: PMC2958516. Search PubMed