What is the pathophysiology of attention-deficit/hyperactivity disorder (ADHD)?

Pathophysiology of ADHD

Neuroanatomical Abnormalities

ADHD involves structural and functional abnormalities in catecholamine-rich fronto-subcortical brain circuits, particularly affecting the frontal lobes, basal ganglia, limbic system, and cerebellar vermis. 1, 2

• Volumetric reductions have been consistently demonstrated in the frontal lobes, caudate nucleus, and cerebellar vermis in patients with ADHD 1, 2
• Decreased neural activity occurs in these same regions, particularly in areas rich in dopamine innervation 1
• The frontal-subcortical dysfunction represents a core pathophysiological feature that underlies the behavioral symptoms of inattention, hyperactivity, and impulsivity 3, 4

Neurotransmitter Dysfunction

Dysregulation of dopaminergic neurotransmission, particularly involving dopamine transporters, represents the primary neurochemical abnormality in ADHD. 1, 3

• Dysfunction of dopamine transporters (DAT) is a central feature, which methylphenidate directly modulates to produce therapeutic effects 1
• Noradrenergic dysfunction also contributes to ADHD pathophysiology, as both catecholamine systems are necessary for clinical efficacy of pharmacological treatments 4
• Dopamine cell firing activity normally transfers from reinforcing events to earlier behavioral sequence time-points as reinforcement becomes predictable; this transfer mechanism fails in ADHD 2

Altered Reinforcement Mechanisms

Altered response to reinforcement, particularly abnormal sensitivity to delay of reinforcement, plays a central role in ADHD symptomatology. 2

• Patients with ADHD demonstrate impaired executive function and reward system dysfunction, described as the "dual pathway model" 1
• The failure of dopamine signaling to transfer appropriately during reinforcement learning gives rise to many core ADHD symptoms 2
• Dysfunction of the default mode network contributes to the inability to sustain attention and regulate behavior appropriately 1

Genetic Architecture

ADHD demonstrates high heritability (approximately 80%), with multiple genes of small individual effect contributing to risk, particularly genes regulating dopamine synthesis and transmission. 5, 4

• Twin studies attribute approximately 80% of ADHD etiology to genetic factors 4
• Candidate genes include DRD4 (dopamine receptor D4) and DAT (dopamine transporter), which are relevant for ADHD pathophysiology 4
• Genetic variations influence structural and functional brain imaging phenotypes in ADHD, affecting neural abnormalities and neurodevelopmental trajectories 5
• Epigenetic modifications and gene-environment interactions also contribute to ADHD development, though the precise mechanisms remain incompletely understood 1

Environmental Risk Factors

Prenatal nicotine exposure and psychosocial adversity represent established environmental risk factors that interact with genetic susceptibility. 4

• Prenatal exposure to nicotine has been identified as a significant environmental risk factor for ADHD 4
• Psychosocial adversity contributes to ADHD risk independently of genetic factors 4
• Severe brain injuries, neuroinflammation, consanguineous marriages, and premature birth also contribute to ADHD risk 5

Neuropsychological Deficits

Executive function impairments and motivational deficits represent the two main neuropsychological domains affected in ADHD, though neither is specific to the disorder. 2

• Executive function deficits affect planning, organization, working memory, and behavioral inhibition 2
• Motivational differences, particularly altered reinforcement sensitivity, are reliably documented in ADHD 2
• These neuropsychological differences arise from the underlying fronto-subcortical dysfunction and dopaminergic abnormalities 2, 3

Clinical Heterogeneity

ADHD is a multifactorial and heterogeneous disorder with variable presentation across the lifespan, requiring recognition of its chronic nature. 6, 5

• The American Academy of Pediatrics recognizes ADHD as a chronic condition requiring management principles consistent with the chronic care model 6
• Symptoms persist from childhood into adulthood in 55-66% of cases 5
• Comorbidity with conduct, depressive, bipolar, and anxiety disorders is a key clinical feature throughout the lifecycle 4