Technical Insight: Attention Deficit/Hyperactivity Disorder (ADHD)
Overview
Attention-deficit/hyperactivity disorder (ADHD) is a neurobehavior disorder affecting over 6.1 million children in the United States as of 2016 (Danielson et al., 2018). Historical research primarily focused on adolescent boys as it was thought to be predominant among that gender. Recent analysis indicates potentially equal prevalence in females and males, and that females are significantly under-diagnosed due to a quieter presentation of symptoms (Quinn & Madhoo, 2014).
ADHD is characterized by three dominant behavior traits: inattention, hyperactivity and impulsivity. Symptoms include distraction; difficulty sustaining focus, tasks or conversation; excessive movement and restlessness; impulsive decisions; and actions that defy normal social behavior. One of three ADHD subtypes, Inattentive, Hyperactive-Impulsive or Combined, is assigned at diagnosis based on the majority of the symptoms presented by an individual (Centers for Disease Control and Prevention, 2020b). However, each individual's journey with ADHD is unique and symptoms are not identical from one individual to the next.
At this time, numerous therapies and treatments work to increase executive function and decrease interruptive social behaviors, but a cure is unknown. Current therapeutic approaches can include any combination of nutritional strategies, exercise, cognitive behavioral therapy, pharmaceuticals, executive function coaches, speech and occupational therapy, stress management practices and acupuncture. Approximately, two-thirds of children struggle with ADHD well into adulthood (Attention Deficit Disorder Association, 2013). Causes and risk factors for ADHD are multi-factorial and not well-established.
Etiology/Pathogenesis
Numerous associative factors have been identified in ADHD, but direct causes remain unknown. Strong evidence suggests ADHD is an inheritable, familial condition, yet how genes are linked to ADHD etiology is still under investigation. Faraone and Larsson compared the results of 37 twin studies conducted from 1971 to 2017, as seen in the below diagram, and calculated ADHD inheritability to be 74% (2019).
(Faraone & Larsson, 2019)
In a cohort study of approximately 32,000 individuals with ADHD in Sweden, individuals were 70 times more likely to be diagnosed with ADHD if they had an identical twin with ADHD and eight times more likely if they had a fraternal twin or sibling with the disorder (Q. Chen et al., 2017). Given ADHD inheritability, scientists initially focused efforts on establishing causality with genes that influence ADHD-associated behaviors, yet were unable to link specific genes responsible for the disorder.
More recent efforts demonstrate scientists’ focus on epigenetics, which is the study of inheritable, external influences on gene expression that do not change an individual’s basic genetic code. Whether a gene is active or inactive is influenced by age, environment, lifestyle and disease (Epigenetics: Fundamentals, n.d.). DNA methylation, histone modification and microRNA have roles in altering genomic expression. Scientists are looking for these biomarkers in genes related to neurodevelopmental processes and establishing statistically relevant prevalence in ADHD cohorts.
DNA methylation is the addition of a methyl group in the DNA major groove. Methylation in the promoter region interferes with transcription of the corresponding gene. Usually the promoter regions of house-keeping genes, genes used to regulate basic cellular functions, are unmethylated (Ruemmele & Garnier-Lengliné, 2012). However, methylation status is affected by the presence or absence of CH3 molecules. DNA methylation plays an integral role in brain development, differentiation and in neurogenesis (Pineda-Cirera et al., 2019).
Strands of DNA are tightly wound around proteins called histones for structural support and storage in the cell nucleus. This packing protects DNA but also serves as an efficient mechanism for turning genes on or off based on geometric access to promoter regions (Ruemmele & Garnier-Lengliné, 2012). Modification of histones by methylation, acetylation or phosphorylation change accessibility of genes for transcription.
(Epigenetics: Fundamentals., n.d.)
MicroRNAs are small non-coding RNAs that regulate coding genes downstream from transcriptional regulation by degrading target mRNA or inhibiting their translation (Felekkis et al., 2010; Ruemmele & Garnier-Lengliné, 2012).
Many environmental factors have epigenetic influences, such as exposure to environmental toxins, stressful life events and nutrition. A few known associations with ADHD include (Centers for Disease Control and Prevention, 2020b; M.-H. Chen et al., 2019; Dunn et al., 2019; Huang et al., 2018; Zhang et al., 2019):
Cesarean births
Premature delivery
Low birth weight
Maternal smoking and/or alcohol use during pregnancy
Maternal acetaminophen use during pregnancy and/or paternal acetaminophen use preconception
Exposure to environmental toxins, such as lead
Maternal infection
Maternal obesity
Pathology/Mechanisms of Disease
Ongoing research demonstrates differences in brain circuitry, development and volume in multiple brain structures in those with ADHD. Structural and chemical differences are tied to genetic polymorphisms as a result of epigenetic influences discussed above. Many details remain unknown, but imaging and clinical studies also implicate neurotransmitter pathways regulating executive function, reward processing, timing and information processing (Faraone & Larsson, 2019).
Neuroanatomical Differences
The gray matter in the brain houses the majority of the brain’s nerve cells. Physical differences noted in ADHD patients include a 4% reduction in overall gray matter (Dunn et al., 2019). Multiple areas of the brain show reduced gray matter and cortical thinning on PET and MRI imaging scans, including the (Dunn et al., 2019; Jagger-Rickels et al., 2018):
Prefrontal cortex connected to planning, working memory, cognitive inhibition and problem solving
Striate cortex which processes visual information
Orbito-limbic circuit regulating emotion and impulse control
Parietal and temporal lobes managing attention
In addition to overall reduced gray matter, children with ADHD have delayed cortical growth. The frontal, parietal, temporal and occipital lobes reach peak volume three years later than typical developing children (Dunn et al., 2019; Jagger-Rickels et al., 2018) The growth delays of these brain regions may correlate with developmental delays seen in children with ADHD. Structural differences and function are also consistently noted in the basal ganglia (Dunn et al., 2019; Jagger-Rickels et al., 2018).
Neurofunction Differences
Deficiencies and impaired function of neurotransmitters affecting mood and behavior are consistently noted in ADHD pathology. Dopamine, serotonin, GABA and glutamate are the most often studied and reported.
Dopamine
Dopamine is synthesized and released in the brain via dopaminergic pathways. While dopaminergic pathways regulate executive function, learning and neuroendocrine function, dopamine is best known for its role in motivation-reward behavior. The anticipation of a reward increases dopamine levels in the brain. Dopamine deficiency has been reported in those with ADHD. In fact, medications, such as methylphenidates and amphetamines, regularly used to treat ADHD, increase levels of dopamine in the synaptic cleft (Dunn et al., 2019). Further noted dopamine discrepancies in patients with ADHD include:
Polymorphisms in genes coding for dopamine transporters, receptors and regulators (Dunn et al., 2019; Volkow et al., 2009)
Lower availability of dopamine transporters and receptors in PET imaging studies in ADHD adults along the mesoaccumbens dopamine pathway (Volkow et al., 2009)
Serotonin
Serotonin is a monoamine transmitter made from tryptophan that regulates mood, sleep, cognition and memory. It is often nicknamed the “good mood” neurotransmitter as low levels are implicated in anxiety and depression. Reduced serotonin levels in the neuronal synapse and reduced serotonin synthesis due to tryptophan deficiency are working theories of serotonin’s involvement in ADHD pathology (Dunn et al., 2019). SSRIs, used to treat Major Depressive Disorder, increase the amount of serotonin in the synapse. SSRIs are often used for patients with ADHD that are not responsive to methylphenidates and amphetamines (De Sousa & Kalra, 2012). In addition, ADHD patients often have comorbidities with anxiety and Major Depressive Disorder, which are linked to serotonin pathways (Dunn et al., 2019).
GABA / Glutamate
GABA and Glutamate are inhibitory and excitatory neurons that project to the striatum and influence dopamine neurotransmission (Dunn et al., 2019). GABA and Glutamate work in a synergistic balance with one another and are proposed to be out of balance in patients with ADHD.
Clinical Manifestations
The key signs and symptoms of ADHD are an array of inattention, hyperactivity and impulsivity behaviors that are considered inappropriate for the child's or adult's current stage of development. All individuals may exhibit these behaviors; however, in an individual with ADHD, the behaviors are more intense, frequent and interfere with daily life and function in multiple settings. An individual may miss details in reading or conversation, make careless mistakes with work, have trouble reading social cues, exhibit difficulty sustaining attention, incorrectly follow directions, lack organizational skills, be restless, impulsive, exhibit unexpected behavior, talk incessantly and/or interrupt others.
Symptoms can present as early as age three but must appear by age twelve to qualify as ADHD. In preschool years, the most common ADHD symptom is hyperactivity and impulsivity, which can be mistaken for disciplinary or emotional issues (The National Institute of Mental Health, 2019). Symptoms of ADHD are also commonly missed in quiet, well-behaved individuals. In particular, females present more often with less obvious inattentive symptoms and are less likely to be referred for diagnosis (Quinn & Madhoo, 2014).
ADHD presentation changes as an individual matures and grows. As a child enters adolescence, inattention may become the more prominent symptom and observed in academic difficulties. Individuals with ADHD often struggle in peer relationships missing social nuances that come with older age. Hyperactivity becomes recognized as restlessness and fidgeting. These behaviors usually persist into adulthood, but not in every case.
Over two-thirds of individuals with ADHD present with additional neurodevelopmental or mental health disorders demonstrating the correlation of numerous health disorders (Children and Adults with Attention-Deficit/Hyperactivity Disorder, n.d.; Danielson et al., 2018). Often these co-occurring disorders complicate diagnosis and treatment as patient presentation becomes unique and atypical. Common other disorders include oppositional defiant disorder, conduct disorder, learning disabilities, anxiety, depression and autism spectrum disorders (Centers for Disease Control and Prevention, 2020a).
Diagnosis
Diagnosis is performed by ADHD specialists, such as a developmental pediatrician, psychologist, or psychiatrist, and includes a thorough medical history, clinical interviews and various assessments measuring symptoms, executive function skills, as well as signs and symptoms of other disorders typically diagnosed alongside ADHD. The provider will begin using the screening criteria outlined by the American Psychiatric Association in the Diagnostic and Statistical Manual, Fifth edition (DSM-5).
To qualify for diagnosis, children up to the age of sixteen must exhibit six or more of the inattention symptoms considered inappropriate for their developmental stage for at least six months. Individuals aged seventeen and older require five or more symptoms. Inattention symptoms include (Centers for Disease Control and Prevention, 2020b):
Often fails to give close attention to details or makes careless mistakes in schoolwork, at work, or in other activities.
Often has trouble holding attention on tasks or play activities.
Often does not seem to listen when spoken to directly.
Often does not follow through on instructions and fails to finish schoolwork, chores, or duties in the workplace (e.g., loses focus, side-tracked).
Often has trouble organizing tasks and activities.
Often avoids, dislikes, or is reluctant to do tasks that require mental effort over a long period of time.
Often loses things necessary for tasks and activities.
Is often easily distracted.
Is often forgetful in daily activities.
Similar to inattention, a child must also exhibit six or more symptoms of hyperactivity-impulsivity. Individuals aged seventeen and older must exhibit five or more symptoms to qualify for diagnosis. Hyperactivity-impulsivity symptoms include (Centers for Disease Control and Prevention, 2020b):
Often fidgets with or taps hands or feet, or squirms in seat.
Often leaves seat in situations when remaining seated is expected.
Often runs about or climbs in situations where it is not appropriate or feels restless.
Often unable to play or take part in leisure activities quietly.
Is often “on the go.”
Often talks excessively.
Often blurts out an answer before a question has been completed.
Often has trouble waiting their turn.
Often interrupts or intrudes on others.
In addition, the following conditions must be met (Centers for Disease Control and Prevention, 2020b):
Several symptoms presented before age twelve
Symptoms presented in more than one environment
Symptoms interfere with social, school or work functioning
Symptoms are not attributable to another mental disorder
The ADHD Diagnosis is further broken down into one of three subtypes (Attention Deficit Disorder Association, 2013):
Combined Presentation: symptoms of both inattention and hyperactivity-impulsivity
Inattentive Presentation: predominant symptoms of inattention
Hyperactive-Impulsive Presentation: predominant symptoms of hyperactivity-impulsivity
Symptoms change over time and can affect the presentation. In addition to the DSM-5 criteria, practitioners employ other tools. As part of a thorough clinical interview, questionnaires completed by teachers, parents and/or the individuals quantify symptoms and how well the individual functions at home, work or school based on a standard ADHD rating scale (Attention Deficit Disorder Association, 2013). Screening tests are administered to rule out common coexisting conditions like learning disorders, spectrum disorders and mood disorders. Intelligence tests are common to measure IQ and screen for learning disabilities common in individuals with ADHD. Tests of specific abilities such as language development, memory recall and motor skills may be used if learning disabilities or processing challenges are suspected. Some providers use computer continuous performance tests (CPTs) to measure attention and impulsivity. MRIs and SPECT brain scans are used in some cases to look for abnormalities in the brain but are not the standard of care (Attention Deficit Disorder Association, 2013).
Comorbidity
Comorbid conditions, such as Major Depressive Disorder, Anxiety, Obsessive-Compulsive Disorder (OCD), Oppositional Defiant Disorder (ODD), Learning Disabilities, Atopic Disease and Language Delays are common in ADHD pathology. A few are discussed here in further detail.
Major Depressive Disorder
Approximately 47% of adults and 14% of children with ADHD are also diagnosed with Major Depressive Disorder (MDD) (Children and Adults with Attention-Deficit/Hyperactivity Disorder, n.d.). ADHD and MDD affect similar regions of the brain and like ADHD, neuroimaging studies have shown differences in volume, activity and neurotransmitter function in the areas related to emotion and mood (Katzman et al., 2017). Dysfunction in the limbic-cortical-striatal-pallidal-thalamic (LCSPT) circuit, which integrates higher cognitive function with environmental inputs, and related neurotransmitters GABA and dopamine have been implicated as playing a key role in both MDD and ADHD pathology (Katzman et al., 2017).
Atopic Disease
Prevalence of ADHD and atopic diseases such as asthma, atopic dermatitis and allergic rhinitis are correlated. Presence of atopic dermatitis before the age of two is associated with an increased probability of ADHD by 16% (Liao et al., 2016). Animal studies provide evidence of strong sensitivity of the neurotransmitter system to inflammation exposure in utero (Dunn et al., 2019). Associated sensitivities and inflammation exposure suggest that a dysfunctional immune response in atopic pathology could exert pathological effects on neurotransmitter development and related ADHD symptomologies.
In addition, the gut brain connection is a possible link between atopic disorders and ADHD. The gut brain connection is a bi-directional pathway of communication between the Central Nervous System and the gut microbiota in the digestive system linked by various afferent and efferent pathways. Intestinal neurotransmitters, like serotonin, inflammatory cytokines and essential metabolites convey directional information to the CNS and the CNS communicates to the gut microbiota, directly altering bacterial composition, through the HJPA axis and sensory nerve fibers. Hyper-inflammatory states in atopic disorders seem to influence the pathogenesis of other inflammatory conditions like ADHD (Petra et al., 2015).
Exercise
Exercise has been studied as a potential factor in modifying ADHD disease symptomology and progression. Moderate intensity exercise has demonstrated a positive impact on brain function in children and adults particularly with ADHD. A clinical trial of 33 children aged 11 to 14 years assessed the effect of swimming on mental health, cognition and motor coordination for eight weeks (Silva et al., 2020). Children in the swimming group demonstrated significant improvement in depression, stress, cognitive flexibility and selective attention compared to the sedentary control group. Improvements were also seen in lower limb coordination and abdominal resistance.
Another clinical trial assigned 46 eight- to twelve-year-old children to either an exergaming intervention undergoing moderate to vigorous activity for 14 minutes or a sedentary control and assessed executive function (Benzing et al., 2018). The intense exercise resulted in improved reaction times in inhibition (attention control and inhibiting predominant responses) and switching between tasks but did not demonstrate change to accuracy or visual working memory. Chang et al. found that 20 minutes of moderate-intensity exercise exhibited the highest improvement in cognitive function for adults, measured by shorter response time and higher accuracy (2015).
Acute exercise increases catecholamine (dopamine, epinephrine and norepinephrine) transmission, improving executive function and attention. In addition, acute exercise modulates event-related potentials (ERPs) or measured brain responses by increasing P3 amplitudes, which are implicated in the process of decision-making, and reducing latencies (Benzing et al., 2018). In adults acute exercise demonstrated increased connectivity in a variety of areas related to executive function and attention, such as the frontoparietal and the ventral attentional network (Weng et al., 2017).
Note from the Author: The Functional Medicine Approach to Treatment
ADHD is a complex, multi-factorial disorder with many therapies. The majority of approaches today work to reduce symptoms but do not treat the root cause of the problem. While ADHD strategies are not the focus of this article, I would be remiss not to mention the Functional Medicine approach to ADHD that I have seen work with much success. Functional Nutrition practitioners work to find and treat the root cause of ADHD symptoms by identifying metabolic, nutritional, environmental and genetic indicators, improving and in some cases eliminating symptoms. In future articles, I will take a deeper look at nutritional deficiencies, genetic variations, neurotransmitter imbalances, pharmaceutical usage, and other treatment approaches.
Extra Reading
A double-blind clinical trial of 50,000IU/week Vitamin D supplementation in ADHD children, demonstrated significant effects in improving ADHD symptoms. Check out this article for more details: https://pubmed.ncbi.nlm.nih.gov/30456564/
Evidence regarding the beneficial effect of Polyunsaturated Fatty Acid Supplementation on ADHD. Check out this article for more details: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5669464/
Mineral-Vitamin Treatment Associated with Remission in ADHD 52 weeks post-baseline. Check out article here for more details: https://www.ohsu.edu/sites/default/files/2019-09/Mineral-vitamin%20treatment%20associated%20with%20remission%20in%20ADHD%20symptoms%20and%20related%20problems.pdf
Ted Talk on Living with ADHD: https://www.ted.com/talks/jessica_mccabe_this_is_what_it_s_really_like_to_live_with_adhd_jan_2017?utm_campaign=tedspread&utm_medium=referral&utm_source=tedcomshare
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