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

Author: Ulrich Brennecke
Review: Dipl.-Psych. Waldemar Zdero

Since DSM 5, the subtypes have been called presentation forms.
DSM 5 distinguishes between three forms of presentation:

• ADHD-HI (predominant hyperactivity)
• ADHD-I (predominant inattention) and
• ADHD-C (attention problems and hyperactivity in equal measure)

A further form of presentation is being discussed:

• ADHD-RI (restrictive inattention)

ADHD-HI is characterized by predominant hyperactivity and impulsivity. People with ADHD often have difficulty controlling their impulses and frequently react excessively. Social problems are common because people with ADHD-HI often do not take other people’s feelings into account. Comorbid disorders are often externalizing and inflammatory problems and a flattened cortisol stress response are more common. ADHD-HI responds well to methylphenidate (MPH).

ADHD-I (ADD) is characterized by predominant inattention. ADHD-I often shows daydreaming, difficulty concentrating, working memory problems and aversion to noisy group situations. Comorbid disorders are usually internalizing, such as anxiety disorders or depression.

ADHD-C (mixed type) is a mixture of ADHD-I and ADHD-HI. People with ADHD show strong symptoms in both core areas of ADHD, namely inattention on the one hand AND hyperactivity / impulsivity on the other.

The pure ADHD-HI type is usually diagnosed up to the age of 6, 7 years at the latest, exceptionally up to 14, 15 years and only rarely occurs later. This is probably mainly due to the fact that inattention symptoms can only be reliably diagnosed from this age onwards. ADHD-C could therefore be referred to as the ADHD-HI type in later development. In adults with ADHD, attention problems can also significantly diminish or disappear, even if they diminish considerably less often than hyperactivity problems: ⇒ ADHD in adults.
The ICD 10 distinguishes between Simple Activity and Attention Disorder (F90.0) and Hyperkinetic Disorder of Social Behavior (F90.1), for which a Social Behavior Disorder is also required. According to DSM, the latter is (in our opinion rightly) considered a comorbidity. ICD 11 has come closer to the DSM.
The presentation forms (subtypes) ADHD-HI, ADHD-I and ADHD-C have been shown to be valid, while the evidence for a subtype of Hyperkinetic Disorder of Social Behavior is insufficient¹

SCT is no longer considered a subtype of ADHD. As SCT appears to be closely related and highly comorbid with ADHD, we have dedicated a separate article to SCT: ⇒ SCT - Sluggish Cognitive Tempo.

• ADHD-C: 56 %² to 62 %³
• ADHD-I: 31 %³ to 37 %²
• ADHD-HI: 2 %² to 7 %³

The (genetic) causes and neurophysiological processes are very similar in all forms of presentation (subtypes). To date, only a few truly reliable distinguishing criteria are known. There are indications of genetic factors for externalizing phenotypes.⁴ The most relevant difference appears to be the endocrine response to acute stress. Since stress-induced neurotransmitter release (especially noradrenaline) appears to parallel these subtype-specific cortisol responses to acute stress, this could explain some of the differences between ADHD-HI/ADHD-C and ADHD-I.

We consider the ADHD subtypes/presentations as different (psychological) forms of reaction to one and the same genetic/neurological source of disorder, whereby essentially the personality traits

• Extroverted / introverted
• Neuroticism
  and next to it
• The personal way of processing stress (BIS/BAS) as a phenotypic stress reaction and
• Learning to deal with stress (role model)

determine which subtype a person with ADHD develops. These are reflected neurophysiologically in the cortisol stress response. More on this below under 1.2.3.1.

The subtype expression of people with ADHD is not necessarily stable throughout their lives.⁵ We know quite a few people with ADHD who report a significant change in subtype.

• 1. Forms of presentation (subtypes) of ADHD according to symptoms
  • 1.1. ADHD-I: predominantly inattentive type
    • 1.1.1. Other names of the ADHD-I subtype
    • 1.1.2. Specific symptoms of ADHD-I
    • 1.1.3. Peculiarities of the medication
    • 1.1.4. Neurophysiological characteristics of ADHD-I
      • 1.1.4.1. Increased cortisol stress response in ADHD-I
      • 1.1.4.2. Further biomarkers for ADHD-I
      • 1.1.4.2.1. Stress responses of cortisol, noradrenaline and dopamine
      • 1.1.4.2.2. CRH
      • 1.1.4.2.3. Dopamine receptors
      • 1.1.4.2.4. Serotonin
      • 1.1.4.2.5. Orexin A
    • 1.1.5. EEG image for ADHD-I
    • 1.1.6. Sluggish Cognitive Tempo (SCT) - independent Disorder
  • 1.2. ADHD-HI: predominantly hyperactive/impulsive subtype
    • 1.2.1. Other names
    • 1.2.2. Specific symptoms
    • 1.2.3. Neurophysiological characteristics of ADHD-HI / ADHD-C
      • 1.2.3.1. Flattened cortisol stress response in ADHD-HI / ADHD-C
      • 1.2.3.2. Deficient HPA axis deactivation in ADHD-HI / ADHD-C
      • 1.2.3.3. CB1 receptors reduced in impulsivity
      • 1.2.3.4. Reduced noradrenaline reduction in ADHD-HI / ADHD-C?
      • 1.2.3.5. Reduced hippocampus volume in ADHD-HI / ADHD-C
      • 1.2.3.6. Indole acetic acid for ADHD-HI / ADHD-C
      • 1.2.3.7. TSH, serum ferritin, lactic acid in hyperactivity (ADHD-HI / ADHD-C)
    • 1.2.4. EEG image in ADHD-HI
  • 1.3. ADHD-C - mixed type of ADHD-HI and ADHD-I
    • 1.3.1. ADHD-C with inhibition deficits, without reward deficits
    • 1.3.2. ADHD-C with inhibition deficits and reward deficits
    • 1.3.3. ADHD-C without reward deficits and without inhibition deficits
  • 1.4. Further subtype classifications
    • 1.4.1. ADHD-RI: Restrictive inattentive subtype
    • 1.4.2. ADHD with oppositional behavior disorder (?)
    • 1.4.3. Rage type (?)
    • 1.4.4. Residual type
    • 1.4.5. ADHD adult subtype pair according to Reimherr
      • 1.4.5.1. Inattentive adult subtype
      • 1.4.5.2. Emotionally dysregulated adult subtype
    • 1.4.6. ADHD presentation forms (subtypes) according to internalizing / externalizing symptoms
    • 1.4.7. ADHD subtypes according to symptom severity
    • 1.4.8. Subtypes / forms of presentation according to emotion profiles
    • 1.4.9. Subtypes / forms of presentation according to microcognition biomarkers
• 2. Neurophysiological and endocrine differences between the subtypes
  • 2.1. Dopamine level
    • 2.1.1. Hyperactivity, impulsivity: dopamine deficiency or excess dopamine in the striatum
    • 2.1.2. Hyperactivity, impulsivity: excess dopamine in the PFC
    • 2.1.3. DAT differences in the forms of presentation (subtypes)
  • 2.2. Exaggerated and flattened endocrine stress responses of the presentation forms (subtypes)
  • 2.3. ADHD subtypes / forms of presentation according to EEG
    • 2.3.1. ADHD-HI subtypes according to EEG
      • 2.3.1.1. Theta frontal increased, beta decreased (ADHD-HI with hyperactivity and impulsivity with hypoactive EEG)
      • 2.3.1.2. Excessive beta (“overactivated” ADHD-HI)
    • 2.3.2. ADHD-I subtypes in the EEG
      • 2.3.2.1. Delta and theta increased, beta decreased
      • 2.3.2.2. Only alpha activity increased
      • 2.3.2.3. Theta posterior increased, alpha and beta decreased
      • 2.3.2.4. Only theta frontal midline (FMT) increased
  • 2.4. ADHD subtypes according to QEEG
  • 2.5. Functional differences in nerve conduction pathways in the brain (?)
  • 2.6. Subtypes / forms of presentation and serotonin
  • 2.7. Neuro-auditory profiles of the subtypes / forms of presentation
• 3. ADHD-HI/ADHD-C and ADHD-I as stress phenotypes
• 4. The problem of subdivision into subtypes / forms of presentation
• 5. ADHD variants according to dopamine level?

1. Forms of presentation (subtypes) of ADHD according to symptoms¶

The specialist literature primarily mentions 3 presentation forms (subtypes) of ADHD: the ADHD-I type (1.1.), the ADHD-HI type (see 1.2.) and ADHD-C (see 1.3). While the ADHD-HI subtype is probably only an early form of the mixed type, sluggish cognitive tempo (SCT) is becoming increasingly clear as an independent disorder. The sporadic forms described further are unlikely to be true subtypes and are only mentioned for the sake of completeness.

Regardless of the typing of ADHD-I, ADHD-HI and ADHD-C based on the observed symptoms, there is a typing that is based on the different EEG patterns measured ⇒ ADHD subtypes according to EEG. This has not yet become established, although it could be measurable using objective biomarkers. So far, there is a lack of experience about the different symptoms of the EEG subtypes and how they react to specific treatments. An attempt to automatically differentiate the presentation forms based on their EEG patterns using AI failed.⁶ In addition, only 84% of people with ADHD could be distinguished from those not affected.

1.1. ADHD-I: predominantly inattentive type¶

1.1.1. Other names of the ADHD-I subtype¶

• ADHD-I (the term we use today)
• ADS (colloquial, used by us in the past)
• ADD (older international colloquial term)
• ADHD-PI (predominantly inattentive)
• Hypoactive (Prof. Simchen)
• Dreamer (colloquially descriptive)
• Underactivated (distractible due to boredom)

1.1.2. Specific symptoms of ADHD-I¶

ADHD is a symptom cluster. The symptoms do not clearly differentiate between the presentation forms (subtypes). In ADHD-I, inattention predominates over hyperactivity, impulsivity and inner restlessness.

• 3 to 6 years⁷

  • Requests are not heeded
    • Therefore does not follow requests
  • Dreamy
  • Stares into space
  • Finds it difficult to occupy himself with something
    • Daydreaming
    • Thoughts wander
  • Loud group situations tend to be perceived as unpleasant
  • Reluctance to change familiar processes
  • Aversion to quick transitions, needs to adjust to new things first

• 6 to 10 years:⁸

  • Inattention
    • Can therefore not follow some lessons
  • Cannot understand some of the subject matter
  • Concentration difficulties
    • On teacher presentation
    • On own work
  • Looks dreamy
  • Lack of active cooperation

• 10 to 20 years:⁸

  • Possible improvement in attention due to subsequent development of the brain
  • Attention problems remain at least partially present
    and are still perceived as very stressful

• Regardless of age:

  • The ADHD-I subtype is more introverted (in contrast to the more extroverted ADHD-HI subtype)⁹
  • Internalizing¹⁰
  • Shy¹¹
  • Increased susceptibility to internalizing disorders¹²
    e.g.
    • Anxiety disorders
    • Depression
  • Social problems of the ADHD-I subtype arise from⁹
    • Too shy
    • Passivity
    • Introversion
    • Being still
  • Disorders primarily in working memory and auditory processing, which places high demands on working memory.¹³
  • More frequent comorbid disorders than ADHD-HI subtype¹⁴
  • Partial performance disorders more frequent
    • Reading and spelling difficulties
    • Dyscalculia (dyscalculia)
  • Often perform better in spatial thinking and artistic drawing than in verbal skills.¹⁵
  • More bored than distracted.¹⁶
  • Motivational problems rather than problems with inhibition.¹⁷
  • Tends to have a high level of self-awareness.¹⁷
  • Lethargic states (to be distinguished from depression)¹⁸
  • A significant subsection of ADHD-I is said to have slowed thinking (Sluggish)¹⁷
    We consider the term “slowed-down thinking” to be inaccurate and inappropriate. We see slowed decision-making. The ability to think quickly is basically present; we suspect an excessive blockade of the PFC by noradrenaline and possibly other neurotransmitters via the alpha-1 adrenoceptor. SCT is no longer considered a subtype of ADHD and is also not considered ADHD-I-specific.
  • More frequent allergies due to the excessive cortisol reaction. Cortisol promotes the immune defense against external stresses.
  • Corresponding disorders of hypercortisolism are¹⁹
    • Depression
    • Anxiety disorder
    • Anorexia
    • Alcoholism
    • Metabolic syndrome
  • Learning disorders
    • More frequently than with ADHD-HI¹⁰
    • A high cortisol response to acute stress, which is typical of ADHD-I, correlates with poorer memory performance when learning vocabulary after exposure to stress - but only in men. Women could be protected against this by their sex hormones.²⁰ Cortisol administration also worsened learning performance.
      Cortisol, which is often elevated as a stress response in ADHD-I, blocks the retrieval of declarative (explicit) memory via the glucocorticoid receptors (GR) in the PFC and hippocampus. The non-declarative (implicit, intuitive) memory is not impaired.²¹ This could explain the more frequent thinking and memory blocks in ADHD-I and also why people with ADHD-I often seem to have a higher level of intuition. In any case, it would stand to reason that the shift in the focus of memory skills leads to a shift in problem-solving patterns. Trappmann-Korr calls this “holistic” perception.
      It is likely that not only the retrieval (remembering), but also the acquisition (learning) and memory consolidation (long-term storage) of information is impaired. Consolidation occurs particularly during sleep in the first half of the night, which is characterized by particularly low basal cortisol levels. Consolidation can be prevented by low cortisol levels.²¹
  • Attention problems
    • Sustained attention (ADHD-HI and ADHD-I subtype)
    • Selective attention (ADHD-I subtype only)²²

• Negative symptom differentiation in ADHD-I:

  • Externalizing behaviour disorders and aggressive behaviour are atypical in ADHD-I and indicate the ADHD-HI subtype.²³.

    • Less frequent symptoms of aggressive or oppositional defiant behavior²⁴²⁵

  • ADHD-I is diagnosed less frequently because it is less likely to be noticed unpleasantly due to the “comfortable” symptoms of internalized stress management for the environment. In addition, research suffers from the fact that many studies do not differentiate the results according to forms of presentation (subtypes) and in particular do not differentiate ADHD-C from the ADHD-I type.

  • Less frequent comorbid oppositional defiant behavior than in ADHD-HI subtype.⁹

  • Lower proportion of smokers than in ADHD-HI subtype (the pathways of action of nicotine and methylphenidate are similar)¹⁷

  • Less frequent inflammatory reactions such as atopic dermatitis due to the excessive cortisol response. Cortisol inhibits the inflammatory processes initiated by CRH and instead promotes defense against foreign bodies, which can manifest as allergies if excessive

Find out more about the required frequency and intensity of ADHD symptoms at ⇒ Symptoms of ADHD in children by age.

1.1.3. Peculiarities of the medication¶

• MPH responding
  • According to one view, a noticeable proportion of methylphenidate non-responders (MPH does not work). If MPH is effective, low doses are often sufficient.¹⁷
  • According to another opinion, ADHD-HI and ADHD-I do not differ in the MPH response rate.²⁶
• A significant proportion of people with ADHD-I respond to amphetamine medication rather than MPH.
• It should also be helpful:
  • Nortriptyline
  • Bupropion (if stronger activation is required)

1.1.4. Neurophysiological characteristics of ADHD-I¶

1.1.4.1. Increased cortisol stress response in ADHD-I¶

ADHD-I often appears to be associated with a particularly strong cortisol response to acute stress. ⇒ Changes in cortisol levels in ADHD in: Cortisol and other stress hormones in ADHD

1.1.4.2. Further biomarkers for ADHD-I¶

1.1.4.2.1. Stress responses of cortisol, noradrenaline and dopamine¶

Underactivation of the PFC in ADHD-I is explained by the fact that the stress responses of cortisol, noradrenaline and dopamine correlate in the brain. More on this at ⇒ Neurotransmitters during stress
* A strong increase in noradrenaline / dopamine shuts down the PFC. This deactivation of the PFC occurs via alpha-1 adrenoceptors, which have a lower noradrenaline and cortisol affinity than alpha-2 adrenoceptors and are therefore only addressed at very high noradrenaline and cortisol levels.^2728293031
A particularly strong increase in DA and NE during severe stress could therefore lead to a (frequent) underactivation of the PFC, as is typical in ADHD-I.
This could explain Raynaud’s and high blood pressure problems in some people with ADHD-I, which are also mediated by alpha-1 adrenoceptors.
The question is whether alpha-1-adrenoceptor antagonists, which are successfully used against Raynaud’s and high blood pressure, might not also be helpful against PFC blockades in ADHD-I.
So far, only alpha-2 adrenoceptor agonists have been used, which are likely to be considered third-line drugs. Guanfacine addresses alpha-2-A and alpha-2-D, yohimbine alpha-2-B adrenoceptors. The agonization of the more affine alpha-2 receptors is contrary in effect to the antagonization of the alpha-1 receptors. As with the cortisol receptors, the less affine receptor is responsible for switching off the system and is only addressed at very high messenger substance levels. If the more affine receptors are too pronounced, the less affine switch-off receptors are not activated.
Guanfacine and yohimbine occupy the more affine alpha-2 receptors, leaving more neurotransmitter for the less affine alpha-1 receptors, which are therefore more easily addressed.

1.1.4.2.2. CRH¶

CRH also has an effect on the PFC and can impair it at high CRH levels.
Increased cortisol responses to a stressor correlate with an increased variance in response time.³² An increased variance in response times could be explained by an impairment in the performance of the PFC, which is particularly pronounced in the ADHD-I subtype. This impairment could be explained by increased noradrenaline responses to acute stress, analogous to the cortisol response. Some diagnosticians pay particular attention to this variance in response times when diagnosing ADHD-I.
Cortisol leads to a decrease in cortisol and noradrenaline
This negative feedback is the consequence of cortisol (it shuts down the HPA axis again) and is independent of the synchronicity of the release of cortisol and noradrenaline in response to stress

1.1.4.2.3. Dopamine receptors¶

The dopamine D4 receptor (DRD4) has a special significance in the PFC, which is why Diamond³³ assumes that a disorder of the DRD4 7R gene is associated with ADHD-I. We do not believe this to be the case.
Noble found that the gene polymorphisms A1, B2 and intron 6 1 of DRD2 and the DRD4 7R polymorphism were associated with an increased Novelty Seeking (sensation seeking) score. However, none of these polymorphisms correlated with a high Harm Avoidance Score (BIS), as is typical for ADHD-I.³⁴
High Novelty Seeking / Sensation Seeking rates are associated with high aversion to boredom and correlate with impulse control disorders.³⁵ Boredom is a cause of inattention in ADHD-I, while impulse control problems are atypical of ADHD-I and more typical of ADHD-HI.

1.1.4.2.4. Serotonin¶

In ADHD-I, there is often said to be a lack of serotonin.³⁶
One study found strong association of the L/L genotype of the 5-HTTLPR gene with ADHD-C and ADHD-HI, while the 5-HTTLPR-L/L genotype showed no difference.³⁷
The 5-HTTLPR-L/L genotype correlates with hyperactive symptoms.³⁸
One study reports a correlation between the presence of a 5-HTTLPR-S allele and inattention.³⁹

1.1.4.2.5. Orexin A¶

ADHD-I might have lower orexin A levels than the ADHD-HI subtype and than non-affected individuals.⁴⁰ More about orexin at ⇒ Orexin / hypocretin In the section ⇒ Hormones in ADHD in the chapter ⇒ Neurological aspects.

1.1.5. EEG image for ADHD-I¶

See below under “Subtypes of ADHD according to EEG”.

1.1.6. Sluggish Cognitive Tempo (SCT) - independent Disorder¶

SCT is now considered a separate Disorder independent of ADHD, even though SCT and ADHD are very often comorbid. However, there are people with SCT without ADHD.
More about SCT at ⇒ SCT - Sluggish Cognitive Tempo.

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

1.2.1. Other names¶

• ADHD-HI (used by us)
• ADHD (colloquially an imprecise collective term for all subtypes)
• ADHD (English; used internationally, but also as a collective term for all subtypes)
• ADHD-PH (predominantly hyperactive/impulsive)
• ADHD-H/I (hyperactive/impulsive)
• Fidget spinner (colloquially descriptive)

1.2.2. Specific symptoms¶

• Clear expression of
  • Hyperactivity
  • Impulsiveness
• No inattention
  • Inattention is added to hyperactivity / impulsivity: ADHD-C, see below
• Social problems very common
  arise because ADHD-HI subtype
  • Offends others
  • Takes things away from them
  • Can’t wait for his turn
  • Is too direct and authoritative
  • Behaves disruptively and
  • Acts without considering the feelings of others⁴¹
• More extroverted (in contrast to the more introverted ADHD-I subtype)¹⁰⁹
• Frequent behavioral disorders and (comorbid) aggressive behavior⁴².
• More frequent comorbidity with oppositional defiant behavior¹⁷
• Disorders primarily in the area of behavioral inhibition¹⁷ and executive functions⁴³
• Is more distractible than bored¹⁷
• Has an inhibition problem rather than a motivation problem.¹⁷
• Tendency towards low self-awareness¹⁷
• Good response to methylphenidate.
  The non-responder rate (MPH does not work) should be 10 %.⁴⁴
• The person with ADHD is primarily the striatum. The fact that DAT1 plays an important role in the striatum and MPH primarily acts on the DAT explains the good effect of MPH in ADHD-HI.¹⁷
• Higher proportion of smokers than in the ADHD-I subtype. (Nicotine acts as a stimulant like methylphenidate)¹⁷
• Hyperactive/impulsive type often only a precursor in childhood/adolescence for later ADHD-C⁴⁵⁴⁶
• Boys are affected 5 times more often than girls⁴⁷.
• More frequent inflammatory reactions than in the ADHD-I subtype due to the flattened cortisol response to stress. Cortisol inhibits the inflammatory response mediated by CRH.
• The corresponding symptoms of hypocortisolism are¹⁹
  • Atypical depression
  • Inflammation problems⁴⁸
    • E.g. irritable bowel syndrome
    • E.g. neurodermatitis
  • Tiredness
    Cortisol inhibits the pro-inflammatory effect of CRH
    promotes cytokines such as interleukin 1 and 6; thus (as with fever) “sickness behavior”:
    • Fatigue
    • Lack of initiative
    • Tiredness
    • E.g. Chronic Fatigue Syndrome
    • E.g. burnout
  • Sensitivity to pain
    Cortisol inhibits prostaglandin synthesis (= disinhibition of prostaglandins)
    Prostaglandins modulate pain perception
    this systemically lowers the pain threshold (pain symptoms “migrate”)
    Hypocortisolism can promote inflammatory processes in the spinal cord (chronic pain)
    • E.g. fibromyalgia⁴⁹
    • E.g. chronic lower abdominal pain
  • Stress intolerance
    Cortisol inhibits locus coeruleus and thus reduces the release of noradrenaline in the CNS
    A low cortisol response causes limited noradrenaline inhibition = loss of an important stress brake
    Hypocortisolism thus causes stress intolerance, irritability, sensitivity to sensory stimuli (noise, etc.)
    Hypocortisolism could promote the development of intrusions as observed in PTSD⁵⁰

Negative symptom differentiation in ADHD-HI:

• If there is inattention and hyperactivity (the latter also as Inner drivenness), this is known as ADHD-C.
  Inattention can usually only be detected between the ages of 6 and 15. ADHD-HI (with hyperactivity without attention problems) can therefore be regarded as an early form of the later mixed type.⁴⁵⁵¹
  The question of whether ADHD exists entirely without inattention has not been conclusively answered. We tend to assume that there is, although this is likely to be a rather rare manifestation.
  The higher the aptitude, the better the coping mechanisms. The older the person with ADHD, the more remitted individual symptoms may be, which is why a lack of (well-hidden) inattention in test settings is quite common. Likewise, a high level of intrinsic interest in the tests on the part of the person with ADHD leads to an equalization of test performance compared to people without ADHD. This is plausible if the stress benefit and thus the mechanisms of the stress symptom of inattention are considered.
• Allergies appear to occur less frequently in ADHD-HI than in the ADHD-I subtype due to the more frequently flattened cortisol response to stress. Cortisol increases the immune response to external stresses such as allergens.

1.2.3. Neurophysiological characteristics of ADHD-HI / ADHD-C¶

In ADHD-HI (with hyperactivity/impulsivity) and also in correlating aggression, the release of catecholamines and cortisol in response to acute stressors is often reduced or absent compared to non-affected people, whereas the cortisol stress response is typically increased in persons with ADHD-I compared to non-affected people.

1.2.3.1. Flattened cortisol stress response in ADHD-HI / ADHD-C¶

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

1.2.3.2. Deficient HPA axis deactivation in ADHD-HI / ADHD-C¶

Since cortisol not only mediates stress symptoms but also switches off the HPA axis, a reduced cortisol stress response leads to a lack of braking of the HPA stress system.
⇒ The HPA axis / stress regulation axis And ⇒ The autonomic nervous system.

1.2.3.3. CB1 receptors reduced in impulsivity¶

• SHR show behavioral subgroups corresponding to ADHD-HI and ADHD-I
  • One study found subgroups of SHR (Spontaneous(ly) hypertensive rat) that differed significantly in terms of impulsivity. Impulsive SHRs showed a significant difference compared to non-impulsive SHRs and WKYs (as controls; no behavioral subgroups were found)⁵²
    • Reduced noradrenaline 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
      • Acute administration of a cannabinoid agonist reduced impulsivity in impulsive SHR, with no change in WKY

CB1 receptors are essential for the shutdown of the HPA axis. CB1 antagonists prevent rapid feedback regulation by GR antagonists, which initiate the shutdown of the HPA axis.

• CB1 receptors regulate the HPA axis:
  • Disorder of the CB1 gene caused hyperactivity of the HPA axis⁵³
  • Endogenous cannabinoids appear to inhibit the HPA axis via CB1 receptors in the brain
  • Anandamide
    • Lowers the corticosterone level in stressed animals⁵⁴
    • Reduces the endocrine stress response of the HPA axis⁵⁵
  • Endogenous cannabinoids inhibit the basal and suppress the stress-induced activity of the HPA axis via the hypothalamus, pituitary gland and adrenal cortex. Stimulation of the central cannabinoid receptors leads to activation of the sympathetic nervous system⁵⁴
  • Activation of peripheral CB1 receptors inhibits noradrenaline release from the sympathetic terminals and adrenaline release from the adrenal glands⁵⁴
  • Endogenous CB1 agonists have an anxiolytic effect and prevent the occurrence of pathological anxiety states⁵⁴
  • CB1 may not affect adaptation to daily chronic stress⁵⁶
  • CB1 mediates the rapid downregulation of the HPA axis by GR agonists (endocrine feedback loop), here by dexamethasone⁵⁷⁵⁸ CB1 antagonists prevent downregulation.

1.2.3.4. Reduced noradrenaline reduction in ADHD-HI / ADHD-C?¶

Cortisol also causes a reduction in noradrenaline.
A too low cortisol response to acute stress and a resulting too low norepinephrine degradation could possibly explain a permanent overactivation of the PFC in ADHD-HI/ADHD-C.
A slightly increased (dopamine and) noradrenaline level in the PFC increases its activation and results in improved cognitive performance.^5960616263 Only a strong increase in noradrenaline / dopamine reduces the PFC.^2728293031

1.2.3.5. Reduced hippocampus volume in ADHD-HI / ADHD-C¶

A fairly extensive study reported reduced hippocampal volume in ADHD-HI as opposed to ADHD-I and non-affected individuals.
* ADHD-HI: Reduction in the hippocampus areas⁶⁴
* CA1
* CA4
* Molecular layer
* Granule cell band of the dentate gyrus
* Presubiculum
* Subiculum
* Hippocampal tail
* Other hippocampal regions were not reduced in size
* ADHD-I: no reliable differences in hippocampal volume compared to controls⁶⁴
* Finally, smaller hippocampal areas correlated with higher behavioral ADHD indices. For example, a smaller subiculum correlated with a higher overall ADHD-HI index and higher hyperactivity/impulsivity and lower IQ.⁶⁴

1.2.3.6. Indole acetic acid for ADHD-HI / ADHD-C¶

In people with ADHD-HI with comorbid depressive symptoms, one study found significantly higher morning than evening levels of indoleacetic acid. MPH reduced this by 50 %. MPH also reduced the morning levels of indolepropionic acid and brought the daily profile back to the levels of healthy control subjects.⁶⁵

1.2.3.7. TSH, serum ferritin, lactic acid in hyperactivity (ADHD-HI / ADHD-C)¶

In 49 children with ADHD with and without hyperactivity were found:⁶⁶

• TSH correlated with Conners 3 scale values (ADHD)
  • so clearly that diagnostic use could be conceivable
• TSH, serum ferritin and lactic acid correlated with HI value
• TSH and lactic acid were independently associated with HI

1.2.4. EEG image in ADHD-HI¶

See below under Forms of presentation (subtypes) in ADHD according to EEG.

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

• Clear manifestation in both core symptom areas:
  • Hyperactivity (in children; in adults; inner restlessness) AND impulsivity
  • Inattention
    • Problems with sustained attention (ADHD-C and ADHD-I)
    • Fewer problems with selective attention (ADHD-I subtype only)²²
• Largely corresponds to Hyperkinetic Disorder according to ICD-10.2.3.1 Subgroups of ADHD-C

A larger study of adolescents found three subgroups of ADHD-C in which the specific symptoms were also reflected in fMRI-measurable changes in brain structure in the brain systems known for these cognitive functions.⁶⁷

A small study replicated previous research that frontal delta and theta power is higher in ADHD-C than ADHD-I and TD groups.⁶⁸

1.3.1. ADHD-C with inhibition deficits, without reward deficits¶

Inhibition deficits refers to deficits in executive functions and inhibitory cognitive functions.

Underfunction within

• Different frontal lobes
• Parietal lobe
• Subcortical
• Cerebellar regions

in the inhibition of motor reactions

and

Anomalies

• Of the posterior default mode
• In the ventral striatum

during error handling.

Executive function deficits also show in other studies^69707172

Underfunction 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 inhibition deficits and reward deficits¶

Overactivation in

• Mostly non-overlapping cortical and subcortical regions

during error processing and

• Overactivated amygdala regions and
• Overactivated ventral striatum regions,

when they made an effort to receive rewards.

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

This was the most common subgroup. No neurological abnormalities were found, corresponding to the absence of the specific symptoms mentioned above

1.4. Further subtype classifications¶

We do not consider the following “subtypes”, which have occasionally been mentioned in the literature, to be true presentations (subtypes) of ADHD.

1.4.1. ADHD-RI: Restrictive inattentive subtype¶

ADHD-RI was not included as a presentation form in DSM 5 due to a lack of robust neurobiological data.
ADHD-RI differs from groups ADHD-I and ADHD-C by:

• less externalizing behaviour⁷³
  • possibly due to less impairment of the DMN and/or greater impairment of the salience network⁷³
• poorer sustained attention⁷³
• better reaction inhibition⁷³
• ADHD-RI had a significantly different neuropsychological profile compared to the other groups, including a
• lower psychomotor speed⁷⁴
• longer response times⁷⁴⁷⁵
• the worst overall performance in the global neurocognitive index⁷⁴⁷⁵
  • poorer neurocognitive index than SCT (p < 0.001)⁷⁵
• significantly increased proportion with a DRD4-7 repeat allele⁷⁴
• attention-related posterior brain regions (especially temporal-occipital areas) activated more strongly for go and no-go cues than for controls and ADHD-I⁷⁴
• slower psychomotor speed than SCT⁷⁵
• only SCT was independently associated with poorer overall memory performance⁷⁵

1.4.2. ADHD with oppositional behavior disorder (?)¶

Oppositional behavior disorder is, in our opinion, a comorbidity that occurs primarily in the ADHD-HI type and not a subtype of ADHD-HI.
Significantly, even among those who assume presentation forms (subtypes) of ADHD with oppositional behavior disorder, this is only described in conjunction with the ADHD-C and ADHD-HI type, but not with the (stress phenotypically introverted) ADHD-I type.

1.4.3. Rage type (?)¶

The Rage type is rarely described as a separate type. It is probably used to describe ADHD-HI with aggressive comorbidity.

Similarly, a subtype with increased emotional irritability/irritability is proposed.⁷⁶

1.4.4. Residual type¶

In some cases, a partially regressed, no longer fully developed but still present ADHD is referred to as a residual type.
This is not a subtype of ADHD, but could explain why there are sometimes people with ADHD who lack individual leading symptoms (e.g. with a largely full symptom picture without attention problems).

1.4.5. ADHD adult subtype pair according to Reimherr¶

In 8 replication studies of 1,490 adults with ADHD, Reimherr et al identified two clusters, the inattentive adult subtype and the emotionally dysregulated adult subtype.⁷⁷. The result is consistent with an earlier study by the authors.⁷⁸
Both forms of presentation (subtypes) benefited equally from MPH treatment.

1.4.5.1. Inattentive adult subtype¶

• Inattentive
• Emotionally dysregulated

1.4.5.2. Emotionally dysregulated adult subtype¶

Emotional dysregulation manifests itself, among other things, in

• Anger
• Affective instability
• Emotional overreactivity

1.4.6. ADHD presentation forms (subtypes) according to internalizing / externalizing symptoms¶

Katsuki et al describe four ADHD subtypes using a cluster analysis of emotional and behavioral symptoms in children aged 4 to 15 years with ADHD:⁷⁹

• “Strongly internalizing/externalizing”
  • Overlapping of internalizing and externalizing symptoms
    • Possibly moderated by emotional dysregulation and associated neurophysiological correlates
  • High rate of comorbid autism spectrum disorders
  • Increased autistic characteristics
• “Inattention and internalization”
  • High rate of predominant inattention (ADHD-I)
• “Aggression and externalization”
  • High rate of comorbid oppositional defiant behavior
  • High rate of comorbid behavioral disorders
• “Minor psychopathology”
  • Low values on all syndrome scales

1.4.7. ADHD subtypes according to symptom severity¶

Volk et al defined seven subtypes.⁸⁰⁸¹ They are presented according to frequency (% in brackets). The frequency of the comorbidities depression, ODD (oppositional defiant disorder) and CD (conduct disorder) within the respective group is also stated.

• “mild ADHD symptoms” (53.4%)
• “slight inattention” (12.3 %)
  thereof
  • Comorbid depression 9.3 %
  • Comorbid ODD 7.7 %
  • Comorbid CD 6.2 %
• “severe inattention” (12.1%)
  • Comorbid depression 6.6 %
  • Comorbid ODD 24.5 %
  • Comorbid CD 10.2 %
• “mild combined symptoms” (6.6%)
  • Comorbid depression 10.7 %
  • Comorbid ODD 30.2 %
  • Comorbid CD 13.6 %
• “severe combined symptoms” (6.1%)
  • Comorbid depression 8.3 %
  • Comorbid ODD 56.6 %
  • Comorbid CD 12.5 %
• “talkative and impulsive” (6, 5 %)
  • Comorbid depression 1.9 %
  • Comorbid ODD 24 %
  • Comorbid CD 4.9 %
• “Hyperactive” (3 %)
  • Comorbid depression 4.4 %
  • Comorbid ODD 16.7 %
  • Comorbid CD 2.2 %

1.4.8. Subtypes / forms of presentation according to emotion profiles¶

One study divided ADHD into three subtypes based on character traits and emotional profiles:⁷⁶

• Mild ADHD subtype
  • Normal emotional functionality was found in this group of people with ADHD.
• Distressed ADHD subtype
  • This subtype was characterized by a particularly high level of hardship.
• Irritable ADHD subtype
  • This subtype showed high negative affect and had the highest external validity.
  • Increased susceptibility to anger
  • The subtype was moderately stable over time and improved prospective prediction of clinical outcomes beyond standard baseline indicators.
  • De subtype was not reducible to ADHD-HI + Oppositional Defiant Disorder (ODD), ADHD-HI + disruptive mood dysregulation disorder, or other patterns of comorbidity.

1.4.9. Subtypes / forms of presentation according to microcognition biomarkers¶

The symptom-based diagnosis does not match the underlying neuropathology, which complicates the development of new therapies and treatment selection for individual patients. Fine-grained, 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 years with ADHD compared performance variables from a Go/NoGo test with n = 58 typically developing (TD) children and identified four subgroups using microcognitive biomarkers identified from thousands of responses during digital neurotherapy:⁸²

• Cluster 4:
  • poor reaction inhibition
  • inconsistent attention
  • 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 reactions than TD
  • better detection of simple targets than TD
  • better working memory than TD
  • Attention problems; significant loss of performance with
    • Pursuit of multiple goals (divided attention)
    • Distraction
• Cluster 1
  • much greater ability to recognize members of abstract categories than natural categories that children learn through physical interaction with the environment

2. Neurophysiological and endocrine differences between the subtypes¶

Hyperactivity is neurologically anchored in the striatum, inattention neurologically primarily in the PFC.⁸³

A further distinction may need to be made between inattention due to boredom caused by an under-activated PFC (in ADHD-I) and distractibility due to over-activation of the PFC (in ADHD-HI).

2.1. Dopamine level¶

This section deals with the question of whether different forms of presentation (subtypes) (according to symptom severity) correlate with certain dopamine (effect) levels. The question of whether dopamine deficiency and dopamine excess are possibly different disorders or at least variants of ADHD that need to be distinguished from each other is dealt with at the end of this chapter.

2.1.1. Hyperactivity, impulsivity: dopamine deficiency or excess dopamine in the striatum¶

Hyperactivity and impulsivity, as exhibited by the ADHD-HI subtype (without inattention) or ADHD-C (with inattention), are primarily caused (in relation to ADHD) by deviations of the dopamine level 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).⁸³⁸⁴⁸⁵

The prevailing opinion in the specialist literature is that ADHD is caused by a dopamine deficiency. However, it is known from animal models (e.g. the DAT-KO mouse) that an excess of dopamine in the striatum can also trigger hyperactivity. For more information, 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 variants must be considered. According to the inverted-U model⁸⁶⁸⁷ , both excess and deficiency of neurotransmitters cause almost identical symptoms, as the functionality of signal transmission is only given at optimal neurotransmitter levels. Nevertheless, the evidence for a lack of phasic dopamine in the striatum in ADHD is far outnumbered.

Since dopamine degradation in the striatum is mainly via DAT, while dopamine degradation in the PFC is mainly via NET and COMT and not via DAT, the DAT-10R gene variant correlated strongly with hyperactivity and impulsivity, but not with inattention.⁸⁸⁸³
Another study found no difference in 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.³⁷

2.1.2. Hyperactivity, impulsivity: excess dopamine in the PFC¶

If the prevailing view in the specialist literature is that hyperactivity and impulsivity (in ADHD-HI and ADHD-C) are caused by a lack of dopamine in the striatum,⁸⁹ the dopamine seesaw between the striatum and PFC consequently leads to increased dopamine levels in the PFC in hyperactivity and impulsivity (in ADHD-HI and ADHD-C). For more information, see ⇒ The dopamine seesaw between the PFC and subcortical regions (including the striatum) In the article ⇒ Dopamine in the chapter ⇒ Neurological aspects

In healthy people, a high dopamine level in the PFC appears to lead to a low dopamine level in the striatum, and vice versa.
A fully utilized PFC (high dopamine level) simply does not seem to need any stimulation from the reinforcement/motivation center and therefore signals to it: “closed due to overcrowding - give it a rest”. The striatum then sulks quietly (underactivated = low in dopamine). This is a normal, healthy control loop.
A long-lasting tonic dopamine deficiency in the striatum leads to an upregulation of the D2 autoreceptors (due to a very long-lasting excess of dopamine in the PFC), which in turn leads to an upregulation of the dopamine transporters in the striatum. See also ⇒ Up- and downregulation of the dopamine transporter In the article ⇒ Dopamine in the chapter ⇒ Neurological aspects. This could explain overactivity of the DAT, which would help explain or exacerbate the tonic dopamine deficiency in the striatum hypothesized in ADHD. .

Since hyperactivity can be mediated by a lack of phasic dopamine in the striatum, it would be understandable from this why this only occurs in ADHD-HI and ADHD-C, which are said to have a permanent overactivation of the PFC. The underactivation of the PFC typical of ADHD-I should rather cause an excess of dopamine in the striatum due to the associated dopamine deficiency in the PFC. Studies show a lack of dopamine in the striatum in ADHD, but do not differentiate between the forms of presentation (subtypes).⁸⁹