ADHD

Attention-Deficit Hyperactivity Disorder (ADHD)

• ADHD is a neurodevelopmental disorder characterized by inattention, impulsiveness, and hyperactivity.
• The DSM 5-TR (American Psychiatric Association, 2022) defines two main domains with three presentations: inattention, hyperactivity/impulsivity, and combined.
• Symptoms vary across childhood and adulthood (at least 6/9 in childhood, 5/9 in adulthood).

Inattentive Symptoms

• Often fails to pay attention to details or makes careless mistakes
• Has difficulty concentrating (e.g., movies, books)
• Does not seem to listen when spoken to directly
• Does not follow through on instructions and fails to finish tasks
• Has difficulty organizing daily activities
• Tends to procrastinate, especially tasks requiring mental effort
• Often loses things
• Is easily distracted by external stimuli
• Is often forgetful in daily activities

Impulsivity-Hyperactivity Symptoms

• Often fidgets
• Cannot stay seated for long
• Feels restless
• Talks excessively
• Has more energy than other people
• Has difficulty awaiting turn
• Often says things without thinking
• Often interrupts others

Prevalence and Demographic Differences

• 4-6% of children and 2-3% of adults have ADHD
• A 2.5:1 male-to-female ratio is observed in children (referral bias)
• No significant differences in prevalence between low- and high-income countries
• ADHD often persists into adolescence (50-80%) and adulthood (30-50%), although with differing symptomatology.

Adult Life

• Functional impairment and presence of typical ADHD symptoms decrease with age.
• However, some individuals continue to experience significant symptoms long into adulthood.

Clinical Cases

• Various examples of patients with different types of ADHD symptoms and how they present have been shown
• Case examples include a 5-year-old girl, a 12-year-old girl, and a 22-year-old man, demonstrating varied behaviors and situations.

ADHD and Everyday Life

• ADHD can affect academic performance, employment and lead to unhealthy behaviours, addictions, and higher risk of physical injury.
• Additional issues include health problems (e.g., obesity, vision problems), emotional and conduct problems (e.g., bullying, criminal behaviors) and teen pregnancies.

Diagnosis

• Age-inappropriate levels of hyperactivity/impulsivity and/or inattentive symptoms for at least 6 months
• Symptoms are observed across multiple settings (e.g., home, school)
• Symptoms affect daily life and functioning
• Some symptoms were observed in early or middle childhood.
• No other disorder can better explain the symptoms.
• Objective markers (child, parent/caregiver), collateral info (school), and rating scales (e.g., Conner's Rating Scales) or neuropsychological tests support diagnosis.

Etiology

• ADHD is not simply caused by genetics or environment, but a combination of risk factors that accumulate to a threshold.
• Genetic factors are influenced by polygenic risk (no single gene) and familiarity.
• Environmental factors, such as toxins, alcohol, and cigarette exposure during pregnancy, nutrient deficiencies, maternal obesity, stress, infection, and poverty, affect the developing brain.

Neurobiology of ADHD

• ADHD symptoms are associated with structural and functional differences in fronto-striatal brain networks.
• Other areas affected include parietal and cerebellar connections.
• Neurological differences are apparent in brain pathways and circuitry.

Catecholaminergic Pathways

• Dopamine (DA) and norepinephrine (NE) modulate brain networks involved in attention, inhibition, motivation, and emotion.
• Activity in these networks is influenced by DA and NE.
• A disruption or imbalance in catecholaminergic pathways is implicated in ADHD pathophysiology

Mesocortical and Mesolimbic Dopaminergic Pathways

• These pathways are involved in executive functions and affect regulation, and their function may be disrupted in ADHD.
• They project to and from the prefrontal and limbic regions.

Noradrenergic Pathways

• Noradrenergic pathways are distributed throughout the brain.
• These originate in the locus coeruleus (LC) which is in the brainstem and communicate with cortical regions of the brain.
• Noradrenergic modulation of brain functions occurs as part of arousal state and attention.

Cortico-Striatal Loops

• These loops are fronto-striatal pathways that have been heavily studied in ADHD research due to cognitive, affective, and motor regulation.
• They are implicated in motor planning and movements; cognitive task learning; and emotional responses, with functions impaired in ADHD.

Stimulant Effects on Brain Regional Structure and Function

• Some early MRI imaging studies suggested an effect on grey matter due to stimulant treatment, however, other studies disagreed.
• Studies have shown that a single dose of stimulants improves brain activity and functional connectivity toward neurotypical levels in aspects such as attention, and response inhibition.
• However, conclusive evidence for the effect of ongoing stimulant treatment on long-term outcomes is not clear.

Stimulant Effects on Brain Structural and Functional Connectivity

• A systematic review of diffusion imaging studies in ADHD observed subtle white matter differences in individuals treated versus untreated.
• Functional connectivity studies suggest short-term stimulant treatment improves functional connectivity towards neurotypical peers, with an effect on task-related fronto-striatal/parietal networks and suppression of the default-mode network (DMN).

Non-Stimulants

• Atomoxetine is a selective NE reuptake inhibitor that primarily targets the prefrontal cortex.
• Guanfacine, a selective alpha-2A receptor agonist, also acts within the prefrontal cortex, promoting NE effects, but with milder sedative and hypotensive effects than clonidine.

Predictors of Treatment Response in Adult ADHD

• A longitudinal placebo-controlled neuroimaging study may identify biological markers predicting treatment response.
• Brain connectivity, such as that of the left superior longitudinal fasciculus (SLF I) volume, can be important factors when considering treatment effectiveness.

Other MRI Modalities for Identifying Predictors

• Alternative MRI modalities may be used, including functional connectivity analysis and structural MRI with virtual histology.
• An acute dose of stimulants may elicit functional changes in patients, leading to a more neurotypical functional connectivity pattern.
• Potential brain alterations and differences in response mechanisms, such as gene expression, are observable.

Machine Learning and Virtual Histology

• Pre-treatment brain characteristics, along with clinical traits, may identify factors correlating with treatment response.
• Combining biological and clinical features can create a more accurate profile for treatment efficacy.

Management of ADHD (NICE Guidelines)

• Pre-schoolers (<5 years): ADHD-focused group parent training, with specialist advice for considerable medication,if symptoms persist in more than one domain
• Children and adolescents (≥5 years): Group-based ADHD support; medication (methylphenidate, lisdexamfetamine, or atomoxetine), or non-stimulant options (e.g., guanfacine); parent training; Cognitive Behavioral Therapy for persistent symptoms
• Adults: Medication (methylphenidate, lisdexamfetamine, or atomoxetine); supportive psychotherapy if medication isn't effective.

Indication for ADHD Medication

• Moderate or severe impairment is a common criterion for stimulant medication use.
• Methylphenidate (e.g., Ritalin, Concerta) is a first-line stimulant.
• Alternative options include lisdexamfetamine, atomoxetine, or guanfacine.

Cautions/Side-Effects

• Stimulants may increase blood pressure and heart rate.
• Stimulants may decrease appetite.
• Stimulants may affect sleep.
• Therefore, routine monitoring of BP, HR, height, and weight is crucial during treatment.

Different Formulations

• Different stimulant formulations (e.g., Ritalin, Concerta) have varying release profiles, with potential implications for effectiveness and side effect management.

MPH vs Amphetamines

• Methylphenidate (MPH) and amphetamines are stimulants used in ADHD treatment.
• Both mechanisms of action focus on modifying dopamine and norepinephrine transmission.

Stimulant Mechanism of Action

• Stimulants act on catecholamine transporters to increase endogenous dopamine, thus increasing stimulation of D1-receptors.
• Enhancement of noradrenaline-dependent mechanisms also alters signal and noise within the glutamatergic circuits.
• Several studies suggest that stimulant treatments can have more nuanced and widespread treatment effects, but the long-term effects and predictors of treatment response require further research.