Attention Deficit Hyperactivity Disorder: A Comprehensive

Analysis of Neurobiology, Manifestations, Treatment, and

Future Directions
1. Introduction to Attention Deficit Hyperactivity Disorder
(ADHD)
Attention Deficit Hyperactivity Disorder (ADHD) represents one of the most common
neurodevelopmental disorders, characterized by persistent patterns of inattention
and/or hyperactivity-impulsivity that significantly interfere with an individual's
functioning and development across various life domains. Understanding its
diagnostic criteria, prevalence, neurodevelopmental origins, and varied presentations
is fundamental to appreciating its complexity and impact.

1.1. Definition and Core Symptoms (DSM-5 Criteria)

The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5),
categorizes ADHD as a neurodevelopmental disorder.1 Its core diagnostic features
involve a persistent pattern of inattention and/or hyperactivity-impulsivity that is
inconsistent with the individual's developmental level and negatively impacts social,
academic, or occupational functioning.1 For a diagnosis, these symptoms must be
present in two or more settings (e.g., home, school, work, with friends).1

The DSM-5 outlines specific criteria for each symptom cluster:

●​ Inattention: Requires five or more symptoms (for individuals aged 17 and older)
or six or more symptoms (for children up to age 16) persisting for at least six
months. These include: often failing to give close attention to details or making
careless mistakes; difficulty sustaining attention in tasks or play; often seeming
not to listen when spoken to directly; often not following through on instructions
and failing to finish tasks; difficulty organizing tasks and activities; often avoiding
or disliking tasks requiring sustained mental effort; often losing necessary items;
being easily distracted by extraneous stimuli (including unrelated thoughts in
adults); and being forgetful in daily activities.1
●​ Hyperactivity and Impulsivity: Requires five or more symptoms (for individuals
aged 17 and older) or six or more symptoms (for children up to age 16) persisting
for at least six months. These include: often fidgeting or tapping hands/feet or
squirming in seat; often leaving seat when remaining seated is expected; often
running or climbing where inappropriate (in adolescents/adults, may be limited to
feeling restless); often unable to play or engage in leisure activities quietly; often
 being "on the go" or acting as if "driven by a motor"; often talking excessively;
often blurting out answers before questions are completed; difficulty waiting turn;
and often interrupting or intruding on others.1

Crucially, several of these symptoms must have been present before the age of 12
years.2 Furthermore, the symptoms cannot be solely attributed to another psychiatric
disorder (e.g., mood disorder, anxiety disorder, psychotic disorder) and must not
occur exclusively during the course of schizophrenia or another psychotic disorder.1
This requirement underscores a significant diagnostic challenge: the need for careful
differential diagnosis, particularly given the high rates of co-occurring conditions such
as Oppositional Defiant Disorder (ODD), Conduct Disorder (CD), learning disabilities,
depression, and anxiety disorders.1 The overlap in symptoms between ADHD and
these other conditions necessitates a thorough clinical evaluation to ensure
diagnostic accuracy and appropriate treatment planning.

1.2. Prevalence and Neurodevelopmental Nature

ADHD is a highly prevalent condition, affecting over 5% of children and adolescents
globally.7 While symptoms may diminish or change form over time, they often persist
into adulthood, impacting long-term educational attainment, occupational success,
health, and overall well-being.1 ADHD is recognized as a neurodevelopmental disorder,
implying that its origins lie in alterations in brain development and function.1 Its
etiology is multifactorial, involving a complex interplay of genetic predisposition
(heritability estimates are high, around 75-91% 9), neurobiological factors, and
environmental influences.1 Potential environmental risk factors include brain injury,
prenatal exposure to alcohol or tobacco, premature delivery, low birth weight, and
exposure to environmental toxins like lead.1 Adverse childhood experiences may also
play a role.1 Viewing ADHD through a neurodevelopmental lens is critical, shifting the
focus from solely behavioral management to understanding the underlying
brain-based differences that drive the symptoms.

1.3. ADHD Presentations

The DSM-5 recognizes three distinct presentations of ADHD, based on the pattern of
core symptoms over the preceding six months 1:
1.​ Predominantly Inattentive Presentation: Sufficient inattentive symptoms are
met, but fewer than the required number of hyperactive-impulsive symptoms are
present.
2.​ Predominantly Hyperactive/Impulsive Presentation: Sufficient
hyperactive-impulsive symptoms are met, but fewer than the required number of
inattentive symptoms are present.
 3.​ Combined Presentation: Criteria for both inattention and
hyperactivity-impulsivity are met.

The prevalence of these presentations can shift across the lifespan. Hyperactivity and
impulsivity are often the most noticeable symptoms in younger children (under 5
years), whereas inattention may become the most prevalent presentation between
ages 6 and 18 as academic and organizational demands increase.1 In adulthood, overt
hyperactivity often decreases, potentially manifesting as internal restlessness or an
inability to relax, while difficulties with inattention, impulsivity, and organization
frequently persist.11 This evolving nature of symptom presentation across development
highlights that ADHD is not a static condition. While the underlying neurobiology likely
persists, its behavioral expression adapts and changes in response to developmental
maturation and shifting environmental demands, necessitating age-appropriate
diagnostic considerations and ongoing management adjustments.

ADHD severity is also categorized as mild, moderate, or severe based on the number
and intensity of symptoms and the degree of functional impairment.3

2. The ADHD Brain: Neurological Underpinnings

Converging evidence from neuroimaging, genetic, and neurochemical studies
indicates that ADHD is associated with distinct differences in brain structure, function,
and connectivity. These differences primarily involve neural networks crucial for
executive functions, attention, and impulse control.

2.1. Structural and Functional Brain Differences

Neuroimaging research has identified several brain regions and networks that differ
structurally and functionally in individuals with ADHD compared to neurotypical
controls.

2.1.1. The Prefrontal Cortex (PFC)

The PFC, the most evolutionarily advanced part of the brain, is central to executive
functions (EFs) – the higher-order cognitive processes that enable goal-directed
behavior.13 These functions include regulating attention (sustaining focus, inhibiting
distractions), behavior (planning, impulse control), and emotion.13 The PFC
orchestrates thoughts and actions through extensive connections with sensory,
motor, and subcortical regions.13

A consistent finding in ADHD research is the association with alterations in PFC

structure and function.13 Studies report weaker function and structural differences,
particularly in the right hemisphere of the PFC, which is specialized for behavioral
inhibition.13 Imaging studies have demonstrated reduced PFC activation in individuals
with ADHD during tasks demanding attention regulation and behavioral control.13
Anatomically, parts of the PFC involved in attention and EF may exhibit reduced
cortical thickness or be underdeveloped.4 Furthermore, some individuals with ADHD
show evidence of delayed PFC maturation, although ADHD often persists into
adulthood, suggesting enduring PFC weaknesses.13 Symptoms observed in ADHD,
such as distractibility, impulsivity, and poor planning, closely resemble those resulting
from PFC lesions.13

2.1.2. Other Affected Brain Regions

While the PFC is a key area, ADHD involves alterations in a distributed network of brain
regions:
●​ Basal Ganglia: These subcortical structures (including the caudate nucleus and
putamen) are involved in motor control, reward processing, and procedural
learning, forming crucial circuits with the PFC.13 Studies report reduced grey
matter volume in parts of the basal ganglia, such as the caudate nuclei and
nucleus accumbens, in individuals with ADHD.4 Interestingly, some evidence
suggests this reduced grey matter may normalize with age, potentially correlating
with the decrease in overt hyperactivity often seen from childhood to adulthood.17
●​ Limbic System: This system, including structures like the amygdala and
hippocampus, is involved in emotional responses, memory, and learning.17
Diminished white matter integrity within the limbic system has been reported in
ADHD, potentially contributing to difficulties with emotional regulation, learning,
and memory.4
●​ Corpus Callosum: This large white matter tract connects the left and right
cerebral hemispheres, facilitating interhemispheric communication.17 Structural
abnormalities, including reduced volume or altered integrity, have been observed
in the corpus callosum in individuals with ADHD, potentially impacting the
integration of information processing between hemispheres.4 These abnormalities
appear to persist even in adults who no longer meet full diagnostic criteria.17
●​ Cerebellum: Traditionally associated with motor control, the cerebellum also
contributes to cognitive functions and emotional regulation through its
connections with the PFC and basal ganglia.13 Some studies report smaller
cerebellar volumes in ADHD.13
●​ Default Mode Network (DMN): The DMN is a network of brain regions (including
the medial PFC, posterior cingulate cortex, and angular gyrus) typically active
during rest or mind-wandering and deactivated during externally focused tasks.17
 In ADHD, there may be altered regulation of the DMN. The network might remain
inappropriately active during tasks requiring focused attention, competing with
executive control networks and making it difficult to suppress internal thoughts or
daydreams.17 Functional connectivity studies also suggest altered connectivity
within the DMN and between the DMN and other networks in ADHD.18

The pattern of findings across multiple brain regions and connecting pathways
underscores that ADHD is better conceptualized as a disorder of distributed neural
network regulation rather than a deficit localized to a single brain area. The dynamic
nature of some findings, such as the potential normalization of basal ganglia volume 17
or the delayed PFC maturation 13, further highlights the neurodevelopmental aspect of
the disorder, where brain differences may change across the lifespan.

2.2. Neurotransmitter Dysregulation

Optimal brain function, particularly within the PFC, relies on a precise neurochemical
balance. ADHD is strongly associated with alterations in the signaling of key
neurotransmitters, primarily the catecholamines: dopamine (DA) and norepinephrine
(NE).

2.2.1. The Role of Dopamine (DA)

Dopamine plays a critical role in reward, motivation, motor control, and executive
functions mediated by the PFC.13 Its influence on ADHD has long been hypothesized,
primarily because the most effective medications, psychostimulants, act on the
dopamine system.23 Specifically, stimulants like methylphenidate and amphetamine
block the dopamine transporter (DAT), increasing the availability of DA in the
synapse.5 Optimal PFC function requires appropriate dopaminergic stimulation,
particularly of D1 receptors.13

However, the widely held popular notion that ADHD is simply caused by a "dopamine
deficiency" or a generalized hypo-dopaminergic state is an oversimplification and
lacks robust, consistent scientific support.23 While multiple lines of evidence implicate
altered dopamine signaling 23, the exact nature of this alteration is complex and
debated. Brain imaging studies using PET and SPECT have yielded conflicting results:
some suggest lower dopamine levels or increased DAT binding (implying lower
synaptic DA), while others suggest higher dopamine levels or decreased DAT binding
in certain brain regions.23 Genetic studies have identified associations between ADHD
and variations in dopamine-related genes (e.g., DAT1, DRD4), but large-scale
genome-wide association studies (GWAS) have not consistently pinpointed these as
the primary risk genes compared to other psychiatric traits.23

More nuanced hypotheses propose alterations in the dynamics of dopamine release.

For example, one PET study reported decreased tonic (baseline) dopamine levels but
increased phasic (burst-like, response-driven) dopamine release in the right caudate
nucleus of individuals with ADHD during a task.18 Another PET study demonstrated
that dopamine release increases during cognitively demanding tasks requiring
flexibility, and higher release correlates with better performance, highlighting
dopamine's general role in executive functions that are often impaired in ADHD.29
Thus, rather than a simple deficit, ADHD likely involves a complex dysregulation of
dopamine signaling dynamics, potentially varying across brain regions and individuals.

2.2.2. The Role of Norepinephrine (NE) and Catecholamines

Norepinephrine, the other major catecholamine implicated in ADHD, is equally crucial
for PFC function, particularly in regulating attention, arousal, and stress responses.13
Optimal PFC function depends on NE stimulating postsynaptic alpha-2A
adrenoceptors.13 Genetic studies suggest that ADHD is associated with alterations in
genes involved in overall catecholamine transmission (both DA and NE).13

Effective pharmacological treatments for ADHD, including both stimulants and

non-stimulants like atomoxetine and guanfacine, enhance catecholamine signaling in
the PFC.13 Animal studies show that therapeutic doses of stimulants preferentially
increase NE levels (along with DA) in the PFC, which correlates with improved
attention and behavioral regulation.13 Research suggests NE and DA play
complementary roles in the PFC: NE enhances the relevant neural "signals"
(strengthening appropriate network connections via alpha-2A receptors), while DA
decreases irrelevant "noise" (weakening inappropriate connections via D1 receptors).13
Blockade of alpha-2 receptors in animal models can induce an ADHD-like profile
(impaired working memory, increased impulsivity, hyperactivity), while stimulation with
alpha-2A agonists like guanfacine can ameliorate these symptoms.13 This highlights
the critical role of balanced noradrenergic signaling for optimal PFC function and its
relevance to ADHD.

2.3. Executive Function Deficits

Executive functions (EFs) encompass a set of high-level cognitive control processes
necessary for goal-directed behavior, adaptation, and complex thought.16 Primarily
orchestrated by the PFC and its associated networks, EFs include planning,
organization, working memory, cognitive flexibility, initiation, sustained attention,
response inhibition, and emotional regulation.13

A hallmark of ADHD is significant impairment across multiple domains of executive

function.16 These deficits are considered a core characteristic of the disorder and
bridge the gap between the observed neurobiological differences and the behavioral
symptoms.32 Specific EF impairments commonly seen in ADHD include 16:
●​ Inhibition: Difficulty suppressing inappropriate or prepotent responses (response
inhibition), stopping an ongoing action when needed, and filtering out
distractions (interference control).13 This is often linked to impulsivity and
hyperactivity.
●​ Working Memory (WM): Reduced capacity to hold information in mind and
mentally manipulate it to guide behavior.16 WM deficits impact learning, following
instructions, problem-solving, and keeping track during complex tasks.16
●​ Activation/Initiation: Difficulty organizing tasks and materials, estimating time
needed for tasks, and initiating effortful activities, often leading to
procrastination.30
●​ Sustained Attention/Focus: Problems maintaining attention over time, especially
on tasks perceived as boring or requiring prolonged mental effort.1
●​ Planning and Organization: Difficulties in sequencing tasks, managing time
effectively, meeting deadlines, and keeping materials organized.1
●​ Cognitive Flexibility/Shifting: Trouble shifting between tasks or adapting
strategies when circumstances change.16
●​ Emotional Regulation: Increased difficulty managing emotional responses,
leading to heightened irritability, frustration intolerance, and mood lability.5
●​ Effort/Processing Speed: Challenges in regulating alertness, sustaining effort
and motivation, and slower speed in processing information and completing
tasks.30

Neuropsychological testing often reveals weaknesses in these areas in individuals with

ADHD, and poor performance on EF tasks correlates with structural and functional
abnormalities in fronto-striatal and fronto-parietal circuits.16 While research has
extensively documented EF deficits in ADHD, identifying a single "core" deficit remains
challenging, with prominent theories emphasizing either inhibitory control or working
memory as the primary impairment.16 The pervasive nature of EF deficits helps explain
the wide range of functional impairments experienced by individuals with ADHD in
academic, occupational, and social settings.

3. Cognitive and Behavioral Manifestations of ADHD

The underlying neurological differences and executive function deficits associated
with ADHD manifest as a wide range of cognitive and behavioral symptoms that
impact daily functioning across the lifespan and in various settings.

3.1. Cognitive Impacts

Beyond the core EF deficits, ADHD significantly affects several cognitive domains:
●​ Sustained Attention: A defining characteristic is the difficulty in maintaining
focus over time, particularly for tasks that are lengthy, repetitive, or lack intrinsic
interest or immediate reward.1 This relates directly to impaired top-down
attentional control mediated by the PFC.13 Individuals may be easily distracted by
external stimuli or internal thoughts, appearing "tuned out" even when addressed
directly.1 While often struggling with "boring" tasks like homework, they might
paradoxically hyperfocus on highly engaging activities like video games.13
●​ Working Memory: Impairments in WM make it difficult to hold and manipulate
information mentally. This affects the ability to follow multi-step instructions,
remember sequences, keep track of progress in complex tasks, comprehend
reading material, and perform mental calculations.16 These WM weaknesses are
strongly linked to academic difficulties.16
●​ Processing Speed (PS): Individuals with ADHD often exhibit slower processing
speed across perceptual, cognitive, and motor output domains.30 This means they
may take longer to perceive information, make decisions, and execute responses
compared to peers.35 Slow PS can impact the speed of reasoning, learning new
information, reading comprehension, and contribute to mental fatigue.35 While
basic reaction time might be intact, speed becomes less efficient as task
demands increase.35 PS deficits appear primarily linked to the inattention
dimension of ADHD.35 It is important to note that slow PS is not related to
intelligence; highly intelligent individuals can have slow processing speed.36
●​ Organization and Planning: Difficulties with organizing tasks, materials, and
time are pervasive.1 This manifests as trouble managing sequential tasks,
prioritizing activities, meeting deadlines, keeping belongings orderly, and poor
time management skills.1
●​ Task Initiation: Overcoming inertia to start tasks, particularly those requiring
sustained mental effort, is a common challenge, often resulting in
procrastination.30

These cognitive impacts collectively contribute significantly to the functional

impairments seen in academic and occupational settings. Difficulties with attention,
memory, organization, and timely task completion lead to careless mistakes, missed
deadlines, underachievement relative to potential, poor grades, job instability, and
unemployment.1 It is crucial to recognize that these difficulties often stem from
underlying cognitive and executive function challenges rather than a lack of ability or
willingness. Misinterpreting these challenges as laziness or lack of effort can lead to
negative feedback cycles, impacting self-esteem and motivation.12 The interplay
between these cognitive deficits can also amplify behavioral issues; for instance, slow
processing speed can make task completion difficult, leading to frustration and
perceived inattention or avoidance.35

3.2. Behavioral Impacts

The core symptoms of inattention, hyperactivity, and impulsivity translate into
observable behaviors that vary across the lifespan and impact functioning in multiple
settings.
●​ Manifestations Across Lifespan:
○​ Children: Often present with prominent hyperactivity (e.g., inability to sit still,
excessive running/climbing, constant fidgeting) and impulsivity (e.g., excessive
talking, interrupting, difficulty waiting turns, acting without thinking).1
Inattention symptoms (e.g., easily distracted, forgetful, difficulty following
instructions) may also be present but can become more impairing as school
demands increase.2 Disruptive behaviors in class and difficulty with peer
interactions are common.1
○​ Adolescents: Overt physical hyperactivity often decreases but may manifest
as subjective feelings of restlessness or fidgeting.2 Inattention and impulsivity
typically persist, contributing to ongoing academic struggles, organizational
challenges, and difficulties in relationships.2 Adolescence is also a period of
increased risk for impulsive behaviors such as substance use, reckless driving,
and unsafe sexual activity.1
○​ Adults: Symptoms become more internalized and subtle compared to
childhood.11 While hyperactivity may lessen further, restlessness, impatience,
and difficulty relaxing often persist.2 Inattention remains a major challenge,
impacting work performance and daily task management.11 Impulsivity can
manifest as impatience, interrupting others, making hasty decisions,
irresponsible spending, or sensation-seeking.11 Adults with ADHD frequently
struggle with poor organizational skills, time management, prioritizing tasks,
completing projects, low frustration tolerance, frequent mood swings,
difficulty coping with stress, and maintaining stable relationships.12
●​ Impact on Daily Functioning:
○​ Home: Difficulty completing chores, maintaining organization, managing
finances, and remembering appointments or daily tasks can cause significant
stress within the family.1 Emotional dysregulation and impulsivity can strain
 relationships with partners and children.1
○​ School/Work: Academic underachievement, lower grades, higher rates of
grade retention and dropout are common in students.33 In the workplace,
challenges with focus, organization, time management, deadlines, and
impulse control can lead to poor performance reviews, difficulties with
colleagues, and job instability or unemployment.1
○​ Social Relationships: Impulsive behaviors like interrupting, talking
excessively, difficulty waiting turns, or intruding on others can hinder social
interactions.1 Difficulty reading social cues or managing emotional responses
can lead to peer rejection in childhood and unstable relationships in
adulthood.12
●​ Emotional Dysregulation: Beyond the core DSM-5 symptoms, difficulties with
emotional regulation are increasingly recognized as a significant feature of
ADHD.5 This can include heightened emotional reactivity, difficulty managing
frustration, pronounced irritability, frequent mood swings, and temper outbursts.5

The link between impulsivity, poor planning (EF deficits), and increased risk-taking
behavior 1 highlights the potential for serious long-term consequences, including
substance use disorders, accidents, and legal troubles, underscoring the importance
of comprehensive management.

4. Brain Imaging Findings in ADHD

Neuroimaging techniques have provided invaluable insights into the structural,
functional, and neurochemical alterations associated with ADHD, reinforcing its status
as a brain-based disorder. While no single imaging finding is currently diagnostic,
patterns of differences are consistently observed at a group level.

4.1. Structural Neuroimaging

Structural neuroimaging examines the physical characteristics of the brain, such as
volume, shape, and tissue integrity.

4.1.1. Magnetic Resonance Imaging (MRI): Volumetric and Cortical Changes

Standard clinical MRI scans for individuals with ADHD are typically interpreted as
normal, as the differences are often subtle.4 However, specialized research protocols
using volumetric analysis and voxel-based morphometry (VBM) have identified
consistent patterns:
●​ Frontal Lobe Alterations: Reduced total frontal lobe volume, decreased cortical
thickness, and reduced surface area, particularly in prefrontal regions (left ventral
 frontal, right prefrontal), are among the most consistent findings.4 Reduced
gyrification (folding) in frontal areas has also been reported.4 These findings align
with the known role of the frontal lobes in executive functions impaired in ADHD.
●​ Subcortical Structures: Reduced volumes have been reported in several
subcortical grey matter structures involved in motor control, reward, and
emotional processing, including the caudate nucleus, putamen, nucleus
accumbens, amygdala, and hippocampus.4 However, findings regarding specific
structures like the caudate nucleus have shown some variability across studies.4
Interestingly, one large meta-analysis found increased grey matter volume (GMV)
in parts of the striatum (lenticular nucleus) alongside decreases in other areas.19
●​ Temporal and Parietal Lobes: Reduced cortical thickness or surface area has
also been observed in temporal lobe regions (e.g., medial temporal lobe, temporal
pole, fusiform gyrus) and parietal areas (e.g., left supramarginal gyrus, left
perirolandic cortex).4
●​ Limbic System and Cingulate Cortex: Reduced GMV is often found in limbic
areas and the anterior cingulate cortex (ACC), regions critical for emotional
regulation and cognitive control.18
●​ Corpus Callosum: Reduced volume or altered shape of the corpus callosum, the
main white matter tract connecting the hemispheres, is also frequently reported.4

A comprehensive meta-analysis combining VBM studies confirmed significant GMV

reductions in ADHD across frontal-parietal networks, the limbic system, and the
corpus callosum.19

4.1.2. Diffusion Tensor Imaging (DTI): White Matter Tract Abnormalities

DTI assesses the integrity and organization of white matter tracts, the brain's
communication pathways. DTI studies in ADHD suggest alterations in connectivity:
●​ Altered Fractional Anisotropy (FA): Lower FA, indicating less organized or less
myelinated white matter tracts, has been reported in various pathways, including
the corpus callosum, corona radiata, superior and inferior longitudinal fasciculi,
internal and external capsules, anterior thalamic radiations, and orbitofrontal
tracts.4
●​ Connectivity Weakness: Findings are consistent with weaker or more
disorganized white matter connectivity, particularly involving tracts emanating
from the PFC.13 Lower FA in certain tracts has been correlated with higher
impulsivity levels.18
●​ Developmental Considerations: DTI findings appear less consistent in children
compared to adults, possibly reflecting ongoing myelination processes during
development.18 This has led to the concept of ADHD involving a "developmental
 dysconnectome," suggesting altered trajectories in the development of brain
connectivity.18

4.2. Functional Neuroimaging

Functional neuroimaging techniques measure brain activity, either during specific
tasks or during rest, providing insights into how brain networks operate differently in
ADHD.

4.2.1. Functional MRI (fMRI): Task-Based and Resting-State

fMRI measures changes in blood flow related to neural activity.
●​ Task-Based fMRI: Studies requiring participants to perform tasks involving
executive functions (e.g., inhibition, working memory, attention) consistently show
altered activation patterns in ADHD. The most robust finding is hypoactivation
(reduced activity) in key nodes of cognitive control networks, particularly the
inferior frontal cortex, anterior cingulate cortex (ACC), supplementary motor area,
basal ganglia (striatum), thalamus, and parietal cortex.8 This fronto-striatal
hypoactivation during cognitive control tasks is a highly replicated finding.8
However, some studies report hyperactivation in certain regions or contexts,
potentially reflecting compensatory effort or different underlying strategies.22
Meta-analyses confirm widespread hypoactivity in frontal, temporal, and parietal
regions during various tasks.19
●​ Resting-State fMRI (rsfMRI): This technique examines spontaneous fluctuations
in brain activity and the functional connectivity (temporal correlation of activity)
between different brain regions when no specific task is being performed. RsfMRI
studies in ADHD have revealed altered connectivity within and between major
brain networks, including the default mode network (DMN), cognitive control
networks, attention networks (dorsal and ventral), and sensorimotor networks.8
Findings include reduced synchrony within networks and disruptions (both hypo-
and hyper-connectivity) in crucial cortico-striato-thalamo-cortical loops involved
in cognition, reward, and emotion.18 A large mega-analysis reported increased
connectivity between striatal regions and parts of the frontal, temporal, and
parietal cortex, as well as between the amygdala and ACC/medial frontal cortex,
potentially related to emotional dysregulation.8 However, the consistency of
rsfMRI findings can vary, with some studies finding differences only during active
tasks rather than rest 42, possibly due to methodological variations or the
heterogeneity of ADHD itself.

4.2.2. Positron Emission Tomography (PET)

PET uses radioactive tracers to visualize and measure changes in metabolic
processes, including neurotransmitter activity.
●​ Dopamine System: As discussed previously (Section 2.2.1), PET studies
investigating the dopamine system have yielded complex and sometimes
contradictory findings regarding transporter density and baseline dopamine
levels.23 However, task-based PET has provided evidence for altered dopamine
dynamics, specifically increased phasic release (in response to stimuli/tasks) and
decreased tonic release (baseline levels) in the right caudate.18 Studies also link
dopamine release to cognitive flexibility, a key executive function often impaired
in ADHD.29
●​ Norepinephrine System: Reduced availability of the norepinephrine transporter
(NET) has been suggested in fronto-parietal-thalamic-cerebellar regions.18
●​ Neuroinflammation: PET imaging has also shown increased activation of
microglia (immune cells in the brain, indicating neuroinflammation) in the
dorsolateral PFC and orbitofrontal cortex in adults with ADHD.18

4.2.3. Magnetic Resonance Spectroscopy (MRS)

MRS measures the concentration of certain brain metabolites, providing insights into
neurochemical composition.
●​ Findings: MRS studies in ADHD have produced inconsistent results, potentially
due to methodological differences.18 While some studies found no significant
differences in common metabolites like N-acetylaspartate (NAA), choline, or
creatine, others reported reductions in these metabolites in specific regions like
the middle frontal gyrus.18 More consistent findings point towards alterations in
excitatory (glutamate, glutamine) and inhibitory (GABA) neurotransmitter systems.
Reports include increased glutamate/glutamine and GABA in frontal-striatal
regions, and reduced striatal GABA in children with ADHD.18 A lower
GABA-to-creatine ratio in the striatum has been linked to poorer behavioral
inhibition.18 These findings suggest potential imbalances in excitatory/inhibitory
signaling may contribute to ADHD pathophysiology.

4.3. Meta-Analytic Findings and Diagnostic Utility

Meta-analyses integrating data from numerous imaging studies confirm consistent
group-level differences between individuals with ADHD and controls. Key findings
include reduced GMV in fronto-parietal-limbic circuits and the corpus callosum 19,
altered white matter integrity 18, and functional alterations such as fronto-striatal
hypoactivation during tasks and disrupted network connectivity at rest.8
However, despite these group-level differences, there is currently no single structural
or functional neuroimaging pattern that can reliably diagnose ADHD at the individual
level.3 This lack of diagnostic utility stems largely from the significant heterogeneity
within the ADHD population itself – different individuals likely have varying underlying
neurobiological profiles contributing to their symptoms.4 Factors such as age, sex,
symptom presentation, comorbidities, and medication history further contribute to the
variability observed in imaging studies.18

The consistent finding of alterations in distributed networks (structural and functional

connectivity) rather than just isolated regional deficits reinforces the view of ADHD as
a disorder of brain network communication and regulation.8 Furthermore, observed
differences in brain alterations between children and adults suggest a dynamic
developmental trajectory, with some features potentially reflecting delayed maturation
while others represent persistent traits.17 While not currently diagnostic, neuroimaging
remains a powerful research tool. Emerging approaches using artificial intelligence
(AI) and machine learning to analyze complex patterns in multimodal imaging data
show promise for potentially improving diagnostic accuracy and subtyping in the
future.4

Table 1: Summary of Key Neuroimaging Findings in ADHD by Modality

Modality Key Brain Regions Consistent Representative

Implicated Findings/Alterations Snippet(s)

Structural MRI Prefrontal Cortex Reduced 4

(Vol/VBM) (PFC), Frontal Lobe, volume/thickness/sur

Basal Ganglia face area (esp.
(Caudate, Putamen), frontal, temporal,
Limbic System cingulate); Altered
(Amygdala, gyrification; Reduced
Hippocampus), GMV
Temporal Lobe, (frontal-parietal,
Parietal Lobe, limbic, CC); Some
Cingulate Cortex, variability/increases
Corpus Callosum, noted
Cerebellum

Diffusion Tensor Corpus Callosum, Reduced Fractional 4

Imaging (DTI) Corona Radiata, Anisotropy (FA);

Longitudinal Disorganized/weaker
Fasciculi, Capsules, white matter tracts
 Thalamic Radiations, (esp. from PFC);
Fronto-Occipital Altered connectivity;
Fasciculus, Cingulum "Developmental
dysconnectome"

Task-Based fMRI Inferior Frontal Hypoactivation in 8

Cortex, ACC, cognitive

Striatum, Thalamus, control/attention
Parietal Cortex, networks (esp.
Temporal Lobe, fronto-striatal); Some
Insula, Cerebellum hyperactivation
reported; Altered
activation during
inhibition, WM tasks

Resting-State fMRI Default Mode Altered intrinsic 8

(rsfMRI) Network (DMN), connectivity

Cognitive Control within/between
Network, Attention networks; Reduced
Networks, synchrony; Disrupted
Sensorimotor cortico-striato-thala
Network, Striatum, mo-cortical loops
Amygdala, ACC (hypo- &
hyper-connectivity)

Positron Emission Caudate, PFC, Altered DA dynamics 18

Tomography (PET) Orbitofrontal Cortex, (↓ tonic, ↑ phasic);

Fronto-parietal-thala Mixed findings on
mic-cerebellar DAT/DA levels;
regions Reduced NET
availability; Increased
microglia activation
(neuroinflammation)

Magnetic Frontal Gyrus, Inconsistent findings 4

Resonance Striatum for

Spectroscopy NAA/Choline/Creatin
(MRS) e; Alterations in
Glutamate,
Glutamine, GABA
levels (potential
excitatory/inhibitory
imbalance)

5. Comprehensive Treatment Approaches for ADHD

Effective management of ADHD typically involves a multimodal approach tailored to
the individual's specific needs, age, symptom severity, co-occurring conditions, and
personal circumstances. Treatment strategies encompass pharmacological
interventions, various forms of behavioral therapy, cognitive training, and lifestyle
adjustments.

5.1. Pharmacological Interventions

Medication is a cornerstone of ADHD treatment, particularly for managing core
symptoms. Medications work by modulating neurotransmitter systems implicated in
ADHD, primarily dopamine and norepinephrine, especially within prefrontal cortex
circuits.13 They are broadly classified into stimulants and non-stimulants.

5.1.1. Stimulant Medications

Stimulants are the most commonly prescribed and generally considered the most
effective first-line pharmacological treatment for ADHD across the lifespan.43 They
work by increasing the synaptic availability of dopamine (DA) and norepinephrine
(NE).13 Despite their name, they do not typically overstimulate individuals with ADHD;
rather, they help to normalize brain activity in key circuits involved in attention and
impulse control.43
●​ Methylphenidate-based (MPH) (e.g., Ritalin, Concerta, Metadate,
Daytrana):
○​ Mechanism: Primarily blocks the reuptake of DA and NE by inhibiting the
dopamine transporter (DAT) and norepinephrine transporter (NET), with a
higher affinity for DAT.5 Some evidence suggests it may also modulate the
vesicular storage of DA.5
○​ Efficacy: Demonstrates moderate to large effect sizes in reducing core ADHD
symptoms and improving emotional regulation in children and adults.5
Response rates are typically estimated at 60-70%.46 Meta-analyses place its
efficacy slightly below amphetamines but significantly above placebo.47
○​ Side Effects: Common side effects include decreased appetite, insomnia,
headache, stomach ache, dry mouth, irritability, and potential mild increases
in heart rate and blood pressure.5 A rebound effect (worsening symptoms as
medication wears off) can occur with short-acting forms.43 While controlled
substances, the abuse potential of oral therapeutic formulations is considered
low.5 Minor, temporary growth slowing may occur in children but does not
typically affect final adult height.43
●​ Amphetamine-based (AMP) (e.g., Adderall, Vyvanse, Dexedrine):
○​ Mechanism: Increase synaptic DA and NE by both blocking their reuptake (via
 DAT and NET) and promoting their release from presynaptic terminals.23
○​ Efficacy: Highly effective, with response rates around 80% for core symptom
reduction.24 Demonstrated benefits in academic achievement and functional
outcomes.24 Long-term use in individuals with ADHD may be associated with
improvements in brain structure and function.24 Lisdexamfetamine (Vyvanse)
is a prodrug converted to dextroamphetamine in the body, providing smooth,
extended release.24 Meta-analyses suggest amphetamines may be slightly
more efficacious than methylphenidate, particularly in adults.48
○​ Side Effects: Similar profile to MPH, including decreased appetite, weight loss,
insomnia, dry mouth, increased heart rate/BP, irritability, and potential mood
swings.24 Risk of misuse/addiction exists, particularly with non-therapeutic use
or specific formulations, but is considered low with prescribed therapeutic
use.24 Cardiovascular monitoring is important.50
●​ General Stimulant Considerations:
○​ Formulations: Both MPH and AMP are available in immediate-release
(short-acting, lasting ~4 hours) and various extended-release (intermediate or
long-acting, lasting 6-16 hours) formulations.43 Extended-release options offer
convenience (once-daily dosing) and potentially smoother symptom control
with fewer "ups and downs".43
○​ Comparative Efficacy: Meta-analyses consistently show stimulants have larger
effect sizes than non-stimulants for core ADHD symptoms in both youth (SMD
~0.8-1.0 vs ~0.6) 44 and adults (Cohen's d ~0.67 vs ~0.59).47

While stimulants are highly effective, the optimal choice and dose are individualized,
requiring careful titration and monitoring for efficacy and side effects.45

5.1.2. Non-Stimulant Medications

Non-stimulant medications provide important alternatives or adjuncts to stimulants.
They are typically considered second- or third-line options due to generally lower
average efficacy or slower onset of action compared to stimulants.51 They may be
preferred when stimulants are ineffective, cause intolerable side effects, when there
are co-occurring conditions (e.g., anxiety, tics), or when there is a concern about
stimulant misuse or diversion.43
●​ Atomoxetine (Strattera):
○​ Mechanism: A selective norepinephrine reuptake inhibitor (SNRI), increasing
NE levels in the synapse.51
○​ Efficacy: Works for approximately 50% of individuals, with about half the
effect size of stimulants on core symptoms.51 May take several weeks (4-8) to
reach full effect.53 Meta-analyses suggest efficacy comparable to viloxazine
 and centanafadine, but less than lisdexamfetamine.48 Can improve cognitive
domains, though perhaps not working memory as effectively as stimulants.52
○​ Side Effects: Common side effects include nausea, decreased appetite,
fatigue, dizziness, dry mouth, headache, insomnia, and mood swings.51 Carries
a US Boxed Warning regarding increased risk of suicidal ideation in children
and adolescents.55
●​ Alpha-2 Adrenergic Agonists (Guanfacine ER - Intuniv; Clonidine ER -
Kapvay):
○​ Mechanism: Activate alpha-2A adrenergic receptors, primarily in the PFC.51
This is thought to strengthen PFC network connectivity and improve
regulation of attention, behavior, and impulsivity.13 Guanfacine is more
selective for the alpha-2A subtype than clonidine.56
○​ Efficacy: Response rates estimated at 55-60%.51 Often used as adjunctive
therapy with stimulants but can be used as monotherapy.51 Meta-analysis
confirms guanfacine efficacy in children and adults.56 May be particularly
helpful for hyperactivity, impulsivity, and emotional dysregulation/aggression.51
○​ Side Effects: Sedation/somnolence is very common, especially initially.51 Other
common effects include fatigue, dizziness, dry mouth, constipation, and
potential decreases in blood pressure and heart rate.51 Abrupt discontinuation
should be avoided due to risk of rebound hypertension.51
●​ Viloxazine ER (Qelbree):
○​ Mechanism: A serotonin norepinephrine modulating agent, primarily acting as
an SNRI.51 May also interact with certain serotonin receptors (5-HT2B/2C).60
○​ Efficacy: FDA-approved for children (6-17) and adults. Meta-analyses show
significant superiority over placebo in reducing ADHD symptoms in pediatric
populations (RR ~1.5-1.6).61 Comparative effectiveness appears similar to
atomoxetine and potentially methylphenidate, but less than
lisdexamfetamine.48 Takes several weeks for full effect.
○​ Side Effects: Common effects include somnolence, decreased appetite,
fatigue, nausea, insomnia, irritability, headache, dry mouth, constipation, and
increases in heart rate and blood pressure.51 Carries a US Boxed Warning for
suicidal thoughts and behaviors, similar to atomoxetine.62

Table 2: Overview of Pharmacological Treatments for ADHD

Drug Class Specific Primary General Common Key

Drug(s) Mechanism Efficacy (vs. Side Effects Snippet(s)
(Examples) of Action Placebo)
Stimulant Methylpheni DA & NE High (SMD Decreased 5

date (Ritalin, Reuptake ~0.5-1.0); appetite,

Concerta) Inhibitor Response insomnia,
(more DAT) ~60-70% headache,
stomach
ache,
irritability,
↑BP/HR,
rebound,
potential
growth
slowing
(minor)

Stimulant Amphetamin DA & NE High (SMD Decreased 24

e (Adderall, Reuptake ~0.8-1.0); appetite,

Vyvanse) Inhibitor & Response insomnia,
Releaser ~80%; weight loss,
Potentially dry mouth,
slightly > ↑BP/HR,
MPH mood
swings,
anxiety;
Lower abuse
risk with
Vyvanse

Non-Stimul Atomoxetine Selective NE Moderate Nausea, 51

ant (Strattera) Reuptake (SMD ↓appetite,

Inhibitor ~0.5-0.6); fatigue,
(SNRI) Response dizziness,
~50%; dry mouth,
Slower onset insomnia,
mood
swings;
Suicidal
ideation
warning

Non-Stimul Guanfacine Selective Moderate Somnolence, 51

ant ER (Intuniv) Alpha-2A (Response fatigue,

Adrenergic ~55-60%); dizziness,
Agonist Often dry mouth,
adjunctive; constipation,
Good for ↓BP/HR; Do
 hyperactivity not stop
/impulsivity/e abruptly
motion reg.

Non-Stimul Clonidine ER Alpha-2 Moderate Somnolence/ 51

ant (Kapvay) Adrenergic (Response Tiredness,

Agonist (less ~55-60%); dizziness,
selective Often dry mouth,
than adjunctive irritability,
Guanfacine) ↓BP/HR; Do
not stop
abruptly

Non-Stimul Viloxazine ER Selective NE Moderate Somnolence, 51

ant (Qelbree) Reuptake (RR ~1.5-1.6 ↓appetite,

Inhibitor vs placebo); fatigue,
(SNRI); Efficacy nausea,
Serotonin similar to insomnia,
modulator? Atomoxetine; irritability,
Slower onset ↑BP/HR;
Suicidal
thoughts/be
haviors
warning

Note: SMD = Standardized Mean Difference; RR = Relative Risk; DA = Dopamine; NE =

Norepinephrine; DAT = Dopamine Transporter; NET = Norepinephrine Transporter; BP
= Blood Pressure; HR = Heart Rate. Efficacy estimates are approximate and can vary
based on study population and methodology.

5.2. Behavioral Therapies

Behavioral therapies are crucial components of ADHD management, particularly for
addressing functional impairments, teaching coping skills, and managing challenging
behaviors. They are often recommended alongside medication, especially for children,
and are a primary treatment for adults seeking to improve organizational and time
management skills.63
●​ Parent Training and Behavior Management (PTBM): Primarily used for children
with ADHD, PTBM equips parents with skills to manage their child's behavior
effectively.1 It focuses on principles of behavior modification, such as using
positive reinforcement for desired behaviors, setting clear rules and expectations,
using consistent consequences (like time-outs or loss of privileges), and
improving parent-child communication.1 Meta-analyses and reviews confirm
 PTBM's effectiveness in reducing disruptive behaviors, including both core ADHD
symptoms and comorbid ODD symptoms, improving parenting skills and
confidence, and enhancing child and parent quality of life.63 It can be delivered
effectively both in person and online.66
●​ Cognitive Behavioral Therapy (CBT): CBT is adapted for ADHD to address the
cognitive and behavioral patterns contributing to functional impairment,
particularly in adolescents and adults.64
○​ For Children/Adolescents: CBT can target self-control, social skills, attention,
and hyperactivity, with studies showing significant positive effects.68
○​ For Adults: CBT focuses on practical skills to manage EF deficits (e.g.,
organization, time management, planning, task initiation), identifying and
modifying unhelpful thought patterns (e.g., related to procrastination,
self-esteem), developing coping strategies for emotional dysregulation and
stress, and improving communication skills.64 Meta-cognitive therapy, a
related approach, focuses on changing how individuals think about their
thinking processes to improve executive control.70 Recent meta-analyses
highlight the effectiveness of specific CBT components, including
organizational skills training, problem-solving techniques, and "third-wave"
approaches incorporating mindfulness and acceptance strategies.69
Combining CBT with medication appears more effective than medication
alone for adult ADHD, at least in the short-to-medium term.64
●​ School-Based Interventions: Given the significant impact of ADHD on academic
performance and classroom behavior, school-based interventions are essential.37
These can include:
○​ Behavioral Strategies: Classroom contingency management (e.g., token
economies, daily report cards), positive reinforcement, and response cost
systems.71
○​ Academic Interventions: Adjustments to tasks (e.g., breaking down
assignments), providing organizational tools (e.g., planners, checklists),
teaching note-taking and study skills.37
○​ Environmental Modifications: Preferential seating (e.g., away from
distractions), clear and concise instructions, established routines.37
○​ Self-Management Training: Teaching students to monitor and manage their
own behavior and academic work.38 Meta-analyses show that behavioral and
academic interventions in schools yield positive effects on both behavior and,
to a lesser extent, academic outcomes, although effect sizes may be smaller
than for medication.71 Cognitive-behavioral strategies also show promise in
school settings.71
5.3. Cognitive Training
Cognitive training, particularly computerized working memory training (CWMT), aims
to improve specific cognitive deficits associated with ADHD, such as working memory
(WM) and attention, through repetitive exercises often presented in a game-like
format.72
●​ Efficacy: Meta-analyses consistently show that cognitive training, especially WM
training, leads to improvements on the trained tasks and closely related
laboratory measures of WM (near transfer).72 Parent ratings of executive function
also show some improvement.73
●​ Limitations (Far Transfer and Blinding): The crucial question is whether these
training gains transfer to improvements in core ADHD symptoms (inattention,
hyperactivity/impulsivity) in real-world settings (far transfer) and academic
performance. Here, the evidence is much weaker and more controversial.72
Meta-analyses indicate that effects on core ADHD symptoms are small to
negligible when assessments are conducted by raters blinded to the treatment
condition (e.g., teachers unaware of whether the child received training or
placebo).73 Effects reported by unblinded raters (e.g., parents involved in the
training) are significantly larger, suggesting a high potential for expectation bias
or placebo effects.73 Furthermore, significant improvements in academic
performance have generally not been found.72
●​ Long-Term Effects: Evidence for the sustainability of cognitive training benefits
is limited and mixed. Some studies suggest effects may not last beyond 6 months,
although verbal WM gains might persist longer.72 One study reported far-transfer
effects at 6 months.72 More longitudinal research is needed.72
●​ Multi-Domain Training: Some evidence suggests that training programs
targeting multiple neuropsychological processes simultaneously might yield
better transfer to clinical symptoms compared to training WM alone.73

Overall, while cognitive training can improve performance on specific cognitive tasks,
its utility as a standalone treatment for core ADHD symptoms remains questionable
due to limited far transfer, particularly when assessed rigorously. It may have a role as
part of a broader intervention package, but should not replace evidence-based
treatments like medication and behavioral therapy.72

5.4. Lifestyle Interventions

Lifestyle factors play a significant role in overall health and can also influence ADHD
symptoms and management.
5.4.1. Diet and Nutrition
The role of diet in ADHD is a topic of considerable interest and ongoing research.
●​ Overall Diet Quality: Evidence suggests a link between general dietary patterns
and ADHD risk or severity. Systematic reviews and meta-analyses indicate that
diets low in fruits, vegetables, and fish, and high in sugar, sweetened beverages,
and processed/junk food ("poor quality diet") are associated with an increased
prevalence of ADHD in both children and adults.74 Conversely, higher quality diets,
such as the Mediterranean diet (rich in plant-based foods, healthy fats, fish, and
low in processed foods and sugar), may be protective or associated with lower
ADHD symptom severity.10 The mechanisms may involve providing essential
nutrients (e.g., fatty acids, vitamins, minerals like zinc, iron, magnesium) crucial for
neurotransmitter metabolism and brain function.10
●​ Elimination Diets:
○​ Food Additives/Colors: Some studies suggest a small effect of eliminating
artificial food colorings on ADHD symptoms, possibly limited to children with
specific sensitivities. Meta-analyses show small effect sizes, particularly
based on parent reports.75
○​ Oligoantigenic Diets: These highly restrictive diets eliminate common food
allergens. While some studies report significant effects, particularly based on
unblinded ratings, meta-analyses using blinded assessments show only small
effects.76 Long-term feasibility and effectiveness are uncertain.
○​ Gluten-Free/Casein-Free (GFCF): Primarily studied in Autism Spectrum
Disorder (ASD), with weak evidence for efficacy in ASD unless comorbid
gastrointestinal issues are present. Evidence for ADHD specifically is lacking.76
●​ Omega-3 Fatty Acid Supplementation: Omega-3 PUFAs (particularly EPA and
DHA) are essential for brain health. Meta-analyses have yielded mixed results
regarding their efficacy for ADHD core symptoms. One recent large meta-analysis
found no significant overall benefit compared to placebo.77 However, a subgroup
analysis in that study suggested a potential benefit with long-term
supplementation (≥4 months).77 An earlier meta-analysis found a modest overall
effect, particularly with higher doses of EPA.78 Overall, the efficacy appears
modest compared to standard pharmacotherapies, but omega-3s may be
considered as an augmentation strategy or for families seeking
non-pharmacological options, given their favorable safety profile.78

While optimizing nutrition is important for everyone, the evidence for specific dietary
interventions as primary ADHD treatments remains limited or requires further
high-quality research. A balanced, healthy diet low in processed foods is generally
advisable.10

5.4.2. Physical Exercise

Physical activity (PA) is increasingly recognized as a beneficial complementary
intervention for ADHD.
●​ Benefits: Regular PA has been shown to improve executive functions (attention,
inhibitory control, working memory, cognitive flexibility), emotional regulation, and
potentially reduce core ADHD symptoms.79 It can also improve physical fitness
and address comorbidities like anxiety and depression.80
●​ Mechanisms: Exercise is thought to exert benefits by enhancing
neurotransmitter function (increasing dopamine and norepinephrine levels, similar
to stimulants), boosting cerebral blood flow, and increasing levels of
brain-derived neurotrophic factor (BDNF), which supports neuroplasticity and
brain health.80
●​ Efficacy: Meta-analyses support the positive impact of exercise. Both acute
(single session) and chronic (regular program) exercise improve inhibitory control
in adults with ADHD.79 Aerobic exercise shows moderate-to-large effects on EF in
children.80 Different types of exercise (aerobic, high-intensity, coordinative like
martial arts) appear beneficial.80
●​ Implementation: PA can be incorporated through traditional sports, aerobic
activities, or newer approaches like exergaming (active video games).80
Consistency is key, though maintaining it can be challenging for individuals with
ADHD.80

Exercise should be recommended as part of a healthy lifestyle for individuals with

ADHD, offering potential benefits for both core symptoms and overall well-being.70

5.4.3. Sleep Interventions

Sleep disturbances are highly prevalent in individuals with ADHD across the lifespan
and can significantly worsen core symptoms and cognitive function.81 The relationship
is bidirectional: ADHD symptoms (e.g., hyperactivity, racing thoughts) and associated
neurochemical imbalances (e.g., dopamine, norepinephrine, GABA, cortisol
dysregulation) can disrupt sleep, while poor sleep exacerbates ADHD symptoms.82
ADHD medications, particularly stimulants, can also interfere with sleep onset.81
●​ Behavioral Sleep Interventions: These are typically the first line of approach.
They focus on establishing healthy sleep habits (sleep hygiene), such as
maintaining consistent bedtimes and wake times, creating a relaxing bedtime
routine, ensuring a dark and quiet sleep environment, limiting screen time before
 bed, and avoiding caffeine late in the day.81 Standardized behavioral strategies
tailored to specific sleep problems (e.g., difficulty falling asleep, night
awakenings) are employed.81 Randomized controlled trials and systematic reviews
show that behavioral sleep interventions can effectively reduce sleep problems
and modestly improve ADHD symptoms, behavior, and quality of life in children.81
A moderate effect size for reducing sleep disturbances was found with moderate
certainty of evidence.84
●​ Pharmacological Interventions: Melatonin is sometimes used to help regulate
the sleep-wake cycle, particularly if a delayed sleep phase is suspected.83 Limited
studies suggest melatonin may improve total sleep time.84 Other sleep
medications (e.g., eszopiclone) have been studied but evidence is sparse.84

Addressing sleep problems is a critical aspect of comprehensive ADHD management

due to the significant impact of sleep quality on symptoms and functioning.82

Table 3: Comparison of Non-Pharmacological Interventions for ADHD

Intervention Target Primary Target General Key Snippet(s)

Type Population Outcomes Effectiveness

Parent Training Children (esp. Child behavior Effective in 1

(PTBM) preschool/schoo (ADHD/ODD reducing

l-age) symptoms), disruptive
Parenting skills, behaviors
Parent stress, (ADHD & ODD),
Parent-child improving
relationship, parenting;
QoL Online
comparable to
face-to-face.

Cognitive Adolescents, EF skills Effective, esp. 64

Behavioral Adults (organization, combined with

Therapy (CBT) time mgmt), meds for adults;
Coping Specific
strategies, components
Emotional (Organizational,
regulation, Third-wave,
Thought Problem-solving
patterns ) most effective;
Moderate-large
effects in
 children/adolesc
ents.

School-Based Children, Academic Behavioral 37

Interventions Adolescents performance, (contingency

Classroom mgmt) &
behavior, academic
Organization, interventions
Homework effective for
completion behavior
(mod-large
effect); Smaller
effects on
academics;
Self-mgmt &
note-taking
show promise.

Cognitive Children, Working Improves 72

Training (esp. Adolescents Memory, performance on

WM) Attention (lab trained tasks
measures) (near transfer);
Limited/inconsis
tent far transfer
to core ADHD
symptoms (esp.
blinded ratings)
or academics.

Diet - Overall All ages General health, High-quality diet 10

Quality Potential (fruits, veg, fish)

reduction in may be
ADHD protective; Poor
risk/severity quality diet
(sugar, junk
food)
associated with
increased risk.

Diet - Children ADHD Small effects, 75

Elimination symptoms possibly limited

(Additives) to sensitive
individuals;
Methodological
concerns
 (blinding).

Diet - Children ADHD Large effects 76

Elimination symptoms (unblinded),

(Oligoantigenic Small effects
) (blinded);
Long-term
efficacy/feasibili
ty unknown.

Diet - Omega-3 Children, Core ADHD Modest/Inconsis 77

Supplementati Adolescents symptoms tent effects

on overall; Potential
benefit with
long-term use
(≥4 months);
Modest vs.
meds.

Physical All ages EF (Inhibitory Effective 70

Exercise control, complementary

attention, WM), approach;
Emotional Improves EF &
regulation, Core emotional
symptoms, regulation; Both
Fitness acute & chronic
exercise
beneficial;
Neurobiological
effects (DA, NE,
BDNF).

Behavioral Children Sleep problems Effective for 81

Sleep (onset, duration, reducing sleep

Interventions quality), ADHD problems
symptoms, (moderate
Behavior, QoL effect); Modest
improvement in
ADHD
symptoms,
behavior, QoL;
Benefits often
sustained.

Note: EF = Executive Function; WM = Working Memory; ODD = Oppositional Defiant

Disorder; QoL = Quality of Life; DA = Dopamine; NE = Norepinephrine; BDNF =
Brain-Derived Neurotrophic Factor. Effectiveness ratings are general summaries
based on cited reviews/meta-analyses.

The selection and combination of treatments should be highly individualized. While

stimulants often show the largest effect sizes for core symptom reduction 46, their
suitability can be limited by side effects or patient preference. Non-stimulants offer
valuable alternatives.51 Behavioral therapies are crucial for addressing functional
impairments and teaching coping skills 63, and evidence suggests combining
medication and behavioral therapy often yields superior outcomes compared to either
modality alone.63 Lifestyle interventions like optimizing diet, ensuring sufficient
exercise, and addressing sleep problems provide a foundational layer of support and
can augment the effects of core treatments.74 Critically evaluating the evidence,
particularly regarding rater blinding in non-pharmacological studies 73, is essential for
making informed treatment decisions.

6. Challenges in ADHD Diagnosis and Treatment

Despite significant advances in understanding and treating ADHD, numerous
challenges remain in accurately diagnosing the disorder, managing it effectively over
the long term, and overcoming societal barriers.

6.1. Diagnostic Accuracy and Challenges

Obtaining an accurate ADHD diagnosis, particularly in adults, can be complex.
●​ Underdiagnosis in Adults: Historically viewed as a childhood condition, ADHD in
adults remains significantly underdiagnosed, with estimates suggesting up to
75-80% of affected adults may not have received a diagnosis.9 This stems from
factors including lack of clinician training in adult ADHD, misconceptions about
adult presentation (e.g., expecting overt hyperactivity), and the absence until
recently of specific adult diagnostic guidelines.9 The consequences of
undiagnosed adult ADHD are profound, including increased risk for secondary
mental health issues, relationship instability, occupational difficulties, and
substance misuse.1
●​ Gender Disparities: Diagnostic biases persist across genders. Boys are
diagnosed more frequently in childhood, often due to more overt
hyperactive/impulsive behaviors aligning with traditional symptom
conceptualizations.11 Girls and women, who may present more often with
inattentive symptoms or internalizing difficulties, are frequently missed or
diagnosed later in life.11 Symptom masking, where individuals intentionally
 compensate to hide difficulties, can further complicate diagnosis in females.85
While women appear to seek treatment more often in adulthood, potentially
"catching up" diagnostically, underlying biases in recognizing female
presentations may still contribute to delayed or missed diagnoses.85
●​ Symptom Overlap and Differential Diagnosis: ADHD symptoms, particularly
inattention, restlessness, and impulsivity, overlap significantly with those of other
common mental health conditions like anxiety disorders, mood disorders
(depression, bipolar disorder), personality disorders, and substance use
disorders.1 This overlap makes differential diagnosis challenging. Clinicians may
misattribute ADHD symptoms to another condition or fail to recognize ADHD
when it co-occurs with a more familiar disorder.86 A thorough assessment is
required to disentangle symptoms and identify all relevant diagnoses.
●​ Assessment Methods: Diagnosis relies heavily on clinical interviews, review of
history (including childhood symptoms, as onset before age 12 is required 2), and
symptom rating scales.9 Obtaining collateral information from family members or
partners is highly recommended, especially as adults may have difficulty
accurately recalling childhood symptoms or may underreport current difficulties
due to lack of insight or attempts to compensate.87 Standardized rating scales like
the Adult ADHD Self-Report Scale (ASRS) are useful screening and monitoring
tools but are not sufficient for diagnosis alone.87 Neuropsychological testing can
be helpful in clarifying cognitive profiles, particularly EF deficits, but is not
required for diagnosis and cannot definitively confirm or rule out ADHD.16
●​ Lack of Objective Biomarkers: Currently, there is no objective biological test
(e.g., brain scan, blood test) to definitively diagnose ADHD.3 Diagnosis remains a
clinical judgment based on established criteria and comprehensive evaluation.

6.2. Co-occurring Conditions

Comorbidity is highly prevalent in ADHD. Many individuals, particularly adults, have
one or more co-occurring psychiatric or neurodevelopmental conditions.1
●​ Common Comorbidities: These include anxiety disorders (social anxiety,
generalized anxiety, separation anxiety), mood disorders (depression, bipolar
disorder, Disruptive Mood Dysregulation Disorder - DMDD), Oppositional Defiant
Disorder (ODD), Conduct Disorder (CD), learning disabilities (dyslexia,
dyscalculia, dysgraphia), substance use disorders, sleep disorders, and tic
disorders.1
●​ Impact: Co-occurring conditions significantly complicate the clinical picture.
They can exacerbate ADHD symptoms, make diagnosis more difficult due to
overlapping features, and negatively impact treatment outcomes if not
 adequately addressed.6 For example, untreated mood disorders can worsen
ADHD-related functional impairments 89, and untreated ADHD can contribute to
the development or worsening of anxiety and depression due to chronic
frustration and failure.12 This potential for a vicious cycle, where undiagnosed
ADHD leads to secondary conditions that then mask or complicate the ADHD
diagnosis, highlights the need for comprehensive assessment.85
●​ Management: Effective management requires identifying and treating all
co-occurring conditions alongside ADHD.40 Treatment plans must be integrated
and consider potential interactions (e.g., some ADHD medications might worsen
anxiety 89). This often necessitates a multidisciplinary approach involving primary
care physicians, psychiatrists, psychologists, and educational specialists.

6.3. Treatment Adherence

Despite the availability of effective treatments, adherence to medication and therapy
regimens is a major challenge in ADHD management, significantly limiting real-world
effectiveness.90
●​ Rates of Non-Adherence: Studies indicate that a large proportion of individuals,
particularly adults, do not take their medication consistently as prescribed.
Adherence rates often drop significantly within the first year of treatment, with
estimates suggesting only 20-40% maintain regular use after 12 months.90
Adherence tends to decline over time, and patterns of stopping and restarting
medication are common.90
●​ Barriers to Adherence: Reasons for poor adherence are multifaceted and
include:
○​ Medication-Related Factors: Troublesome side effects (e.g., appetite loss,
sleep problems), perceived lack of efficacy, inconvenience of dosing
schedules (especially multiple daily doses).65
○​ Patient/Family Factors: Forgetfulness, disorganization, and time management
difficulties inherent to ADHD itself (i.e., EF deficits) make remembering to take
medication or attend appointments challenging.65 Negative beliefs about
medication (safety concerns, fear of dependence), disbelief in the ADHD
diagnosis, stigma associated with taking medication, and patient/adolescent
unwillingness also play roles.65
○​ Systemic Factors: Cost of medication, lack of insurance coverage, difficulty
accessing providers, lack of adequate follow-up and titration support from
clinicians.65
●​ Strategies for Improvement: Enhancing adherence requires a proactive and
collaborative approach:
 ○​ Education: Thoroughly educating patients and families about ADHD
neurobiology, the rationale for treatment, medication effects (benefits and
side effects), and realistic expectations.65
○​ Collaboration: Building a strong clinician-patient alliance where treatment
decisions are made collaboratively.91
○​ Medication Optimization: Careful titration to find the optimal dose,
considering long-acting formulations for simpler regimens 65, and promptly
addressing side effects or lack of efficacy.65
○​ System Support: Ensuring regular follow-up, especially early in treatment 65,
utilizing pharmacy reminders or automatic refills, and addressing cost barriers
where possible.65
○​ Behavioral Strategies: Using reminders (alarms, pill boxes), linking
medication-taking to daily routines, and employing caregiver training for
behavioral support.65 Addressing the executive function challenges that
impede adherence is crucial.91

6.4. Stigma
Social stigma surrounding ADHD remains a significant barrier, impacting individuals
with the diagnosis and their families.39
●​ Sources and Types: Stigma arises from misconceptions, lack of understanding,
negative stereotypes (e.g., ADHD as laziness, poor parenting, or not a "real"
disorder), and often inaccurate media portrayals.39 It can be external (public
stigma involving bias, discrimination, exclusion) or internal (self-stigma involving
shame, low self-esteem, concealment).39 Families can experience affiliate stigma,
feeling blamed or judged.1
●​ Impact: Stigma contributes directly to many of the challenges discussed:
○​ Delayed Help-Seeking: Fear of judgment prevents individuals from seeking
diagnosis or treatment.39
○​ Diagnostic Barriers: Clinician bias or lack of belief in adult ADHD can hinder
accurate diagnosis.39
○​ Treatment Non-Adherence: Individuals may avoid medication due to perceived
stigma.90
○​ Social and Emotional Consequences: Stigma leads to peer rejection, social
isolation, bullying, excessive negative feedback, low self-esteem, and
increased risk for anxiety and depression in both individuals with ADHD and
their caregivers.1
○​ Functional Impairment: Discrimination in school or the workplace can limit
opportunities and contribute to poorer long-term outcomes.39
The intertwined nature of stigma with diagnostic and treatment barriers creates a
significant obstacle course for those affected by ADHD. Overcoming stigma requires
continued public education, improved clinician training, and fostering environments of
understanding and support.

7. Future Directions in ADHD Research and Treatment

The field of ADHD research is rapidly evolving, driven by advances in neuroscience,
genetics, and technology. Future directions aim to refine our understanding of the
disorder's etiology, develop more objective diagnostic tools, innovate therapeutic
approaches, and ultimately move towards more personalized and effective care.

7.1. Advances in Neuroscience

Neuroscience research continues to probe the biological underpinnings of ADHD,
seeking to identify causal pathways and potential targets for intervention.

7.1.1. Understanding Etiological Pathways

Research is moving beyond simply identifying risk factors towards understanding the
complex mechanisms through which they contribute to ADHD. Key areas include:
●​ Genetics and Epigenetics: While specific gene variants (e.g., in DAT1, DRD4)
show associations 26, the focus is shifting towards understanding how multiple
genes interact (polygenic risk) and how environmental factors influence gene
expression through epigenetic modifications (changes that alter gene activity
without changing the DNA sequence).26 Investigating gene-environment (GxE)
interactions and the impact of early environmental influences (including prenatal
factors like maternal stress or nutrition, and postnatal factors like toxin exposure
or psychosocial stress) on brain development and ADHD risk is a priority.26
●​ Neurodevelopmental Trajectories: Longitudinal studies tracking brain
development (using neuroimaging) and behavior from infancy or childhood
through adolescence and adulthood are crucial for understanding how ADHD
emerges and evolves over time, and identifying critical periods for intervention or
factors predicting persistence versus remission.26

7.1.2. Biomarkers for Diagnosis and Treatment Response

A major goal is to identify reliable biological markers (biomarkers) that can aid in
diagnosis, predict treatment response, or delineate neurobiologically distinct
subtypes of ADHD.27 Current diagnosis relies on subjective behavioral criteria 88,
leading to challenges discussed earlier. Potential biomarkers under investigation
include 27:
●​ Genetic Markers: Specific variants in candidate genes (e.g., DAT1, DRD4, NET1,
ADRA2A) or polygenic risk scores.
●​ Neurochemical Markers: Levels of neurotransmitters or their metabolites (e.g.,
NE, MHPG, PEA), enzymes (e.g., MAOA, DBH), or neurotrophic factors (e.g., BDNF)
in peripheral fluids (blood, urine).
●​ Neuroimaging Markers: Patterns of brain structure (MRI volumes/thickness),
white matter integrity (DTI-FA), or function (EEG measures like theta/beta ratio,
event-related potentials; fMRI activation patterns or connectivity metrics).
●​ Neurophysiological/Cognitive Markers (Endophenotypes): Measures like
reaction time variability (RTV), performance on specific EF tasks, or eye-tracking
patterns.

The Research Domain Criteria (RDoC) initiative encourages integrating data across
these levels (genetics, imaging, cognition, behavior) to define neurobiologically
grounded constructs relevant to mental disorders.27 Advanced computational
methods, including machine learning and AI, are being applied to analyze complex
multimodal data to identify predictive signatures.4 While promising, no single
biomarker is currently validated for clinical use, and future work requires large-scale
replication and validation studies.27

7.1.3. Novel Neural Targets

Research is expanding beyond the traditional focus on dopamine and norepinephrine
systems to explore other neurotransmitter systems and neural pathways that may be
dysregulated in ADHD and offer potential therapeutic targets:
●​ Glutamatergic System: Glutamate is the primary excitatory neurotransmitter.
Modulating glutamatergic signaling, potentially via NMDA or AMPA receptors or
metabotropic glutamate receptors (mGluRs), is being investigated as a way to
influence neuronal plasticity, hyperactivity, and cognitive function relevant to
ADHD.93 Drug candidates like NRCT-101SR (targeting glutamatergic synapses) and
amantadine (NMDA antagonist) represent this approach.93
●​ Nicotinic Acetylcholine Receptors (nAChRs): Cholinergic systems, particularly
those involving nAChRs (especially the α4β2 and α7 subtypes), play a role in
attention, arousal, and cognition.94 Nicotine itself can improve attention but has
significant adverse effects. Novel, selective nAChR agonists (e.g., ABT-418,
ABT-089) have shown preliminary efficacy signals in adult ADHD trials,
particularly for improving attention and organization, with potentially better safety
profiles than nicotine.47 Combining alpha7 nAChR agonists with stimulants is also
 being explored.93
●​ Other Systems: Research continues into other potential targets, including the
serotonergic system (relevant given SNDRIs like centanafadine), histaminergic
pathways involved in arousal, and potentially neuroinflammatory pathways
suggested by PET findings of microglia activation.28

7.2. Pharmacological Innovations

Drug development for ADHD aims to improve upon existing treatments by enhancing
efficacy, duration of action, tolerability, and safety, as well as offering novel
mechanisms.

7.2.1. New Drug Candidates

Several new chemical entities are in various stages of development:
●​ Centanafadine (EB-1020): A novel serotonin-norepinephrine-dopamine
reuptake inhibitor (SNDRI) with a unique reuptake inhibition profile (NE:DA:SE ratio
1:6:14).49 Phase 3 trials in adults showed statistically significant improvements in
ADHD symptoms compared to placebo, with generally good tolerability and
potentially lower abuse potential than traditional stimulants.49 Indirect
comparisons suggest efficacy comparable to atomoxetine and viloxazine, less
than lisdexamfetamine, but with a potentially more favorable side effect profile.48
●​ Other Novel Mechanisms: Drugs targeting the glutamatergic (e.g., NRCT-101SR)
or nicotinic (e.g., nAChR agonists) systems represent distinct approaches moving
through the pipeline.93

7.2.2. Novel Drug Delivery Systems

Optimizing how existing medications are delivered is a major focus:
●​ Extended Duration: Achieving true once-daily, full-day (e.g., up to 16 hours)
coverage remains a goal to improve convenience and adherence, and provide
consistent symptom control without the need for booster doses.93
●​ Precision Timed Release: Technologies like Cingulate's PTR platform (used for
CTx-1301, a dexmethylphenidate formulation) aim to deliver multiple, precisely
timed releases of medication from a single dose to achieve rapid onset and
sustained effect throughout the day, potentially mimicking multiple
administrations of immediate-release forms but with once-daily dosing.93
●​ Prodrugs: Designing medications as inactive prodrugs (like lisdexamfetamine)
that require metabolic conversion in the body to become active can lead to
smoother pharmacokinetic profiles (less peak-and-trough variation) and
 potentially reduce abuse liability, as the active drug is released more gradually.93

7.2.3. Focus on Improved Side-Effect Profiles

A key driver for innovation is reducing the burden of side effects associated with
current medications, such as appetite suppression, insomnia, and cardiovascular
effects, which are common reasons for non-adherence.93 Novel mechanisms and
delivery systems are often engineered with the specific goal of improving tolerability.54

7.3. Advancements in Non-Pharmacological Treatments and Integrated Care

Future research will also focus on refining and enhancing non-pharmacological
interventions:
●​ Personalizing Behavioral Therapies: Identifying which specific components of
CBT are most effective for particular individuals or symptom profiles 69 and
developing more targeted interventions.
●​ Optimizing Cognitive Training: Improving the design of cognitive training
programs to enhance far transfer to real-world functioning and academic skills,
possibly by targeting multiple cognitive domains or integrating training with other
therapies.72
●​ Leveraging Technology: Utilizing digital platforms for delivering interventions
(e.g., online CBT, telehealth PTBM, exergaming for physical activity 80, mobile
apps for reminders and skill-building) to increase accessibility and engagement.
Technology also plays a critical role in research through advanced data analysis
techniques.26
●​ Integrated Care Models: Further developing and evaluating models that
effectively integrate pharmacological, behavioral, educational, and lifestyle
interventions, ensuring coordinated and comprehensive care across different
settings (home, school, clinic).

The overarching trend is towards a more personalized approach to ADHD care. By

combining deeper etiological understanding, objective biomarkers, novel therapeutic
targets, optimized drug delivery, and refined non-pharmacological strategies, the
future holds promise for treatments tailored to the individual's unique neurobiological
and clinical profile, leading to improved outcomes and quality of life.

8. Conclusion
8.1. Summary of Key Findings
Attention Deficit Hyperactivity Disorder (ADHD) is a complex and prevalent
neurodevelopmental disorder characterized by impairing levels of inattention,
hyperactivity, and impulsivity. Its roots lie in distinct neurobiological differences,
particularly involving the structure and function of the prefrontal cortex and its
associated networks (including the basal ganglia, limbic system, and cerebellum), as
well as dysregulation in key neurotransmitter systems, notably dopamine and
norepinephrine. These neurological underpinnings manifest as significant deficits in
executive functions – such as working memory, inhibition, planning, and emotional
regulation – which, in turn, drive the cognitive and behavioral symptoms observed
across the lifespan. Neuroimaging studies consistently reveal group-level differences
in brain structure, function, and connectivity in individuals with ADHD, providing
strong evidence for its biological basis, although these findings are not yet specific
enough for individual diagnosis due to the disorder's heterogeneity. The cognitive
impacts (e.g., difficulties with sustained attention, organization, processing speed)
and behavioral manifestations (e.g., restlessness, impulsivity, task incompletion, social
difficulties) pervasively affect academic, occupational, social, and personal
functioning.

8.2. Recap of Treatment Efficacy and Modalities

A range of effective treatments exists for managing ADHD. Pharmacological
interventions, particularly stimulant medications (methylphenidate and amphetamine
derivatives), remain the most potent treatments for core symptom reduction,
demonstrating high response rates and significant effect sizes. Non-stimulant
medications (atomoxetine, alpha-2 agonists like guanfacine and clonidine, and
viloxazine) provide valuable alternatives or adjuncts, especially when stimulants are
contraindicated, poorly tolerated, or insufficient. Behavioral therapies, including
Parent Training and Behavior Management (PTBM) for children and Cognitive
Behavioral Therapy (CBT) for adolescents and adults, are essential for teaching
coping skills, managing challenging behaviors, and addressing functional impairments
related to executive dysfunction. School-based interventions are critical for
supporting academic and social success. Cognitive training shows promise for
improving specific cognitive skills like working memory, but evidence for broad
transfer to real-world functioning remains limited. Lifestyle interventions focusing on a
healthy diet, regular physical exercise, and adequate sleep provide foundational
support and can yield modest benefits for ADHD symptoms and overall well-being.

8.3. Emphasis on Personalized, Multimodal Treatment and Ongoing Research

Given the heterogeneity of ADHD and the multifaceted nature of its impact, a
personalized, multimodal treatment approach is paramount. Optimal management
involves tailoring interventions to the individual's specific symptom profile, age,
co-occurring conditions, functional impairments, and personal preferences.
Combining evidence-based strategies – often medication alongside behavioral
therapy and lifestyle support – generally yields the best outcomes. However,
significant challenges persist, including difficulties in achieving accurate and timely
diagnosis (especially in adults and females), managing common co-occurring
conditions, overcoming treatment non-adherence, and combating societal stigma.

Future research holds considerable promise for addressing these challenges and
further improving care. Advances in neuroscience, including genetics, epigenetics,
and advanced neuroimaging, aim to unravel the complex etiological pathways of
ADHD and identify reliable biomarkers for diagnosis, subtyping, and predicting
treatment response. This knowledge fuels the exploration of novel neural targets (e.g.,
glutamatergic, nicotinic systems) and the development of innovative pharmacological
agents (e.g., centanafadine) and drug delivery systems designed for enhanced
efficacy, duration, tolerability, and safety. Concurrently, research continues to refine
non-pharmacological interventions, investigate their mechanisms, and leverage
technology for improved delivery and accessibility. The ultimate goal is to move
towards a future of precision medicine for ADHD, where treatments can be more
effectively matched to the individual's underlying neurobiology and specific needs,
leading to more substantial and sustained improvements in functioning and quality of
life for those affected by this challenging, yet manageable, disorder.

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