ADHD

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Questions and Answers

What structural difference has been observed between treated and untreated individuals with ADHD?

Enlargement of the amygdala

Subtle white matter differences in the inferior longitudinal fasciculus (correct)

Widespread cortical thinning in the frontal lobes

Increased volume in the anterior cingulate cortex

What effect do acute doses of stimulants have on brain functional connectivity?

They enhance connectivity towards that of neurotypical peers (correct)

They decrease connectivity of task-related fronto-striatal networks

They solely inhibit the default mode network (DMN)

They have no significant impact on brain activity

Which of the following statements regarding prolonged stimulant treatment is accurate?

It always leads to long-lasting changes in brain anatomy.

It has no effects on brain functional connectivity.

It may not translate into significant long-lasting changes. (correct)

It has been conclusively shown to enhance white matter integrity.

What is the mechanism of action of Atomoxetine in treating ADHD?

It functions as a selective norepinephrine reuptake inhibitor. Signup and view all the answers

Which medication is considered safer due to lower levels of norepinephrine transporter (NET) in the nucleus accumbens?

Atomoxetine Signup and view all the answers

What type of study was conducted to identify biological predictors of treatment response in adults with ADHD?

Longitudinal placebo-controlled study Signup and view all the answers

Which brain characteristics were associated with clinical response at two months according to Parlatini et al.?

Pre-treatment brain characteristics Signup and view all the answers

What was the purpose of combining biological and clinical characteristics in the study?

To create a more accurate profile of treatment response factors Signup and view all the answers

What specific method was used to assess brain connectivity in the study?

Machine learning & virtual histology Signup and view all the answers

Which aspect does the referenced study by Faraone et al., 2021, likely address?

The biological predictors of treatment response Signup and view all the answers

What is a primary criterion for diagnosing ADHD in individuals?

Symptoms must manifest for at least 6 months. Signup and view all the answers

Which of the following symptoms is NOT typically associated with ADHD?

Persistent high levels of anxiety Signup and view all the answers

What is one environmental factor linked to the development of ADHD?

Maternal obesity Signup and view all the answers

Which age group demonstrates adequate levels of hyperactivity and inattentiveness for the diagnosis of ADHD?

Children in early to mid-childhood Signup and view all the answers

In understanding ADHD etiology, which model is referenced?

Liability threshold model Signup and view all the answers

Which neurobiological area is primarily associated with ADHD symptoms?

Fronto-striatal networks Signup and view all the answers

What is a common challenge faced by individuals diagnosed with ADHD?

Struggles with social relationships Signup and view all the answers

What is the role of rating scales and neuropsychological tests in ADHD diagnosis?

They support the clinician's judgment. Signup and view all the answers

How do stimulants enhance PFC function?

By reducing neural 'noise' and enhancing 'signal' in glutamatergic circuits. Signup and view all the answers

Which brain network's activation is reduced by stimulant use in individuals with ADHD?

Default-mode network (DMN). Signup and view all the answers

What is one of the suggested effects of stimulants on catecholaminergic availability in ADHD?

They increase catecholaminergic availability in cortico-striatal regions. Signup and view all the answers

What structural changes are associated with stimulant treatment in children with ADHD?

Attenuation or absence of some grey matter volumetric alterations. Signup and view all the answers

What does PET/SPECT evidence suggest about the action of stimulants?

They support engagement of task-related brain networks. Signup and view all the answers

What outcomes have been observed from chronic treatment with MPH?

Inconclusive evidence on improvement of brain function after treatment wash-out. Signup and view all the answers

During which tasks do individuals with ADHD show modulated brain activity toward neurotypical levels with stimulant use?

Attention and response inhibition tasks. Signup and view all the answers

How is DA release perceived during rewarded tasks in the context of stimulant use?

It is higher, leading to events being perceived as more salient. Signup and view all the answers

What is the primary source of dopamine (DA) synthesis in the brain?

Substantia nigra pars compacta and ventral tegmental area Signup and view all the answers

How do noradrenergic pathways primarily influence brain function?

Through the regulation of arousal state and attention Signup and view all the answers

Which of the following pathways is involved in cognitive functions such as planning complex movements?

DLFPC-striatum-thal-premotor Cx/PFC Signup and view all the answers

What role does dopamine (DA) play in glutamatergic circuits?

It weakens inappropriate neural connections Signup and view all the answers

What impact does norepinephrine (NE) have on cAMP production?

It inhibits cAMP production through α2A receptors Signup and view all the answers

Which brain regions are primarily connected through cortico-striatal loops?

Cortex, basal ganglia, and thalamus Signup and view all the answers

Which aspect of brain function is primarily influenced by dopamine and norepinephrine interactions?

Regulation of attention, inhibition, motivation, and emotion Signup and view all the answers

What is a primary cognitive function associated with the activation of mesocortical and mesolimbic pathways?

Affect regulation Signup and view all the answers

What is the purpose of the longitudinal placebo-controlled neuroimaging study?

To identify biological predictors of treatment response in adults with ADHD Signup and view all the answers

Which treatment was administered on Day 2 of the study?

Placebo Signup and view all the answers

What does the term 'individual variability' refer to in the context of ADHD treatment?

Differences in treatment responses among individuals Signup and view all the answers

What was measured with BAARS-IV and QbDD tests during the study?

Changes in ADHD symptoms and brain connectivity Signup and view all the answers

What is the primary concern that this study addresses about ADHD treatment?

Pressure on services with long waiting times Signup and view all the answers

Which of the following best describes the subjects involved in the study?

60 adults with ADHD and 20 matched controls Signup and view all the answers

On which day did participants undergo MRI scans?

On Day 1 and Day 2 Signup and view all the answers

What role does brain connectivity play in this study?

It is a predictor of treatment response for ADHD. Signup and view all the answers

Study Notes

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.

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