The subtypes of ADHD: ADHD-HI (predominantly hyperactive), ADHD-C (combined type), ADHD-I (ADD)

Author: Ulrich Brennecke
Review: Waldemar Zdero, M.A. in Psychology (as of April 2024)

ADHD does not manifest the same way in everyone. Some people are primarily characterized by restlessness and impulsivity, others by inattention and daydreaming, and still others by both. These different manifestations are called presentation forms. They used to be called subtypes.

(ADxS assessment): The DSM-5 diagnostic manual distinguishes three forms of presentation:

• ADHD-HI: predominantly hyperactive and impulsive. People with ADHD are restless, often act before they think, and tend to overreact. This frequently leads to conflicts with others.
• ADHD-I: predominantly inattentive. This type used to be called ADD. People with this type daydream a lot, lose their train of thought easily, forget things, and avoid noisy groups. They don’t stand out much to others and are therefore often diagnosed late.
• ADHD-C: the combined type. In this type, both symptoms are pronounced—that is, inattention as well as hyperactivity and impulsivity.

(ADxS Assessment): The purely hyperactive form of ADHD-HI is diagnosed almost exclusively in younger children, typically up to about six or seven years of age. This is primarily because attention problems only become apparent when prolonged concentration is required in school. Children who are classified as having ADHD-HI when they are young are therefore often reclassified as having the combined type later on.

(ADxS assessment): The prevalence of each form depends heavily on who was studied. In large systematic reviews, all three forms are roughly of the same magnitude. In smaller individual studies, however, the figures vary considerably. This demonstrates one thing above all: chance plays a major role in the composition of the study groups.

It is important to note that these presentation forms are not distinct disorders. The causes and brain mechanisms are very similar across all three forms. There is merely evidence suggesting that certain genetic factors are more likely to contribute to outwardly visible symptoms.(E 2b)⁹ The three forms—ADHD-HI, ADHD-I, and ADHD-C—are considered well-established. However, there is insufficient evidence to support a separate subtype involving social behavior disorders, as outlined in the older diagnostic manual, ICD-10. (E 4)¹⁰

(ADxS Assessment): In our view, the most important difference between the subtypes concerns the body’s response to stress. When under stress, the body releases, among other things, the hormone cortisol. In ADHD-I, this cortisol response tends to be too strong, while in ADHD-HI and ADHD-C, it tends to be too weak. This aligns with the outward behavior: Those who react strongly with cortisol tend to withdraw when under stress. Those who barely react tend to turn outward.

(ADxS assessment): We therefore view these presentation forms as different ways of responding to one and the same underlying disorder. Which form develops likely depends primarily on personality and on how one has learned to cope with stress, particularly on

• whether someone is more extroverted or more introverted,
• how sensitive someone is to stress,
• what one’s personal approach to coping with stress looks like, and
• how a person has learned to cope with stress from those around them.

Other mental disorders, such as depression or anxiety disorders, also exhibit these inward- and outward-directed manifestations. (E 4)¹¹

The way the condition presents itself can change over the course of a person’s life. (E 2b)¹² (ADxS experience): We know quite a few people with ADHD who report a significant change.

(ADxS Assessment): In addition to these three categories, researchers have proposed many other classifications, such as those based on brainwave patterns (EEG), emotional profiles, cognitive abilities, or comorbid conditions. None of these classifications has gained widespread acceptance so far. The second part of this article presents them. They do not currently play a role in everyday treatment.

(ADxS assessment): Four things in particular are relevant for people with ADHD:

• The presentation of ADHD provides insight into how the disorder manifests, but says nothing about the severity of a person’s symptoms or how well treatment works.
• ADHD-I is often overlooked because people with ADHD do not appear to have any outward symptoms. A late diagnosis does not mean that the symptoms are less severe.
• The way things are presented may change. It’s possible that someone’s perspective today is different from what it was ten years ago.
• There are currently no reliable measurement methods that could determine shape on a case-by-case basis. All of the measurements described below reveal differences between groups, not among individual people.

(ADxS Assessment): SCT (Sluggish Cognitive Tempo) is no longer considered a subtype of ADHD, but rather a distinct condition that frequently co-occurs with ADHD. We have dedicated a separate article to it: ⇒ CDS - Cognitive Disengagement Syndrome (SCT - Sluggish Cognitive Tempo)

1. Presentation Forms (Subtypes) of ADHD Based on Symptoms¶

The literature primarily identifies three presentation forms (subtypes) of ADHD: ADHD-I (1.1.), ADHD-HI (see 1.2.), and ADHD-C (see 1.3). While the ADHD-HI subtype likely represents merely an early form of the combined type, Sluggish Cognitive Tempo (SCT) is increasingly recognized as a distinct disorder. The forms described sporadically below are unlikely to represent true subtypes and are mentioned here solely for the sake of completeness.

Regardless of the classification of ADHD-I, ADHD-HI, and ADHD-C based on observed symptoms, there is a classification system based on different measured EEG patterns ⇒ ADHD Subtypes Based on EEG. This classification has not yet gained widespread acceptance, even though it could be measured using objective biomarkers. To date, there is a lack of experience regarding the different symptom presentations of the EEG subtypes and how they respond to specific treatments. An attempt to automatically distinguish between presentation types based on their EEG patterns using AI failed. (E 3)¹³ Furthermore, only 84% of people with ADHD could be distinguished from people without the condition.

1.1. ADHD-I: predominantly inattentive type¶

In ADHD-I, attention problems are the primary concern, not motor restlessness. Typical symptoms include daydreaming, forgetfulness, a slower work pace, difficulty keeping track of multiple tasks, and organizational problems. Restlessness can manifest internally. Because people with this form of ADHD barely cause outward disruption, ADHD-I is often diagnosed late (particularly frequently in girls and women). This does not mean that the burden is any less severe. It is also notable that many people with ADHD react strongly to stress and tend to withdraw when under pressure.

1.1.1. Other names for the ADHD-I subtype¶

• ADHD-I (the term we use today)
• ADS (colloquial term; we used to use it)
• ADD (an older, colloquial international term)
• ADHD-PI (predominantly inattentive)
• Hypoactive (Prof. Simchen)
• Daydreamer (colloquial, descriptive)
• Underactive (easily distracted due to boredom)

1.1.2. Specific Symptoms of ADHD-I¶

ADHD is a cluster of symptoms. The symptoms do not clearly distinguish one presentation type (subtype) from another. In ADHD-I, inattention predominates over hyperactivity, impulsivity, and restlessness.

• , ages 3 to 6 (E 4)¹⁴

  • Requests are not being acted upon
    • therefore does not comply with requests
  • dreamy
  • stares into space
  • has a hard time keeping himself occupied with anything
    • Daydreaming
    • My mind wanders
  • Noisy group situations tend to be perceived as unpleasant
  • Reluctance to change established routines
  • Aversion to rapid changes; needs time to adjust to new situations

• Ages 6 to 10: (E 4)¹⁵

  • Inattention
    • is therefore sometimes unable to follow along in class
  • has difficulty understanding some of the material covered in class
  • Difficulty concentrating
    • based on a teacher’s presentation
    • on one’s own work
  • seems dreamy
  • lack of active participation

• , ages 10 to 20: (E 4)¹⁵

  • possible improvement in attention due to continued brain development
  • Attention problems persist, at least to some extent
    and are still perceived as very stressful

Regardless of age:

• The ADHD-I subtype tends to be more introverted (in contrast to the more extroverted ADHD-HI subtype) (E 4)¹⁶
• internalizing (E 4)¹⁷
• shy (E 4)¹⁸
• increased vulnerability to internalizing disorders (E 4)¹⁹
  e.g.,
  • Anxiety Disorders
  • Depression
• Social problems associated with the ADHD-I subtype arise from (E 4)¹⁶
  • excessive shyness
  • Passivity
  • Introversion
  • Being quiet
• Disorders primarily in working memory and auditory processing, which places high demands on working memory. (E 4)²⁰
• Common comorbid disorders associated with the ADHD-HI subtype (E 4)²¹
• Specific learning disabilities are more common
  • Reading and Spelling Difficulties
  • Dyscalculia (mathematical learning disability)
• Often perform better in spatial reasoning and artistic drawing than in verbal skills. (E 4)²²
• More bored than easily distracted. (E 4)²³
• Problems with motivation rather than problems with inhibition. (E 4)²⁴
• Tends to have a high level of self-awareness. (E 4)²⁴
• Lethargic states (to be distinguished from depression) (E 4)²⁵
• A significant subset of ADHD-I is said to have slowed thinking (sluggish) (E 4)²⁴

(ADxS Assessment): We consider the term “slowed thinking” to be inaccurate and inappropriate. We observe slowed decision-making. The ability to think quickly is fundamentally present. We suspect an excessive blockade of the PFC by norepinephrine and, possibly, other neurotransmitters via the alpha-1 adrenoceptor. SCT is no longer considered a subtype of ADHD, nor is it considered specific to ADHD-I.

 

• More frequent allergies due to an excessive cortisol response. Cortisol supports the immune system’s defense against external stressors.
• Conditions associated with hypercortisolism include (E 4)²⁶
  • Depression
  • Anxiety Disorder
  • Anorexia
  • Alcoholism
  • Metabolic Syndrome
• Learning Disabilities
  • more common than in ADHD-HI (E 4)¹⁷
  • A high cortisol response to acute stress, as is typical of ADHD-I, correlates with poorer memory performance when learning vocabulary after exposure to stress (though only in men). Women may be protected against this by their sex hormones. (E 4)²⁷ Cortisol administration also impaired learning performance.

Cortisol, which is often elevated in ADHD-I as a stress response, blocks the retrieval of declarative (explicit) memory via the glucocorticoid receptors (GR) in the PFC and hippocampus. Non-declarative (implicit, intuitive) memory is not impaired. (E 4)²⁸ This could explain the more frequent thinking and memory blocks seen in ADHD-I, as well as why people with ADHD-I often seem to possess greater intuition. In any case, it would seem obvious that a shift in the focus of memory abilities would lead to a shift in problem-solving patterns. Trappmann-Korr refers to this as “holistic” perception.
It is likely that not only retrieval (recall) but also acquisition (learning) and memory consolidation (long-term storage) of information are impaired. Consolidation occurs primarily during sleep in the first half of the night, which is characterized by particularly low basal cortisol levels. Consolidation can be inhibited by low cortisol administration. (E 4)²⁸

 

• Attention problems

  • Sustained attention (ADHD-HI and ADHD-I subtypes)
  • selective attention (ADHD-I subtype only) (E 4)²⁹

• Negative symptom criteria for ADHD-I:

  • Externalizing behavioral disorders and aggressive behavior are atypical in ADHD-I and indicate the ADHD-HI subtype. (E 4)³⁰.

    • less common symptoms of aggressive or oppositional defiant behavior (E 4)³¹ (E 4)³²

  • ADHD-I is diagnosed less frequently because its symptoms—which involve internalized stress management and are “convenient” for the environment—are less likely to be noticed in an unpleasant way. Furthermore, research is hampered by the fact that many studies do not differentiate their results by presentation type (subtypes) and, in particular, do not distinguish ADHD-C from ADHD-I.

  • Oppositional defiant behavior occurs less frequently as a comorbidity than in the ADHD-HI subtype. (E 4)¹⁶

  • A lower proportion of smokers than in the ADHD-HI subtype. (The mechanisms of action of nicotine and methylphenidate are similar.) (E 4)²⁴

  • rare inflammatory reactions, such as atopic dermatitis, resulting from an excessive cortisol response. Cortisol inhibits the inflammatory processes initiated by CRH and instead promotes the body’s defense against foreign substances; when cortisol levels become excessive, this can manifest as allergies

  • Tests of auditory neuropsychological functions using the Integrated Visual and Auditory Test (IVA) show (E 3)³³

    • Individuals with ADHD-I have poorer auditory attention compared to those without the condition
    • ADHD-I has better outcomes than ADHD-C
      • auditory attention
      • Reaction control
      • sustained attention
      • Prudence
      • Consistency

For more information on the required frequency and intensity of ADHD symptoms, visit ⇒ ADHD Symptoms in Children by Age.

1.1.3. More Omission Errors in the CPT¶

In a computer-based attention test, people with ADHD-I are more likely to make mistakes because they fail to respond. People with ADHD-HI or ADHD-C are more likely to make mistakes because they respond too quickly. This is consistent with what we observe in everyday life, but it is not suitable as a diagnostic tool. These differences apply to groups, not to individuals.

ADHD-I correlates with more omission errors in the Continuous Performance Test (CPT). (E 4)³⁴
ADHD-HI / ADHD-C, on the other hand, correlate with more commission errors.

1.1.4. Special Considerations Regarding Medication¶

(ADxS Assessment): Whether ADHD medications are effective—and to what extent—cannot be predicted based on their formulation. There is evidence that lower doses are sometimes sufficient for ADHD-I and that some people with ADHD respond better to amphetamine-based medications than to methylphenidate. However, it is disputed whether the response rates differ at all.
The right medication and the right dose can only be determined through careful trial and error under a doctor’s supervision. If one medication doesn’t work, that doesn’t mean that no medication will work.

• MPH-Responding
  • According to one view, there is a significant proportion of methylphenidate nonresponders (MPH is ineffective). If MPH is effective, even low doses are often sufficient. (E 4)²⁴
  • According to another view, ADHD-HI and ADHD-I do not differ in terms of the MPH response rate. (E 1b)³⁵
• A significant proportion of people with ADHD-I respond better to amphetamine medications than to MPH.
• The following may also be helpful:
  • Nortriptyline
  • Bupropion (if stronger stimulation is needed)

1.1.5. Neurophysiological Characteristics of ADHD-I¶

(ADxS Assessment): This section explains what might be different in the body in cases of ADHD-I. One of the most important points is that, in ADHD-I, the cortisol response to stress is often too strong. This explains why concentration and memory suffer particularly under stress and why rest and avoiding stimuli often help more than exertion.

(ADxS assessment): The other factors (neurotransmitters, receptors, genes) are still under investigation. None of them can be measured or treated. They may explain why the forms differ, but so far they do not contribute to diagnosis or treatment.

1.1.5.1. Elevated Cortisol Stress Response in ADHD-I¶

ADHD-I appears to be frequently associated with a particularly strong cortisol response to acute stress. ⇒ Changes in Cortisol Levels in ADHD in: Cortisol and Other Stress Hormones in ADHD

1.1.5.2. Stress Responses Involving Cortisol, Norepinephrine, and Dopamine¶

Underactivation of the PFC in ADHD-I can be explained by the fact that the stress responses of cortisol, norepinephrine, and dopamine in the brain are correlated. For more on this, visit ⇒ Neurotransmitters and Stress

1.1.5.3. CRH¶

CRH also affects the PFC and, at high levels, can impair its function.
Elevated cortisol responses to a stressor correlate with increased variance in response time. (E 3)⁴¹ Increased variance in response times could be explained by impaired PFC function, which is particularly pronounced in the ADHD-I subtype. This impairment could also be explained by increased norepinephrine responses to acute stress, analogous to the cortisol response. Some clinicians pay particular attention to this variance in response times when diagnosing ADHD-I.
Cortisol leads to a decrease in cortisol and norepinephrine. This negative feedback is the consequence of cortisol (which shuts down the HPA axis again) and is independent of the synchrony of cortisol and norepinephrine release in response to stress.

1.1.5.4. Dopamine receptors¶

The dopamine D4 receptor (DRD4) plays a particularly important role in the PFC, which is why Diamond (E 4)⁴² posits that a disorder in the DRD4 7R gene is associated with ADHD-I. We do not believe this to be accurate.

1.1.5.5. Serotonin decreases¶

A serotonin deficiency is often thought to be present in ADHD-I. (E 4)⁴⁵
One study found a strong association between the L/L genotype of the 5-HTTLPR gene and ADHD-C and ADHD-HI, while the 5-HTTLPR L/L genotype showed no difference. (E 1b)⁴⁶
The 5-HTTLPR L/L genotype is associated with hyperactivity symptoms. (E 3)⁴⁷
A study reports a correlation between the presence of the 5-HTTLPR-S allele and inattention. (E 3)⁴⁸

1.1.5.6. Orexin A reduces¶

The ADHD-I subtype may have lower levels of orexin A than the ADHD-HI subtype and than non-affected individuals. (E 3)⁴⁹ For more information on orexin, visit ⇒ Orexin / Hypocretin In the section ⇒ Hormones in ADHD in the chapter ⇒ Neurological Aspects.

1.1.6. EEG Findings in ADHD-I¶

See “ADHD Subtypes Based on EEG” below for more information.

1.1.7. Sluggish Cognitive Tempo (SCT) as a Distinct Disorder¶

SCT describes a state characterized by dreaminess, slowness, and mental absent-mindedness.
SCT is now considered a distinct disorder separate from ADHD, even though SCT and ADHD very often occur together. However, there are people with SCT who do not have ADHD.
If you recognize yourself in the description of ADHD-I but, above all, struggle with lethargy and daydreaming, it’s worth taking a look at the linked post.

Learn more about SCT at ⇒ SCT (Sluggish Cognitive Tempo).

1.2. ADHD-HI: predominantly hyperactive/impulsive subtype¶

In this subtype, restlessness and impulsivity are the primary characteristics. People with ADHD act before they can think, interrupt others, get angry quickly, and are more likely to get into conflicts. This subtype becomes apparent early on and is therefore usually diagnosed early. Pure ADHD-HI occurs almost exclusively in younger children. Later on, attention problems almost always develop, resulting in the combined type. An important difference from ADHD-I: The body’s stress response tends to be too weak in this case.

1.2.1. Other names¶

• ADHD-HI (as used by us)
• ADHD-H/I (hyperactive/impulsive)’
• ADHD-PH (predominantly hyperactive/impulsive)
• ADHD (colloquially used as the counterpart to ADD; however, it encompasses both ADHD-HI and ADHD-C. It competes with the colloquial use of ADHD as an umbrella term for all subtypes)
• Fidgety Phil (colloquial term; however, it also applies to ADHD-C)

1.2.2. Specific symptoms¶

This list describes the symptoms that occur more frequently in ADHD-HI.
The symptoms are directed outward. This leads to conflicts within the family, at school, and at work, and these conflicts are usually more stressful than the symptoms themselves. Impulsivity leads to reactions that people with ADHD often regret afterward. This is not a character flaw, but rather part of the disorder. Because this form becomes apparent at an early age, it is more easily recognized early on (more frequently in boys than in girls).

• a pronounced manifestation of
  • Hyperactivity
  • Impulsivity
• no inattention
  • if inattention is present in addition to hyperactivity/impulsivity: ADHD-C, see below
• Social problems are very common
  • occur because of the ADHD-HI subtype
    • offends others
    • takes things away from them
    • can’t wait for his turn
    • comes across as too direct and assertive
    • behaves in a disruptive manner and
    • acts without considering the feelings of others (E 4)⁵⁰
• more extroverted (in contrast to the more introverted ADHD-I subtype) (E 4)¹⁷ (E 4)¹⁶
• Frequent behavioral disorders and (comorbid) aggressive behavior (E 4)⁵¹.
• Common comorbidities associated with oppositional defiant disorder (E 4)²⁴
• Disorders primarily involving behavioral inhibition (E 4)²⁴ and executive functions (E 4)⁵²
• Is more easily distracted than bored (E 4)²⁴
• Has more of an inhibition problem than a motivation problem. (E 4)²⁴
• A tendency toward low self-awareness (E 4)²⁴
• Good response to methylphenidate.
  • The nonresponder rate (MPH is ineffective) is estimated to be 10 percent (E 4)⁵³, compared to the usual overall rate of 20 to 30 percent.
  • The striatum is primarily affected. The fact that DAT1 plays an important role in the striatum and that MPH primarily acts on DAT explains the positive effect of MPH in ADHD-HI. (E 4)²⁴
• A higher proportion of smokers than in the ADHD-I subtype. (Like methylphenidate, nicotine acts as a stimulant.) (E 4)²⁴
• The hyperactive/impulsive subtype is often merely a precursor in childhood or adolescence to later ADHD-C (E 4)⁵⁴ (E 4)⁵⁵
• Boys are 5 times more likely to be affected than girls (E 4)⁵⁶.

Negative Symptom Delimitation in ADHD-HI:

• If inattention and hyperactivity (the latter also referred to as inner drivenness) are present, the condition known as ADHD-C is diagnosed.
  Inattention can usually only be diagnosed between the ages of 6 and 15. ADHD-HI (with hyperactivity but without attention problems) can therefore be considered an early form of the later combined type. (E 4)⁵⁴ (E 4)⁵⁷

(ADxS Assessment): The higher the level of giftedness, the better the coping mechanisms. The older the people with ADHD are, the more individual symptoms may have remitted, which is why inattention that is absent in test settings (but well-masked) does indeed occur. Similarly, the people with ADHD’s high intrinsic interest in the tests leads to a leveling of test performance compared to people without ADHD. This is plausible when considering the stress-related benefits and, consequently, the mechanisms underlying the stress symptom of inattention.

• In ADHD-HI, allergies appear to occur less frequently than in the ADHD-I subtype, likely due to the more commonly blunted cortisol response to stress. Cortisol enhances the immune response to external stressors such as allergens.

1.2.3. More pulse errors in the CPT¶

The attention test reveals a picture of everyday life: reactions that are too quick rather than impulsive ones. Here, too, the test cannot determine the form of presentation.

ADHD-HI / ADHD-C correlate with more commission errors in the Continuous Performance Test (CPT). (E 4)³⁴
(No evidence): ADHD-I, on the other hand, correlates with more omission errors

1.2.4. Neurophysiological Characteristics of ADHD-HI / ADHD-C¶

In ADHD-HI (with hyperactivity/impulsivity) and similarly in cases of associated aggression, the release of catecholamines and cortisol in response to acute stressors is often reduced or absent compared to non-affected individuals, whereas the cortisol stress response in people with ADHD-I is typically elevated compared to people without the condition.

1.2.4.1. A Flattened Cortisol Stress Response in ADHD-HI / ADHD-C¶

ADHD-HI is often associated with a blunted cortisol response to acute stress. ⇒ Cortisol in ADHD

• Conditions associated with hypocortisolism include: (E 4)²⁶

  • Atypical depression
  • Inflammatory problems (E 4)⁵⁸ are more common than in the ADHD-I subtype. Cortisol inhibits the CRH-mediated inflammatory response
    • e.g., irritable bowel syndrome
    • e.g., atopic dermatitis
  • Fatigue
    • Cortisol inhibits the pro-inflammatory effects of CRH
    • Cortisol stimulates cytokines such as interleukin 1 and 6. This leads to “sickness behavior” (as seen with a fever):
      • Exhaustion
      • Lack of initiative
      • Fatigue
    • e.g., Chronic Fatigue Syndrome
    • e.g., burnout
  • Sensitivity to pain
    • Cortisol inhibits prostaglandin synthesis (= disinhibition of prostaglandins)
    • Prostaglandins modulate pain perception
    • resulting in a systemic lowering of the pain threshold (pain symptoms “wander”)
    • Hypocortisolism can promote inflammatory processes in the spinal cord (chronic pain)
    • e.g., fibromyalgia (E 3)⁵⁹
    • e.g., chronic lower abdominal pain
  • Stress intolerance
    • Cortisol inhibits the locus coeruleus, thereby reducing norepinephrine release in the CNS
    • A low cortisol response results in reduced inhibition of norepinephrine = loss of an important stress-regulating mechanism
    • Hypocortisolism thus causes stress intolerance, irritability, and sensitivity to sensory stimuli (noise, etc.)
    • Hypocortisolism could promote the development of intrusions such as those observed in PTSD (E 3)⁶⁰

• Inadequate HPA axis suppression in ADHD-HI / ADHD-C

  • Since cortisol not only mediates stress symptoms but also shuts down the HPA axis, a reduced cortisol stress response results in a lack of a brake on the HPA stress system.
    ⇒ The HPA Axis / Stress Regulation Axis And ⇒ The Autonomic Nervous System.

1.2.4.2. Reduced CB1 Receptors in Impulsivity¶

• Children with SHR exhibit behavioral subgroups corresponding to ADHD-HI and ADHD-I

  • A study identified subgroups of SHR (spontaneously hypertensive rats) that differed significantly in terms of impulsivity. Impulsive SHR showed, compared to non-impulsive SHR and WKY (used as controls, in which no behavioral subgroups were found) (E 2b)⁶¹
    • reduced norepinephrine levels
      • in the cingulate cortex
      • in the medial frontal cortex
    • reduced serotonin turnover
      • in the medial frontal cortex
    • reduced density of CB1 cannabinoid receptors
      • in the PFC
      • A single administration of a cannabinoid agonist reduced impulsivity in impulsive SHR, with no change observed in WKY rats

• Inadequate HPA axis suppression in ADHD-HI / ADHD-C

  • CB1 receptors are essential for the downregulation of the HPA axis. CB1 antagonists prevent the rapid feedback regulation mediated by GR antagonists, which initiates the downregulation of the HPA axis.
  • CB1 receptors regulate the HPA axis:
    • A disorder in the CB1 gene caused hyperactivity of the HPA axis (E 2b)⁶²
    • Endogenous cannabinoids appear to inhibit the HPA axis via CB1 receptors in the brain
    • Anandamide
      • lowers corticosterone levels in stressed animals (E 2b)⁶³
      • reduces the endocrine stress response of the HPA axis (E 2b)⁶⁴
    • Endogenous cannabinoids inhibit the basal activity of the HPA axis and suppress its stress-induced activity via the hypothalamus, pituitary gland, and adrenal cortex. Stimulation of central cannabinoid receptors leads to activation of the sympathetic nervous system (E 2b)⁶³
    • Activation of peripheral CB1 receptors inhibits the release of norepinephrine from sympathetic terminals and the release of epinephrine from the adrenal glands (E 2b)⁶³
    • Endogenous CB1 agonists have an anxiolytic effect and prevent the onset of pathological anxiety (E 2b)⁶³
    • CB1 may not influence adaptation to daily chronic stress (E 2b)⁶⁵
    • CB1 mediates the rapid downregulation of the HPA axis by GR agonists (endocrine feedback loop), in this case by dexamethasone (E 2b)⁶⁶ (E 2b)⁶⁷ CB1 antagonists block this downregulation.

1.2.4.3. Reduced Norepinephrine Breakdown in ADHD-HI / ADHD-C?¶

Cortisol also causes the breakdown of norepinephrine.

(ADxS assessment): An insufficient cortisol response to acute stress and the resulting inadequate breakdown of norepinephrine could potentially explain the persistent overactivation of the PFC in ADHD-HI/ADHD-C.
A slightly elevated level of (dopamine and) norepinephrine in the PFC increases its activation and leads to improved cognitive performance. (E 2b)⁶⁸ (E 2b)⁶⁹ (E 2b)⁷⁰ (E 2b)⁷¹ (E 3)⁷² Only a sharp increase in norepinephrine/dopamine shuts down the PFC. (E 2b)³⁶ (E 2b)³⁷ (E 2b)³⁸ (E 2b)³⁹ (E 2b)⁴⁰

1.2.4.4. Reduced hippocampal volume in ADHD-HI / ADHD-C¶

A fairly extensive study reported a reduced hippocampal volume in ADHD-HI compared to ADHD-I and non-affected individuals: (E 2b)⁷³
* ADHD-HI: Reduction in hippocampal regions
* CA1
* CA4
* Molecular layer
*, the granular cell layer of the dentate gyrus
* Presubiculum
* Subiculum
* Hippocampus tail
*; other regions of the hippocampus were not reduced in size
* ADHD-I: No Reliable Differences in Hippocampal Volume Compared to Controls
* Finally, smaller hippocampal regions correlated with higher behavioral ADHD indices. For example, a smaller subiculum correlated with a higher total ADHD-HI index, higher hyperactivity/impulsivity, and a lower IQ.

1.2.4.5. Indoleacetic acid in ADHD-HI / ADHD-C¶

A study found that people with ADHD-HI and comorbid depressive symptoms had significantly higher morning levels of indoleacetic acid than evening levels. MPH reduced this by 50%. At the same time, MPH reduced morning levels of indolepropionic acid and brought the daily profile back in line with the levels observed in healthy control subjects. (E 2b)⁷⁴

1.2.4.6. TSH, Serum Ferritin, Lactic Acid in Hyperactivity (ADHD-HI / ADHD-C)¶

Among 49 children with ADHD, both with and without hyperactivity, the following was found: (E 3)⁷⁵

• TSH correlated with Conners-3 scale scores (ADHD)
  • so clear that diagnostic use might be conceivable
• TSH, serum ferritin, and lactate correlated with the HI value
• TSH and lactic acid were independently associated with HI

1.2.4.7. Volume of the Gray Matter¶

A study found differences in gray matter volume (GMV) among ADHD subtypes: (E 3)⁷⁶

• ADHD-C: GMV significantly increased
  • compared to ADHD-I
    • in the left caudate nucleus
  • compared to those who are not affected
    • right precentral gyrus
    • right inferior frontal gyrus
    • right superior frontal gyrus
    • left cingulate gyrus
• ADHD-I: GMV significantly increased in
  • compared to those not affected
  • right cingulate gyrus

1.2.4.8. DlPFC Activation During Movement While Performing Executive Functions¶

Children with ADHD completed a Stroop test as an executive function task while sitting still or pedaling on a desk bike. Changes in oxygenated and deoxygenated hemoglobin in the left DLPFC differed according to ADHD subtype, ADHD severity, and gender: (E 3)⁷⁷

• Individuals with ADHD-HI, ADHD-C, and severe ADHD, as well as men, showed greater dlPFC activation during the executive task while engaging in physical activity than while sitting still.
• ADHD-I, mild and moderate ADHD, and women showed greater dlPFC activation during the executive task while sitting still than during physical activity
• In women with ADHD-I, inhibitory control improved when they sat still.

1.2.5. EEG Findings in ADHD-HI¶

See the section below on “Presentation Forms (Subtypes)” for ADHD based on EEG.

1.3. ADHD-C (a mixed type of ADHD-HI and ADHD-I)¶

(ADxS Assessment): The mixed-type ADHD-C is the most common form among children who seek treatment. In this type, both areas are strongly pronounced. Within this group, researchers further distinguish whether a person primarily has difficulty inhibiting actions (action impulsivity), or primarily has difficulty waiting for a reward (choice impulsivity), or both, or neither. It is noteworthy that these subgroups appear almost identical from the outside but differ significantly in the brain. This suggests that different underlying mechanisms may be responsible for the same set of symptoms.

• pronounced symptoms in both core symptom areas:
  • Hyperactivity (visibly evident in children, but more often manifested as inner restlessness in adults) AND impulsivity
  • Inattention
    • Problems with sustained attention (ADHD-C and ADHD-I)
    • fewer problems with selective attention (ADHD-I subtype only) (E 4)²⁹
• Largely corresponds to the hyperkinetic disorder as defined in ICD-10.2.3.1. Subgroups of ADHD-C

A large-scale study of adolescents identified three subgroups of ADHD-C in which the specific symptoms were accompanied by changes in brain structure—as measured by fMRI—in the brain systems known to be involved in these cognitive functions. (E 3)⁷⁸

A small study replicated earlier findings indicating that frontal delta and theta power is higher in the ADHD-C group than in the ADHD-I and TD groups. (E 3)⁷⁹

The following sections describe subgroups within the mixed type. This classification is based on research and is not used in practice. It is noteworthy that these subgroups differ barely in behavior but show significant differences in brain activity. This suggests that the same behavior can have different causes.

1.3.1. ADHD-C with inhibitory control deficits, without reward deficits¶

“Inhibitory deficits” refers to deficits in executive functions and inhibitory cognitive functions.

Hypofunction within

• various frontal lobes
• Parietal lobe
• subcortical
• Cerebellar regions

in the inhibition of motor responses

and

Anomalies

• the posterior default mode
• in the ventral striatum

during error handling.

Executive function deficits are also evident in other studies. (E 3)⁸⁰ (E 1a)⁸¹ (E 1a)⁸² (E 2b)⁸³

Hypothyroidism in

• frontal gyrus
  • pre-supplementary motor area (pre-SMA)
  • middle frontal gyrus
  • precentral frontal gyrus
• Insula
• Caudates
• Thalamus

Hyperfunction in the

• inferior frontal gyrus
• postcentral gyrus
• Precuneus

1.3.2. ADHD-C with inhibitory control deficits and reward processing deficits¶

This subgroup experiences both difficulties at the same time: restraining their actions and waiting for a reward. In everyday life, this manifests as particularly pronounced impatience combined with impulsive behavior. This classification is based on research and is not used in practice.

Overactivation in

• cortical and subcortical regions that generally do not overlap

during error handling, as well as

• overactive amygdala regions and
• overactive ventral striatum regions,

when they made an effort to earn rewards.

1.3.3. ADHD-C without reward deficits and without inhibition deficits¶

(No evidence): This was the most common subgroup. Consistent with the absence of the specific symptoms mentioned, no neurological abnormalities were found.

1.4. Other ADHD Classifications¶

This section compiles numerous other proposed classification systems, such as those based on emotional profiles, cognitive abilities, brain findings, or comorbid conditions. These represent the current state of research, not diagnostic practice. This suggests that the current classification is not the only possible approach. This currently has no practical consequences for diagnosis or treatment.

The “subtypes” listed below, which have been mentioned sporadically in the literature, do not represent true presentation forms (subtypes) of ADHD, but rather possible grouping models that categorize more typical forms of ADHD.

1.4.1. ADHD-RI: Restrictive-Inattentive Subtype¶

(ADxS assessment): This refers to a particularly “pure” form of inattention with almost no hyperactivity. Background: The standard ADHD-I category includes people with up to five hyperactive symptoms. ADHD-RI has stricter criteria. Individuals with ADHD have poorer sustained attention but better impulse control than others. To date, this distinction has not played a role in diagnosis.

(No evidence): ADHD-RI was not included as a presentation type in DSM-5 due to a lack of robust neurobiological data.
(No evidence): ADHD-RI differs from ADHD-I and ADHD-C in the following ways:

• fewer externalizing behaviors (E 3)⁸⁴
  • possibly due to less impairment of the DMN and/or greater impairment of the salience network (E 3)⁸⁴
• Impaired sustained attention (E 3)⁸⁴
• improved reaction inhibition (E 3)⁸⁴
• The ADHD-RI group exhibited a neuropsychological profile that was significantly different from that of the other groups, including a
• reduced psychomotor speed (E 3)⁸⁵
• longer response times (E 3)⁸⁵ (E 3)⁸⁶
• the lowest overall score on the global neurocognitive index (E 3)⁸⁵ (E 3)⁸⁶
  • a lower neurocognitive index than SCT (p < 0.001) (E 3)⁸⁶
• a significantly higher proportion with a DRD4-7-repeat allele (E 3)⁸⁵
• Attention-related posterior brain regions (particularly temporal-occipital areas) were more strongly activated in response to both “Go” and “No-Go” cues than in controls and ADHD-I (E 3)⁸⁵
• slower psychomotor speed than SCT (E 3)⁸⁶
• Only SCT was independently associated with poorer overall memory performance (E 3)⁸⁶

1.4.2. ADHD with oppositional defiant disorder (?)¶

(ADxS Assessment): Oppositional behavior (i.e., frequent contradicting, defiance, and arguing) is common in ADHD-HI and ADHD-C. In our view, however, it is not a distinct form of ADHD, but rather a comorbid condition.
A comorbid condition is treated in addition to, and in conjunction with, other medications and forms of therapy.

(ADxS assessment): In our view, oppositional defiant disorder is a comorbidity that occurs primarily in individuals with ADHD-HI and is not a subtype of ADHD-HI.
Significantly, even those who accept that there are presentation forms (subtypes) of ADHD associated with oppositional defiant disorder describe this condition only in connection with the ADHD-C and ADHD-HI subtypes, but not with the (stress-phenotypically introverted) ADHD-I subtype.

1.4.3. Rage Type (?)¶

The “rage” type is rarely described as a distinct category. It is thought to refer to ADHD-HI with aggressive comorbidities.

Similarly, a subtype characterized by increased emotional excitability/irritability has been proposed. (E 2b)⁸⁷

1.4.4. Residual Type¶

The term “residual type” refers to people with ADHD who have the condition only partially evident in adulthood—that is, who exhibit ADHD that has partially remitted, is no longer fully pronounced, but is still present.
This does not automatically rule out a diagnosis, and treating the remaining symptoms may still be appropriate.

1.4.5. ADHD Adult Type Pairs According to Reimherr¶

Reimherr classifies adults based on whether their primary issues are attention problems or difficulties managing their own emotions. According to this perspective, suffering from severe mood swings, irritability, and the feeling of being unable to control one’s own emotions is a core characteristic of a specific subtype.

In eight replication studies involving 1,490 people with ADHD, Reimherr et al. identified two clusters: the inattentive adult subtype and the emotionally dysregulated adult subtype. (E 2b)⁸⁸. The findings are consistent with an earlier study by the authors.(E 2b)⁸⁹ Both presentation forms (subtypes) benefited equally from MPH treatment.

1.4.5.1. The “Inattentive Adult” Type¶

• inattentive
• emotionally dysregulated

1.4.5.2. Emotionally Dysregulated Adult Type¶

Emotional dysregulation manifests itself, among other things, in

• Anger
• emotional lability
• emotional overreactivity

1.4.6. ADHD Presentation Types (Subtypes) Based on Internalizing/Externalizing Symptoms¶

(ADxS assessment): This classification is based on symptoms directed inward and outward.
In the underlying study, nearly six out of ten children also had an autism spectrum disorder. The group with the most pronounced symptoms is therefore primarily characterized by autistic traits, which significantly limits the generalizability of the findings to ADHD without autism.

Katsuki et al. describe four ADHD subtypes based on a cluster analysis of emotional and behavioral symptoms in children aged 4 to 15 with ADHD: (E 2b)⁹⁰

• “Highly internalizing/externalizing”
  • Overlap between internalizing and externalizing symptoms
    • possibly mediated by emotional dysregulation and associated neurophysiological correlates
  • high rate of comorbid autism spectrum disorders
  • increased autistic traits
• “Inattention and Internalization”
  • high rate of predominantly inattentive ADHD (ADHD-I)
• “Aggression and Externalization”
  • high rate of comorbid oppositional defiant behavior
  • high rate of comorbid behavioral disorders
• “Mild Psychopathology”
  • low scores on all syndrome scales

1.4.7. ADHD Groups by Symptom Severity¶

This classification is organized by severity and lists the associated conditions for each category. The percentages should not be interpreted to mean that specific associated conditions belong to specific groups.

1.4.8. ADHD Groups Based on Emotional Profiles¶

This classification is based on emotional characteristics: a low-key group, an adventurous group, and an irritable group. Over time, the irritable group is more likely to develop additional medical conditions. Interestingly, this classification has remained more stable over the years than the classification into ADHD-I, ADHD-HI, and ADHD-C. Irritability could therefore be a highly informative characteristic.

A study classified ADHD into three subtypes based on personality traits and emotional profiles: (E 2b)⁸⁷

• Mild ADHD subtype
  • Normal emotional functioning was observed in this group of people with ADHD.
• Distressed ADHD subtype
  • This subtype was characterized by a particularly severe crisis.
• Irritable ADHD subtype
  • This subtype exhibited high levels of negative affect and had the highest external validity.
  • increased tendency to get angry
  • The subtype remained moderately stable over time and improved the prospective prediction of clinical outcomes beyond standard baseline indicators.
  • The subtype could not be attributed to ADHD-HI + Oppositional Defiant Disorder (ODD), ADHD-HI + disruptive mood dysregulation disorder, or other patterns of comorbidity.

1.4.9. ADHD Groups Based on Microcognitive Biomarkers¶

In this study, children were divided into four groups based on subtle differences in performance on a computer test. According to the authors, these four groups do not correspond to ADHD-I, ADHD-HI, and ADHD-C. It is also noteworthy that two of the four groups performed better than children without ADHD in several areas.
(ADxS assessment): The data comes from a company that markets a digital training program for ADHD, and both authors are employed by that company.

(ADxS assessment): The symptom-based diagnosis does not correspond to the underlying neuropathology, which complicates the development of new therapies and the selection of treatment for individual patients. Highly granular, cost-effective, non-invasive, and scalable digital microcognition biomarkers could identify patients with the same symptom-based diagnosis but different neuropathology.
A study of n = 69 children aged 6 to 9 with ADHD compared performance variables from a Go/NoGo test with those of n = 58 typically developing children (TD) and identified four subgroups using microcognitive biomarkers derived from thousands of responses during digital neurotherapy: (E 3)⁹³

• Cluster 4:
  • poor reaction inhibition
  • inconsistent attention
  • a much greater ability to recognize natural categories—which children learn through physical interaction with the environment—than members of abstract categories
• Cluster 3
  • poor reaction inhibition
• Cluster 2
  • Faster and more consistent responses than TD
  • Better detection of simple targets than TD
  • better working memory than TD
  • Attention problems; significant decline in performance when
    • Pursuing multiple goals (divided attention)
    • Distraction
• Cluster 1
  • a much greater ability to recognize members of abstract categories than natural categories, which children learn through physical interaction with the environment

1.4.10. ADHD Groups Based on Fractional Anisotropy of White Matter¶

Two groups differ in the structure of their neural pathways and respond to methylphenidate to varying degrees. This sounds like a way to predict the drug’s effect. However, the data on response are based on only 52 of 227 children, and they come from retrospectively analyzed medical records, not from a planned study. An MRI cannot currently predict how the medication will work.

1.4.11. ADHD Groups as Cognitive Biotypes¶

In this study, two groups were formed based on cognitive performance and then compared using EEG, heart rate, and response to atomoxetine. Methodologically, this is one of the better studies in this chapter because it is based on a blinded, placebo-controlled drug trial.

For the most part, the groups identified could not be mapped onto the usual classification systems. The authors therefore consider cognitively defined groups to be biologically more meaningful than the current classification based on symptoms.

1.4.12. ADHD Groups Based on Emotional Dysregulation¶

This classification distinguishes between cases where there are difficulties with emotional regulation and those where there are not. Important to note for context: The study included students with self-reported diagnoses or self-assessed symptoms—without medical evaluation—70 percent of whom were women. The results therefore cannot be readily generalized to all people with ADHD.

A study analyzing people with ADHD in terms of emotional dysregulation identified three groups: (E 3)⁹⁶

• predominantly inattentive / exhibits emotional dysregulation / emotionally unstable
• Moderate ADHD severity / no emotional dysregulation / unremarkable personality traits
• Severe ADHD / no emotional dysregulation / unremarkable personality traits

1.4.13. ADHD Groups Based on Topological Deviations in Network Hubs¶

(ADxS assessment): Here, people with ADHD are grouped based on abnormalities in highly interconnected brain regions. This is currently purely basic research involving complex imaging techniques. It has no significance for diagnosis or treatment.

A study identified 3 ADHD groups based on topological differences in morphometric similarity networks using degree centrality (local connection density), node efficiency (shortest communication path), and the participation coefficient (cross-module diversity) of brain morphometry: (E 3)⁹⁷

• the most severe symptoms of hyperactivity/impulsivity and inattention
  • Long-term emotional dysregulation
  • 25% comorbid affective disorders
  • marked changes in the mPFC and pallidum
  • accompanied by spatially correlated increases in receptor levels of
    • Serotonin (5-HT4, r = 0.37; 5-HTT, r = 0.37)
    • Dopamine (D2, r=0.25)
    • Acetylcholine (α4β2, r=0.26; M1, r=0.41)
    • Histamine (H3, r=0.29).
  • The authors cite relevant findings:
    • Tonic, spontaneously firing dopamine neurons are regulated by inhibitory striatal projections (E 4)⁹⁸ and interact with the serotonergic system via orbitofrontal-striatal circuits, which modulates hyperactivity/impulsivity in ADHD (E 4)⁹⁹.
    • Cholinergic dysfunction in the PFC is characteristic of ADHD-C mixed type (E 3)¹⁰⁰ (E 2b)¹⁰¹ (E 3)¹⁰² and particularly impairs motor control and attention
    • Neuroinflammation may play a crucial role in the pathophysiology of ADHD (E 4)¹⁰³, which correlates with elevated H3R levels
• predominant impulsivity and hyperactivity
  • Long-term improvement in emotional dysregulation
  • 9.8% with comorbid affective disorders
  • marked changes in the ACC and pallidum
  • along with a spatially correlated decrease in receptor levels of
    • Glutamate (mGluR5, r = −0.24)
    • Cannabinoid (CB1, r = −0.37)
    • Serotonin (5-HT1A, r = −0.30; 5-HT2A, r = −0.34)
  • The authors cite relevant findings:
    • Changes in the glutamate system could indicate impaired excitatory neurotransmission in caudate-related circuits that mediate cognitive and affective processes, including reward processing (E 3)¹⁰⁴
    • An RCT showed a significant improvement in hyperactivity/impulsivity symptoms with cannabinoids (E 1b)¹⁰⁵
• predominant inattention
  • Long-term reduction in emotional dysregulation
  • 5% comorbid affective disorders
  • marked changes in the superior frontal gyrus
  • along with a spatially correlated decrease in receptor levels of
    • Serotonin (5-HT2A, r = −0.25)

These groups largely correspond to the three well-known presentation types described in the DSM-5.
It is well known that emotional dysregulation correlates more strongly with hyperactivity/impulsivity—or the combined type of ADHD—than with predominantly inattentive ADHD, and that more severe ADHD symptoms correlate with greater emotional dysregulation. For more on this, see Emotional Dysregulation / Emotional Symptoms in ADHD

Figure from Pan N, Long Y, Qin K, Pope I, Chen Q, Zhu Z, Cao Y, Li L, Singh MK, McNamara RK, DelBello MP, Chen Y, Fornito A, Gong Q (2025): Mapping ADHD Heterogeneity and Biotypes through Topological Deviations in Morphometric Similarity Networks. medRxiv [Preprint]. March 28, 2025:2025.03.27.25324802. doi: 10.1101/2025.03.27.25324802. PMID: 40196255; PMCID: PMC11974972. under Creative Commons Attribution 4.0 International License

1.4.14. ADHD Groups Based on Comorbidities¶

(ADxS Assessment): Here, people with ADHD are categorized based on what other conditions they have. This is often more important for treatment than the clinical presentation, because the presence of an additional anxiety disorder, depression, or social behavior disorder significantly influences treatment planning. Therefore, it is worthwhile to have comorbid conditions explicitly assessed.

An analysis of the MTA study identified four clinical profiles that are sufficiently distinct to warrant classification as ADHD subtypes: (E 3)¹⁰⁶

• ADHD without a comorbid disorder
  • responded best to pharmacological MTA treatments (with or without behavioral therapy)
• ADHD combined with internalizing disorders (ADHD + ANX, primarily anxiety disorders reported by parents)
  • appeared to respond equally well to behavioral therapy and medication-based MTA treatments
• ADHD with ODD/CD, but without anxiety (ADHD + ODD/CD)
  • responded best to pharmacological MTA treatments (with or without behavioral therapy)
• ADHD with anxiety and ODD/CD (ADHD + ANX + ODD/CD)
  • responded best to combined MTA treatments involving medication and behavioral therapy

2. Neurophysiological and Endocrine Differences Among the Subtypes¶

Hyperactivity is neurologically rooted in the striatum, while inattention is primarily rooted in the PFC. (E 4)¹⁰⁷

(No evidence): It may be necessary to further distinguish between inattention caused by boredom due to an underactive PFC (in ADHD-I) and distractibility caused by overactivity of the PFC (in ADHD-HI).

2.1. Dopamine levels¶

(No evidence): This section addresses the question of whether different presentation forms (subtypes) (based on symptom severity) correlate with specific dopamine (activity) levels. The separate question of whether dopamine deficiency and dopamine excess might represent different disorder patterns—or at least distinguishable variants of ADHD—is addressed at the end of this chapter.

2.1.1. Hyperactivity, Impulsivity: Dopamine Deficiency or Dopamine Excess in the Striatum¶

Hyperactivity and impulsivity, as seen in the ADHD-HI subtype (without inattention) or ADHD-C (with inattention), are (in the context of ADHD) primarily caused by deviations in dopamine levels from the optimal dopamine level in the right-hemispheric striatum (involving the frontostriatal loop, consisting of the PFC, caudate nucleus, and globus pallidus, but not the putamen).(E 4)¹⁰⁷ (E 3)¹⁰⁸ (E 3)¹⁰⁹

According to the prevailing view in the scientific literature, ADHD is associated with a dopamine deficiency. However, animal models (e.g., the DAT-KO mouse) have shown that an excess of dopamine in the striatum can also trigger hyperactivity. For more on this, see ⇒ ADHD in Animal Models in the chapter ⇒ Neurological Aspects. As long as ADHD is not neurobiologically defined (and diagnosed) as a dopamine deficit in the striatum (and/or PFC), but is diagnosed solely on the basis of symptoms, both possibilities must be considered. According to the inverted-U model, both an excess and a deficiency of neurotransmitters (E 4)¹¹⁰ (E 4)¹¹¹, since signal transmission functions properly only at optimal neurotransmitter levels. Nevertheless, the evidence for a deficiency of phasic dopamine in the striatum in ADHD far outweighs the evidence for an excess.

Since dopamine breakdown in the striatum occurs primarily via DAT, whereas dopamine breakdown in the PFC occurs primarily via NET and COMT and not via DAT, the DAT-10R gene variant correlated strongly with hyperactivity and impulsivity, but not with inattention.(E 3)¹¹² (E 4)¹⁰⁷
Another study found no difference in the DAT 9/9, 9/10, or 10/10 gene variants (or in DRD4 gene variants) between ADHD-I on the one hand and ADHD-C and ADHD-HI on the other. (E 1b)⁴⁶

2.1.2. Hyperactivity, Impulsivity: Excess Dopamine in the PFC¶

2.1.3. DAT Differences in Presentation Forms (Subtypes)¶

Various studies suggest a higher number of DATs in ADHD-HI compared to ADHD-I.

However, it is questionable whether DAT actually regulates dopamine levels in the way that has been assumed so far. (E 3)¹¹⁴

2.1.4. Insensitivity to pain as an indicator of a possible high-dopamine subtype?¶

Like all catecholamines, dopamine follows an inverted U-shaped curve: too little is just as harmful as too much.
ADHD is typically characterized by a deficiency of extracellular dopamine. ADHD medications primarily act as dopamine reuptake inhibitors, thereby increasing extracellular dopamine levels. However, the large number of animal models with elevated extracellular dopamine levels suggests that there are likely also cases of ADHD with elevated dopamine levels.
To date, our understanding of this topic has been very limited due to the great difficulty of measuring dopamine in the brain in vivo.
We therefore want to use this section to compile a list of indicators that may suggest elevated dopamine levels in the brain.

Dopamine is an important factor in pain regulation. Chronic pain is usually characterized by reduced dopamine levels. This explains why chronic pain is a common comorbidity of ADHD. Schizophrenia is characterized by elevated dopamine levels and is simultaneously associated with a significantly reduced pain threshold.
For more information, visit ⇒ Chronic Pain and Muscle Tension in ADHD—Neurophysiological Correlates

(ADxS assessment): We derive from this the working hypothesis that reduced pain sensitivity in ADHD could be indicative of a (likely rare) ADHD subtype characterized by elevated dopamine levels.

2.2. Excessive and blunted endocrine stress responses in the different forms (subtypes)¶

In ADHD-I, endocrine stress responses appear to be much more pronounced than in ADHD-HI and ADHD-C.
An endocrine stress response is the release of hormones (and neurotransmitters) in response to an acute stressor.
The ADHD-I subtype often exhibits an exaggerated cortisol stress response, whereas ADHD-HI and ADHD-C are frequently associated with a blunted cortisol stress response. Thus, the ADHD-I subtype typically represents a case of hypercortisolism, whereas ADHD-HI and ADHD-C tend to represent cases of hypocortisolism.
For more information, visit ⇒ Changes in Cortisol Levels in ADHD in: Cortisol and Other Stress Hormones in ADHD

(ADxS Assessment): Since hypocortisolism can be a long-term consequence of hypercortisolism, if persistently elevated cortisol levels trigger a downregulation response (⇒ Downregulation / Upregulation. ⇒ Changes in hormone and neurotransmitter levels depending on the stress phase in the article ⇒ Human Stress Systems (Fundamentals of Stress) In the chapter “ ” ⇒ Stress) of the glucocorticoid (cortisol) receptor systems, one could conclude that ADHD-I represents a preliminary stage and ADHD-HI and ADHD-C represent subsequent stages of ADHD. However, this is contradicted by the fact that the nature of the cortisol response to acute stress tends to reflect a stress phenotype that is already observed in healthy individuals. In disorders with externalizing symptoms (aggression, ODD, CD, etc.), cortisol responses to acute stress are typically blunted, whereas in disorders with internalizing symptoms (depression, anxiety, etc.), cortisol responses are typically elevated.

Elevated cortisol levels are associated with the stress-induced release of norepinephrine and the activation of α1-adrenergic receptors.(E 4)¹²⁶ (E 2b)¹²⁷ Parallel to the issue discussed here regarding the correlation between the neurotransmitter norepinephrine and cortisol, there is a correlation between cortisol and dopamine release.(E 3)¹²⁸ Cortisol levels correlate positively with AMP-induced dopamine release in the left ventral striatum and the dorsal putamen.

(ADxS assessment): We assume that the cortisol, adrenaline, norepinephrine, and dopamine responses in the brain to acute stress are correlated, such that a high cortisol response to acute stress is associated, on the one hand, with high (hormonal)norepinephrine release in the sympathetic nervous system, on the one hand, and with a high (neurotransmitter) norepinephrine and dopamine release in the central nervous system (= brain), on the other. Low levels are also likely to correlate. This could provide a coherent explanation for several patterns observed in ADHD subtypes.

• Mesocortical / mesolimbic system (dopaminergic)
• Amygdala (serotonergic, acetylcholinergic)
• Hippocampus (serotonergic, acetylcholinergic)

2.3. ADHD Presentation Patterns According to EEG¶

Most studies have identified various EEG subtypes in people with ADHD.
Externalizing individuals show a flattened error-related negativity (ERN), while internalizing individuals show an elevated ERN. (E 1a)¹⁶⁰ The ERN is a component of event-related potentials (qEEG). It occurs immediately after an incorrect motor response (given under time pressure). ERN is primarily measured over the PFC.
An attempt to automatically distinguish subtypes based on their EEG patterns using AI failed. (E 3)¹³

The largest study known to us identified five EEG subtypes and showed that externalizing symptoms (ADHD-HI, ADHD-C) were primarily associated with increased slow EEG activity in the theta and delta bands, whereas internalizing symptoms (ADHD-I) were associated with increased activity in the alpha and beta bands.(E 3)¹⁶¹ In contrast, a study of 94 boys between the ages of 6 and 9 found, despite differentiation by subtype, consistently elevated total alpha activity with a reduced alpha peak frequency, reduced alpha bandwidth and reduced alpha amplitude suppression, as well as an increased alpha1/alpha2 (a1/a2) ratio. (E 3)¹⁶²

EEG microstate B is thought to be promising for distinguishing between different presentations of ADHD based on differences in visual network function. (E 4)¹⁶³

2.3.1. ADHD-HI Subtypes Based on EEG Findings¶

In ADHD-HI, EEG abnormalities are primarily found in the striatum and the frontostriatal region. (E 4)¹⁶⁴

2.3.1.1. Increased frontal theta, decreased beta (ADHD-HI with hyperactivity and impulsivity and a hypoactive EEG)¶

2.3.1.2. Elevated beta (“overactivated” ADHD-HI)¶

2.3.2. ADHD-I Subtypes on the EEG¶

In ADHD-I, EEG abnormalities are thought to occur primarily in the PFC and the frontoparietal region. (E 4)¹⁶⁴

2.3.2.1. Delta and Theta increased, Beta decreased¶

2.3.2.2. Only alpha activity is elevated¶

2.3.2.3. Posterior theta increased, alpha and beta decreased¶

2.3.2.4. Only frontal midline theta (FMT) is elevated¶

2.4. ADHD Subtypes According to QEEG¶

A study involving 69 participants identified three QEEG subtypes: (E 3)¹⁹³

• Increased absolute and relative beta performance
  • K-ARS: 25.31
• Increased, relatively rapid alpha and beta power
  • K-ARS: 21.67
• increased absolute slow-wave frequency (delta and theta power)
  • K-ARS: 12.64, which is barely higher than the 11.07 recorded for those not affected
  • WURS: 55.82, significantly higher than the 42.81 for those not affected

The third group was therefore identified only using the WURS (Wender-Utah Rating Scale) and not the K-ARS (Korean ADHD Rating Scale, the most widely used scale in Korea).

2.5. Functional Differences in the Nerve Pathways of the Brain (?)¶

Studies suggesting specific functional differences in the brain’s neural pathways for ADHD-HI and ADHD-I (E 3)¹⁹⁵ (E 3)¹⁹⁶ suffer from very small sample sizes (n < 50), which compromises the reliability of the results (more on this at: ⇒ Studies prove (sometimes nothing at all)).

2.6. Subtypes / Forms of Presentation and Serotonin¶

It has been suggested that serotonin levels differ among the various subtypes, with ADHD-I being associated with the 5-HT1B receptor and ADHD-HI with the 5-HT2A/C receptors. (E 4)¹⁹⁷

2.7. Neuro-auditory Profiles of the Subtypes / Forms of Presentation¶

A study demonstrated differences between ADHD-HI, ADHD-I, and controls in the auditory brain regions, the Heschl’s gyrus (HG) and the planum temporale (PT). ADHD-HI and ADHD-I participants showed reduced gray matter volumes in the left Heschl’s gyrus, resulting in lower HG/PT ratios in the left hemisphere. ADHD-HI showed a lower right HG/PT ratio in the right hemisphere, while ADHD-I did not differ from the controls. ADHD-HI exhibited left-right asynchrony, whereas ADHD-I and controls showed balanced hemispheric response patterns. (E 3)¹⁹⁸

2.8. Amplitude of Low-Frequency Fluctuation (ALFF) and Functional Connectivity (FC)¶

The amplitude of low-frequency fluctuation (ALFF) measures the strength of low-frequency oscillations in a region of the brain. High ALFF values indicate greater local metabolism and more spontaneous neuronal activity, while low ALFF values indicate lower local activity. (E 3)¹⁹⁹
 
A study using functional near-infrared spectroscopy (fNIRS) at rest in children with ADHD-C compared to ADHD-I: (E 3)¹⁹⁹

• increased amplitude of low-frequency fluctuations (ALFF) in certain brain regions
• reduced functional connectivity (FC)

2.9. Phase-Amplitude Coupling¶

Phase-amplitude coupling refers to the phenomenon in which the phase of a slow brain oscillation systematically influences the amplitude of a faster oscillation. It is an important mechanism of neural communication and is involved in attention, sensory processing, and working memory. (E 3)²⁰⁰
A study examined intra- and inter-channel PAC differences across various spatial scales and analyzed the PAC-based properties of the brain network: (E 3)²⁰⁰

• ADHD-I, and even more so ADHD-C, show a stronger α-γ-PAC than healthy controls.
• ADHD-I showed primarily intrahemispheric changes
• In ADHD-C, the left hemisphere and occipital regions are particularly affected.
• In ADHD-C, the PAC in the α-β band was significantly higher than in ADHD-I, particularly in the left hemisphere.
• ADHD-I also showed an increased inter-channel δ-β-PAC with a widespread distribution compared to healthy control subjects.
  The authors conclude that this indicates the presence of compensatory hyperactivation mechanisms in ADHD, particularly in ADHD-C.

2.10. ACC-PI signaling pathway¶

The ACC-PI signaling pathway (from the ACC to the posterior insula, PI) regulates central (pain) sensitization mechanisms. ADHD-related ACC-PI activity can increase or decrease pain sensitivity and may trigger hyperactivity (ergomania). (E 3)²⁰¹

• 6-OHDA-treated mice, an animal model for ADHD, show increased spontaneous activity in the ACC-PI signaling pathway (E 2b)²⁰²
• 6-OHDA mice exhibit a sex-specific neuroinflammatory response to dopamine neuron loss caused by 6-OHDA: (E 2b)²⁰³
  • Males: Dopamine loss triggered inflammation only in the ACC
    • Consequences:
      • Hyperactivity
      • no increased sensitivity to pain (no hyperalgesia)
  • Females: Dopamine depletion triggered inflammation in the ACC-PI signaling pathway
    • Consequences:
      • no hyperactivity
      • increased sensitivity to pain (hyperalgesia)

2.11. Pregnancy complications are more common in ADHD-HI and ADHD-C than in ADHD-I¶

A study compared the pregnancies of 7,103 mothers with ADHD-HI or ADHD-C and 2,928 mothers with ADHD-I. Compared to mothers with ADHD-I, mothers with ADHD-HI or ADHD-C were or had: (E 3)²⁰⁴

• often younger than 25
• more often have black skin
• more often from a lower income quartile
• 32.3% more smoked tobacco during pregnancy (25.8% vs. 19.5% in ADHD-I)
  • 526% higher than among those without ADHD (4.9% in that group)
• used illegal drugs more frequently
• 19% higher incidence of hypertensive disorders of pregnancy
• 19% higher rate of preterm births
• 39% higher incidence of maternal infections
• 33% higher incidence of newborns who are small for their gestational age (SGA newborns)

3. ADHD-HI/ADHD-C and ADHD-I as Stress Phenotypes¶

See ⇒ Stress Theories and Stress Phenotypes: A Possible Explanation for ADHD Subtypes In the chapter ⇒ Stress

4. Issues with Classifying into Subtypes / Forms of Presentation¶

(ADxS assessment): One problem with the classification into subtypes or presentation forms may be that some people with ADHD redirect brain activity from affected brain regions to other brain regions—that is, they “repurpose” brain regions—in order to compensate for the impaired functions of the affected brain regions.

This makes it more difficult to diagnose the condition using questionnaires and tests.

(ADxS assessment): A more objective determination of the specific ADHD subtype or presentation form could be achieved through a more detailed medical history, along with EEG or QEEG measurements, and an assessment of stress system reactivity using the dexamethasone, ACTH, or CRH test.

5. ADHD Subtypes Based on Dopamine Levels?¶

(ADxS Assessment): Most sources in the scientific literature link ADHD to reduced dopamine levels. This description likely also encompasses situations where dopamine levels are normal but receptor sensitivity is reduced, or where dopamine is broken down too quickly. As a result, there is an insufficient amount of dopamine (or its effects).
Apart from the fact that this description usually does not specify more precisely in which region of the brain the dopamine deficit is located and whether it involves a deficit in tonic or phasic dopamine release or in basal dopamine levels, there is conflicting evidence suggesting that an excess of dopamine can also cause ADHD symptoms. See, among other sources, ⇒ ADHD in animal models In the chapter ⇒ Neurological Aspects.
This is consistent with the inverted-U model, according to which both an excess and a deficiency of a neurotransmitter can cause strikingly similar symptoms, because optimal signal transmission depends on a specific (“medium”) neurotransmitter level. Signal transmission is impaired equally by both elevated and reduced neurotransmitter levels.

(ADxS Assessment): As long as ADHD is defined and diagnosed based solely on symptoms, this inevitably leads to people with a dopamine deficiency being treated in exactly the same way as people with an excess of dopamine (even though we suspect the latter group is likely to be rare, or at least less common). Against this backdrop, the question arises as to whether it would not make sense to either

• To define ADHD neurobiologically as a dopamine (functional) deficit and to classify all forms (even those with similar symptoms) that involve a dopamine surplus differently,
  or
• ADHD can be divided neurobiologically into two dopaminergic variants*: the hypodopaminergic variant (dopamine deficiency) and the hyperdopaminergic variant (dopamine excess).

(ADxS assessment): Contrary to our initial expectations, however, findings on the effects of ADHD medications in both hypodopaminergic and hyperdopaminergic animal models indicate that the medications primarily used to date appear to have comparable effects in both variants.
Stimulants act primarily as dopamine reuptake inhibitors, thereby increasing the level of dopamine available in the synaptic cleft. Nevertheless, stimulants also reduce hyperactivity in animal models with excess dopamine, such as the DAT-KO mouse, without reducing extracellular dopamine levels. Atomoxetine, on the other hand, appears to reduce hyperactivity only in animal models with dopamine deficiency, but not in those with dopamine excess. Cognitive impairments such as inattention and learning deficits are apparently improved by stimulants as well as by atomoxetine in cases of dopamine excess. More on this at ⇒ ADHD in Animal Models In the chapter ⇒ Neurological Aspects.

(ADxS Assessment): Even though the medications used to date appear to be equally effective in cases of both dopamine deficiency and dopamine excess, we believe it would be desirable to distinguish more clearly between these different variants of ADHD. The fact that existing medications work the same way in both cases could also be a consequence of the fact that the effects of medications have not yet been evaluated separately for the two variants. It is entirely conceivable that, with appropriate differentiation, individual medications—which have so far been dismissed as less effective—could show that they work differently. (compared to the stimulants primarily used to date) lower efficacy, might prove effective for one variant and ineffective for the other—as appears to be the case with atomoxetine in relation to hyperactivity. In this case, the efficacy would need to be reevaluated with regard to the indicated uses.

(ADxS Assessment): The question of ADHD subtypes (hypodopaminergic/hyperdopaminergic) is unlikely to have any practical significance as long as there is no affordable, reliable, and side-effect-free method for determining dopamine (activity) levels in specific brain regions of people with ADHD. However, in scientific research on ADHD and in an in-depth examination of the pharmacological treatment of ADHD, we would like to see greater consideration given to this aspect, as well as a consistent differentiation of study results according to subtypes and presentation forms.