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)

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 there are more frequent inflammatory problems and a flattened cortisol stress response. 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 the DSM, the latter is (in our opinion rightly) regarded as a comorbidity. ICD 11 has come very close to the DSM here.
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.

According to major reviews, the prevalence of the forms of presentation is as follows:

In children and adolescents: (review, 13 meta-analyses with k = 588 primary studies, n = 3,277,590)²
ADHD-I: 35.76 %
ADHD-C: 35.16 %
ADHD-HI: 29.08 %

In adults: (review, 5 meta-analyses with k = 57 primary studies, n = 21,142,129)³⁴
ADHD-I: 36.16 %
ADHD-C: 18.82 %
ADHD-HI: 45.02 %

The results are particularly surprising in terms of the high number of hyperactive presentations in children and adolescents and even more so in terms of their relative increase in adults, as motor hyperactivity normally decreases in adults.
The reviews reported high ADHD-HI scores in adults particularly from the USA and New Zealand, not from Europe.

The prevalence figures in small studies are different and show how great the influence of chance is on the composition of subjects in ADHD studies. The totals line adds up the study results, weighted according to the number of test subjects. The total shows massively differing figures. However, these are more in line with our subjective experience, according to which we experience ADHD-HI much less frequently than is stated in the large studies.

Source / subtype	ADHD-I	ADHD-C	ADHD-HI	n
5	31.00 %	62.00 %	7.00 %	107
6	37.00 %	56.00 %	2.00 %	149
7,	49.50 %	42.00 %	8.40 %	379
8	63.50 %	26.00 %	10.50 %	193
9	58.43 %	34.61 %	6.96 %	575
Total weighted	52.35 %	39.78 %	7.31 %	1403

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.¹⁰ 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.
Other disorders such as depression or anxiety disorders also have internalizing and externalizing characteristics¹¹ and have different forms of presentation.

The subtype expression of people with ADHD is not necessarily stable throughout their lives.¹² We know quite a few people with ADHD who report a significant change in subtype.

• 1. Presentation forms (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. More omission errors in the CPT
    • 1.1.4. Peculiarities of the medication
    • 1.1.5. Neurophysiological characteristics of ADHD-I
      • 1.1.5.1. Increased cortisol stress response in ADHD-I
      • 1.1.5.2. Stress responses of cortisol, noradrenaline and dopamine
      • 1.1.5.3. CRH
      • 1.1.5.4. Dopamine receptors
      • 1.1.5.5. Serotonin reduced
      • 1.1.5.6. Orexin A reduces
    • 1.1.6. EEG image for ADHD-I
    • 1.1.7. 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. More pulse errors in the CPT
    • 1.2.4. Neurophysiological characteristics of ADHD-HI / ADHD-C
      • 1.2.4.1. Flattened cortisol stress response in ADHD-HI / ADHD-C
      • 1.2.4.2. CB1 receptors reduced in impulsivity
      • 1.2.4.3. Reduced noradrenaline reduction in ADHD-HI / ADHD-C?
      • 1.2.4.4. Reduced hippocampus volume in ADHD-HI / ADHD-C
      • 1.2.4.5. Indole acetic acid for ADHD-HI / ADHD-C
      • 1.2.4.6. TSH, serum ferritin, lactic acid in hyperactivity (ADHD-HI / ADHD-C)
      • 1.2.4.7. Volume of gray matter
      • 1.2.4.8. DlPFC activation during movement during executive tasks
    • 1.2.5. 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 ADHD 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 type pair according to Reimherr
      • 1.4.5.1. Inattentive adult type
      • 1.4.5.2. Emotionally dysregulated adult type
    • 1.4.6. ADHD presentation forms (subtypes) according to internalizing / externalizing symptoms
    • 1.4.7. ADHD groups according to symptom severity
    • 1.4.8. ADHD groups according to emotional profiles
    • 1.4.9. ADHD groups according to microcognition biomarkers
    • 1.4.10. ADHD groups according to fractional white matter anisotropy
    • 1.4.11. ADHD groups as cognitive biotypes
    • 1.4.12. ADHD groups after emotional dysregulation
    • 1.4.13. ADHD groups based on topological deviations in network hubs
    • 1.4.14. ADHD groups based on comorbidities
• 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)
    • 2.1.4. Insensitivity to pain as an indication of a possible high-dopamine subtype?
  • 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
  • 2.8. Amplitude of low-frequency fluctuation (ALFF) and functional connectivity (FC)
  • 2.9. Phase-amplitude coupling
  • 2.10. ACC-PI signal path
  • 2.11. Pregnancy problems more common in ADHD-HI and ADHD-C than in ADHD-I
• 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. Presentation forms (subtypes) of ADHD according to symptoms¶

The specialist literature primarily mentions 3 forms of presentation (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.¹³ Moreover, only 84% of people with ADHD could be distinguished from those without.

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 years¹⁴

  • 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:¹⁵

  • 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:¹⁵

  • 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)¹⁶
  • Internalizing¹⁷
  • Shy¹⁸
  • Increased susceptibility to internalizing disorders¹⁹
    e.g.
    • Anxiety disorders
    • Depression
  • Social problems of the ADHD-I subtype arise from¹⁶
    • Too shy
    • Passivity
    • Introversion
    • Being still
  • Disorders primarily in working memory and auditory processing, which places high demands on working memory.²⁰
  • More frequent comorbid disorders than ADHD-HI subtype²¹
  • Partial performance disorders more frequent
    • Reading and spelling difficulties
    • Dyscalculia (dyscalculia)
  • Often perform better in spatial thinking and artistic drawing than in verbal skills.²²
  • More bored than distracted.²³
  • Motivational problems rather than problems with inhibition.²⁴
  • Tends to have a high level of self-awareness.²⁴
  • Lethargic states (to be distinguished from depression)²⁵
  • A significant subsection of ADHD-I is said to have slowed thinking (Sluggish)²⁴
    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 are²⁶
    • Depression
    • Anxiety disorder
    • Anorexia
    • Alcoholism
    • Metabolic syndrome
  • Learning disorders
    • More frequently than with ADHD-HI¹⁷
    • 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.²⁷ 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.²⁸ 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.²⁸
  • Attention problems
    • Sustained attention (ADHD-HI and ADHD-I subtype)
    • Selective attention (ADHD-I subtype only)²⁹

• Negative symptom differentiation in ADHD-I:

  • Externalizing behaviour disorders and aggressive behaviour are atypical in ADHD-I and indicate the ADHD-HI subtype.³⁰.

    • Less frequent symptoms of aggressive or oppositional defiant behavior³¹³²

  • 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.¹⁶

  • Lower proportion of smokers than with ADHD-HI subtype (the pathways of action of nicotine and methylphenidate are similar)²⁴

  • 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

  • Tests of auditory neuropsychological functions using the Integrated Visual and Auditory Test (IVA) show³³

    • ADHD-I has poorer auditory attention compared to non-affected people
    • ADHD-I has better symptoms compared to ADHD-C
      • Auditory attention
      • Reaction control
      • Sustained attention
      • Prudence
      • Consistency

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

1.1.3. More omission errors in the CPT¶

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

1.1.4. 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.²⁴
  • According to another opinion, ADHD-HI and ADHD-I do not differ in the MPH response rate.³⁵
• 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)

1.1.5. Neurophysiological characteristics of ADHD-I¶

1.1.5.1. 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

1.1.5.2. 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.^3637383940
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 hypertension, 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.

1.1.5.3. 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.⁴¹ 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

1.1.5.4. Dopamine receptors¶

The dopamine D4 receptor (DRD4) has a special significance in the PFC, which is why Diamond⁴² 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.⁴³
High Novelty Seeking / Sensation Seeking rates are associated with high aversion to boredom and correlate with impulse control disorders.⁴⁴ Boredom is a cause of inattention in ADHD-I, while impulse control problems are atypical of ADHD-I and more typical of ADHD-HI and ADHD-C.

1.1.5.5. Serotonin reduced¶

In ADHD-I, there is often said to be a lack of serotonin.⁴⁵
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.⁴⁶
The 5-HTTLPR-L/L genotype correlates with hyperactive symptoms.⁴⁷
One study reports a correlation between the presence of a 5-HTTLPR-S allele and inattention.⁴⁸

1.1.5.6. Orexin A reduces¶

ADHD-I might have lower orexin A levels than the ADHD-HI subtype and than non-affected individuals.⁴⁹ More about orexin at ⇒ Orexin / hypocretin In the section ⇒ Hormones in ADHD in the chapter ⇒ Neurological aspects.

1.1.6. EEG image for ADHD-I¶

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

1.1.7. 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-H/I (hyperactive/impulsive)’
• ADHD-PH (predominantly hyperactive/impulsive)
• ADHD (colloquially as the opposite of ADS, alerdigs ADHD-HI and ADHD-C together. Competes with the colloquial use of ADHD as a generic term for all subtypes)
• Fidget spinner (colloquially descriptive, but also applies to ADHD-C)

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 others⁵⁰
• More extroverted (in contrast to the more introverted ADHD-I subtype)¹⁷¹⁶
• Frequent behavioral disorders and (comorbid) aggressive behavior⁵¹.
• More frequent comorbidity with oppositional defiant behavior²⁴
• Disorders primarily in the area of behavioral inhibition²⁴ and executive functions⁵²
• Is more distractible than bored²⁴
• Has an inhibition problem rather than a motivation problem.²⁴
• Tendency towards low self-awareness²⁴
• Good response to methylphenidate.
  • The non-responder rate (MPH does not work) is said to be 10 %.⁵³, compared to the usual 20 % to 30 % overall.
  • 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.²⁴
• Higher proportion of smokers than in the ADHD-I subtype. (Nicotine acts as a stimulant like methylphenidate)²⁴
• Hyperactive/impulsive type often only a precursor in childhood/adolescence for later ADHD-C⁵⁴⁵⁵
• Boys are affected 5 times more often than girls⁵⁶.

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.⁵⁴⁵⁷
  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 persons with ADHD leads to an equalization of test performance compared to non-affected people. 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. More pulse errors in the CPT¶

ADHD-HI / ADHD-C correlate with more commission errors in the Continuous Performance Test (CPT).³⁴
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 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.

1.2.4.1. 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

• The corresponding symptoms of hypocortisolism are²⁶

  • Atypical depression
  • Inflammatory problems⁵⁸ more frequently than in the ADHD-I subtype. Cortisol inhibits the inflammatory response mediated by CRH
    • E.g. irritable bowel syndrome
    • E.g. neurodermatitis
  • Tiredness
    • Cortisol inhibits the pro-inflammatory effect of CRH
    • Cortisol 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. fibromyalgia⁵⁹
    • 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 PTSD⁶⁰

• 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.

1.2.4.2. 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)⁶¹
    • 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

• Deficient HPA axis deactivation in ADHD-HI / ADHD-C

  • 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 axis⁶²
    • Endogenous cannabinoids appear to inhibit the HPA axis via CB1 receptors in the brain
    • Anandamide
      • Lowers the corticosterone level in stressed animals⁶³
      • Reduces the endocrine stress response of the HPA axis⁶⁴
    • 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 system⁶³
    • Activation of peripheral CB1 receptors inhibits noradrenaline release from the sympathetic terminals and adrenaline release from the adrenal glands⁶³
    • Endogenous CB1 agonists have an anxiolytic effect and prevent the occurrence of pathological anxiety states⁶³
    • CB1 may not affect adaptation to daily chronic stress⁶⁵
    • CB1 mediates the rapid downregulation of the HPA axis by GR agonists (endocrine feedback loop), here by dexamethasone⁶⁶⁶⁷ CB1 antagonists prevent downregulation.

1.2.4.3. 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.^6869707172 Only a strong increase in noradrenaline / dopamine reduces the PFC.^3637383940

1.2.4.4. 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 areas⁷³
* 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 controls⁷³
* 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.⁷³

1.2.4.5. 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.⁷⁴

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

In 49 children with ADHD with and without hyperactivity were found:⁷⁵

• 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

1.2.4.7. Volume of gray matter¶

One study found differences in gray matter volume (GMV) between ADHD subtypes:⁷⁶

• ADHD-C: GMV significantly increased
  • Compared to ADHD-I
    • In the left caudate nucleus
  • Compared to those 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 during executive tasks¶

Children with ADHD completed a Stroop test as an executive task while sitting still or cycling on a desk bike. Changes in oxygenated and deoxygenated hemoglobin in the left DLPFC differed by ADHD subtype, ADHD severity and gender:⁷⁷
ADHD-HI, ADHD-C, severe ADHD, and males showed greater dlPFC activation during the executive function task during physical exercise than during sitting still.
ADHD-I, mild and moderate ADHD, and females showed greater dlPFC activation during the executive function task while sitting still than during physical exercise
Inhibitory control improved in women with ADHD-I when sitting still.

1.2.5. 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)²⁹
• 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.⁷⁸

A small study replicated previous research that frontal delta and theta power is higher in ADHD-C than ADHD-I and TD groups.⁷⁹

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^80818283

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 ADHD classifications¶

The “subtypes” mentioned below, which have occasionally been mentioned in the literature, do not represent true forms of presentation (subtypes) of ADHD, but possible grouping models that summarize more typical forms 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 behaviour⁸⁴
  • possibly due to less impairment of the DMN and/or greater impairment of the salience network⁸⁴
• poorer sustained attention⁸⁴
• better reaction inhibition⁸⁴
• ADHD-RI had a significantly different neuropsychological profile compared to the other groups, including a
• lower psychomotor speed⁸⁵
• longer response times⁸⁵⁸⁶
• the worst overall performance in the global neurocognitive index⁸⁵⁸⁶
  • poorer neurocognitive index than SCT (p < 0.001)⁸⁶
• significantly increased proportion with a DRD4-7 repeat allele⁸⁵
• attention-related posterior brain regions (especially temporal-occipital areas) activated more strongly for go and no-go cues than for controls and ADHD-I⁸⁵
• slower psychomotor speed than SCT⁸⁶
• only SCT was independently associated with poorer overall memory performance⁸⁶

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.⁸⁷

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 type 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.⁸⁸. The result is consistent with an earlier study by the authors.⁸⁹
Both forms of presentation (subtypes) benefited equally from MPH treatment.

1.4.5.1. Inattentive adult type¶

• Inattentive
• Emotionally dysregulated

1.4.5.2. Emotionally dysregulated adult type¶

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:⁹⁰

• “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 groups according to symptom severity¶

Volk et al defined seven subtypes.⁹¹⁹² 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. ADHD groups according to emotional profiles¶

One study divided ADHD into three subtypes based on character traits and emotional profiles:⁸⁷

• 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. ADHD groups 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:⁹³

• 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

1.4.10. ADHD groups according to fractional white matter anisotropy¶

A study that divided children with ADHD into subgroups based on white matter microstructural features found no differences in ADHD symptoms, however:⁹⁴

• a group with
  • reduced fractional anisotropy of the white matter
  • reduced processing speed
  • better response to MPH
• a group with
  • higher fractional anisotropy of the white matter
  • reduced reaction inhibition
  • poorer sustained attention
  • poorer response to MPH

1.4.11. ADHD groups as cognitive biotypes¶

Leikauf et al identified two biotypes in children with ADHD by applying unsupervised machine learning to 20 cognitive test measures and validating the results with EEG and ECG measurements and different responses to medication:⁹⁵

• impulsive cognition
  • fewer omission errors
  • more action errors
  • poorer inhibition
  • shorter response times
  • higher EEG theta and delta power
  • higher resting heart rate
• inattentive cognition
  • more omission errors
  • longer response times
  • more variable response times
  • lower EEG beta power
  • Resting heart rate as in unaffected people
  • strong correlation between response to atomoxetine and improvement in immediate recall of verbal memory

1.4.12. ADHD groups after emotional dysregulation¶

One study analyzing people with ADHD in relation to emotional dysregulation found three groups:⁹⁶

• predominantly inattentive / emotional dysregulation present / emotionally unstable
• moderate ADHD severity / no emotional dysregulation / inconspicuous personality traits
• high ADHD severity / no emotional dysregulation / inconspicuous personality traits

1.4.13. ADHD groups based on topological deviations in network hubs¶

One 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 participation coefficient (cross-module diversity) brain morphometry:⁹⁷

• highest symptoms for hyperactivity/impulsivity and inattention
  • long-term persistent emotional dysregulation
  • 25 % comorbid affective disorders
  • pronounced changes in the mPFC and pallidum
  • spatially correlated increased 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 refer to relevant findings:
    • tonic spontaneously firing dopamine neurons are regulated by inhibitory striatal projections⁹⁸ and interact with the serotonergic system via orbitofrontal-striatal circuits, modulating hyperactivity/impulsivity in ADHD⁹⁹.
    • Cholinergic dysfunction in the PFC is typical of ADHD-C mixed type^{100101 102} and impairs motor control and attention in particular
    • Neuroinflammation may have a crucial role in the pathophysiology of ADHD¹⁰³, which correlates with increased H3R
• predominant impulsivity and hyperactivity
  • long-term decline in emotional dysregulation
  • 9.8 % Comorbid affective disorders
  • pronounced changes in the ACC and pallidum
  • spatially correlated reduced 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 refer to relevant findings:
    • Alterations in the glutamate system may indicate impaired excitatory neurotransmission in caudate-related circuits that mediate cognitive and affective processes, including reward processing¹⁰⁴
    • one RCT showed significant improvement in hyperactivity/impulsivity symptoms with cannabinoids¹⁰⁵
• predominant inattention
  • long-term decline in emotional dysregulation
  • 5 % Comorbid affective disorders
  • pronounced changes in the superior frontal gyrus
  • spatially correlated reduced receptor levels of
    • Serotonin (5-HT2A, r=-0.25)

The groups largely correspond to the known 3 forms of presentation according to DSM 5.
It is known that emotional dysregulation correlates more with hyperactivity/impulsivity or the ADHD mixed type than with predominant inattention and that more severe ADHD symptoms correlate with greater emotional dysregulation. More on this under Emotional dysregulation / Emotional symptoms in ADHD

Graphic 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]. 2025 Mar 28:2025.03.27.25324802. 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¶

An analysis of the MTA study found four clinical profiles that are sufficiently different to warrant classification as ADHD subtypes:¹⁰⁶

• ADHD without comorbid Disorder
  • responded best to MTA drug treatments (with or without behavioral therapy)
• ADHD together with internalizing disorders (ADHD + ANX, mainly anxiety disorders reported by parents)
  • responded equally well to the behavioral therapy and medication MTA treatments
• ADHD with ODD/CD, but without anxiety (ADHD + ODD/CD)
  • responded best to MTA drug treatments (with or without behavioral therapy)
• ADHD with anxiety and ODD/CD (ADHD + ANX + ODD/CD)
  • responded best to combined drug and behavioral MTA treatments

2. Neurophysiological and endocrine differences between the subtypes¶

Hyperactivity is neurologically anchored in the striatum, inattention neurologically primarily in the PFC.¹⁰⁷

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).^107108109

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 model¹¹⁰¹¹¹ , 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.¹¹²¹⁰⁷
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.⁴⁶

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,¹¹³ 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 an overactivity of the DAT, which would help explain or reinforce the tonic dopamine deficiency in the striatum assumed 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).¹¹³

2.1.3. DAT differences in the forms of presentation (subtypes)¶

Various studies suggest an increased number of DAT in ADHD-HI compared to ADHD-I.

• In a SPECT examination of 31 adults with ADHD, a greater increase in DAT was found in ADHD-HI sufferers than in ADHD-I sufferers. However, DAT were still elevated in persons with ADHD-I compared to those without. Smoking significantly reduced DAT to or below the level of non-affected individuals in both forms of presentation.¹¹⁵ One study compared DAT in the Spontanuous(ly) hypertensive rat (SHR), which is a validated model of the ADHD-C subtype, and a substrain of the Wistar Kyoto rat, which was used here as a model of the purely inattentive ADHD-I subtype. The ADHD-HI subtype rat formed more DAT than the ADHD-I subtype rat, supporting our conclusion. MPH decreased DAT density more in ADHD-HI rats than in ADHD-I rats.¹¹⁶
• Another study compared rats considered to be ADHD-HI models, ADHD-I models and unaffected models. It found that ADHD-HI rats had significantly lower levels of dopamine in the dorsal striatum, while in ADHD-I rats this was sometimes the same and sometimes even higher than in non-affected rats. Similarly, the ADHD-HI rats had faster dopamine uptake in the ventral striatum and nucleus accumbens, while the ADHD-I rats had faster dopamine uptake only in the nucleus accumbens, both compared to the unaffected rats.¹¹⁷ Another study also found lower dopamine levels (and slightly higher norepinephrine levels) in the striatum in ADHD-HI rats compared to unaffected rats.¹¹⁸ This suggests increased DAT in ADHD-HI compared to ADHD-I.
• MPH, which significantly reduces the number of DAT, is said to be nowhere near as effective in ADHD-I as in ADHD-HI, according to one study.¹¹⁹ Another study reports a good effect of MPH in ADHD-I.¹²⁰
• SCT persons with ADHD (we had previously considered SCT to be an extreme form or subtype of ADHD-I) are particularly frequent MPH nonresponders. In particular, elevated SCT sluggish/sleepy factor values indicate MPH nonresponding. Neither elevated SCT daydreamy symptoms, nor did ADHD subtype (ADHD-HI or ADHD-I) differ in MPH responding rates. The latter supports that SCT is not a subtype of ADHD-I.³⁵
• Genetic differences between the presentation forms (subtypes) in relation to the ADHD-associated polymorphisms of the DAT1 gene should suggest an association between DAT1 gene polymorphisms and ADHD-HI, but not with ADHD-I. The DAT-10R gene variant correlated strongly with hyperactivity and impulsivity, but not with inattention.¹²¹¹⁰⁷ However, another study was unable to confirm this.¹²² Another study found an association of DAT1 10/10 with ADHD-I, with DAT1 10/10 being associated with increased DAT expression and reduced dopamine uptake. The results of this study do not match any of the previously known results in other respects either.¹²³ Another study found that
  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.⁴⁶
  COMT Val/Val and DAT 10R in combination correlated with increased hyperactivity and increased ADHD symptoms at age 18 in 11- to 15-year-old boys, but not in girls¹²⁴

DAT 10R stands for more active DAT.¹²⁵

However, it is questionable whether DAT actually regulates dopamine levels in the way previously assumed.¹¹⁴

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

Like all catecholamines, dopamine acts in an inverted-U form: Too little is just as detrimental as too much.
ADHD is typically characterized by an extracellular dopamine deficiency. ADHD medications primarily act as dopamine reuptake inhibitors, thus increasing extracellular dopamine. However, the high number of animal models with elevated extracellular dopamine levels suggest that there may also be ADHD cases with elevated dopamine levels.
So far, the findings are very limited due to the great difficulty of measuring dopamine in the brain in vivo.

At this point, we therefore want to collect indicators that can point to an increased brain dopamine level.

Dopamine is an important factor in pain regulation. Chronic pain is usually characterized by reduced dopamine. This explains why chronic pain is a common comorbidity of ADHD. Schizophrenia is characterized by excessive dopamine levels and is also associated with a significantly reduced level of pain.
We derive from this the working hypothesis that reduced pain sensitivity in ADHD could indicate a (probably rather rare) ADHD subtype with elevated dopamine levels.

2.2. Exaggerated and flattened endocrine stress responses of the presentation forms (subtypes)¶

The endocrine stress responses appear to be much stronger in ADHD-I than in ADHD-HI and ADHD-C.
An endocrine stress response is the amount of hormones (and neurotransmitters) released in response to an acute stressor.
The ADHD-I subtype often shows an exaggerated cortisol stress response, while the ADHD-HI and ADHD-C often correlate with a flattened cortisol stress response. Thus, the ADHD-I subtype is typically a case of hypercortisolism, while ADHD-HI and ADHD-C are more a case of hypocortisolism.
⇒ Changes in cortisol levels in ADHD in: Cortisol and other stress hormones in ADHD

As hypocortisolism can be a long-term follow-up reaction to hypercortisolism, if a downregulation adjustment (⇒ downregulation / upregulation) is necessary due to permanently excessive cortisol levels Downregulation / Upregulation; ⇒ Changed hormone and neurotransmitter levels depending on the stress phase in the article ⇒ The human stress system - the basics of stress In the chapter ⇒ Stress) of the glucocorticoid (cortisol) receptor systems, it could be concluded that the ADHD-I type represents a precursor and the ADHD-HI and ADHD-C a subsequent stage of ADHD. However, this is contradicted by the fact that the type of cortisol response to acute stress tends to reflect a stress phenotype that is already found in healthy individuals. In disorders with externalizing symptoms - aggression, ODD, CD, etc. - the cortisol responses to acute stress are regularly flattened, while in disorders with internalizing symptoms - depression, anxiety, etc. - the cortisol responses are regularly elevated.

Increases in cortisol are associated with the stress-induced release of noradrenaline and α1-adrenergic receptor activation.¹²⁶¹²⁷ Parallel to the issue of the correlation of neurotransmitter noradrenaline and cortisol discussed here, there is a correlation between cortisol and dopamine release.¹²⁸ Cortisol levels correlate positively with AMP-induced dopamine release in the left ventral striatum and dorsal putamen.

We assume that the cortisol, adrenaline, noradrenaline and dopamine responses in the brain to acute stress correlate, so that a high cortisol response to acute stress is accompanied by a high (hormone) noradrenaline release in the sympathetic nervous system on the one hand and a high (neurotransmitter) noradrenaline and dopamine release in the central nervous system (= brain) on the other. Low values are also likely to correlate. This could conclusively explain several patterns of ADHD subtypes.

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

A very strong increase in noradrenaline / dopamine shuts down the PFC and shifts behavioral control to posterior brain regions.^3637383940 There are connections between cortisol and the stimulation of D1 receptors.¹¹⁸
The PFC reacts very sensitively to its neurochemical environment. Too little (drowsiness) or too much (severe stress) catecholamine release in the PFC weakens cognitive control of behavior and attention.¹⁵⁸is the PFC remains permanently activated in ADHD-HI and ADHD-C - which is just too much at some point.

People with ADHD-I, on the other hand, suffer from an endocrinological overreaction to acute stress. Assuming the hypothesis put forward on this side that in ADHD-I, in addition to the cortisol stress response, the release of noradrenaline in the brain in response to acute stress is also excessive, the established finding that greatly increased noradrenaline levels block the PFC would explain why ADHD-I sufferers often experience mental blocks and excessive demands when making decisions.
The strong stress cortisol response in ADHD-I, which occurs on the 3rd increment of the HPA axis some time after the noradrenaline release, leads to a strong brake on the release of noradrenaline. The noradenaline brake of the PFC is therefore released again in ADHD-I and the PFC starts up again after some time. The PFC therefore does not remain permanently in a dysfunctional state (as in ADHD-HI/ADHD-C). A merely temporary hypofunction of the PFC therefore does not lead to a permanent excess of dopamine in the striatum, which is why ADHD-I does not cause such severe striatal problems. (Excess and deficiency both cause disorders of nerve communication and can therefore trigger different or almost identical symptoms in the same brain region, because the communication of signals in the brain only works properly when neurotransmitter levels are optimal).

The various forms of presentation (subtypes) can - in accordance with the endocrinological / neurological characteristics described - also be conclusively described as stress phenotypes.
Stress phenotypes mean a typified reaction to stress.

More on this below under 6.

The PFC is deactivated by alpha-1 adrenoceptors, which have a lower affinity for noradrenaline and cortisol than alpha-2 adrenoceptors and are therefore only addressed at very high noradrenaline and cortisol levels.

On the other hand, it is assumed that a strong increase in dopamine/noradrenaline is the cause of the underactivation of the PFC typical of ADHD-I.
Since ADHD-HI (and ADHD-C) involves a flattened cortisol response to an acute stressor, a parallel flattened norepinephrine/dopamine release would lead to a permanent mild stress state that does not shut down the PFC but permanently overactivates it.

Due to a weaker cortisol response to acute stress, the cortisol level at the end of a stress reaction in ADHD-HI and ADHD-C is in any case (and regardless of the hypothesis of a correlation of the amounts released on this side) less able to shut down the stress systems of the HPA axis and the release of noradrenaline in the brain.

An increased cortisol response to stress in 3-month-old babies correlated with greater methylation of the NR3C1 gene.¹⁵⁹ Maternal depression or anxiety in the third trimester correlated with increased DNA methylation of the NR3C1 promoter in the umbilical cord blood of newborns.¹⁵⁹ The NR3C1 gene encodes the glucocorticoid receptor, which is designed to shut down the HPA axis (and thus also the cortisol level) in response to high cortisol levels at the end of a stress reaction. The specific CpG methylation in NR3C1 triggered by maternal stress correlated with attenuated gene expression, which was functionally associated with increased cortisol reactivity in these infants at three months of age.

2.3. ADHD subtypes / forms of presentation according to EEG¶

Most examinations find different EEG subtypes in people with ADHD.
Externalizing characters show a flattened error-related negativity (ERN), internalizing characters an increased ERN.¹⁶⁰ The ERN is a component of the event-related potentials (qEEG). It occurs immediately after an incorrect motor response (given under time pressure). ERN is primarily measured via the PFC.
An attempt to automatically differentiate subtypes based on their EEG patterns using AI failed.¹³

The largest study known to us found a differentiation into 5 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, while internalizing symptoms (ADHD-I) were associated with increased activity in the alpha and beta bands.¹⁶¹ In contrast, a study of 94 boys between 6 and 9 years of age found uniformly increased total alpha activity with reduced alpha peak frequency, reduced alpha bandwidth and reduced alpha amplitude suppression magnitude as well as an increased alpha1 / alpha2 (a1 / a2) ratio, despite differentiation by subtype.¹⁶²

EEG microstate B is reported to be promising for discriminating between ADHD presentation forms based on differences in visual network function.¹⁶³

2.3.1. ADHD-HI subtypes according to EEG¶

EEG abnormalities in ADHD-HI are primarily found in the striatum and in the frontal-striatal area.¹⁶⁴

2.3.1.1. Theta frontal increased, beta decreased (ADHD-HI with hyperactivity and impulsivity with hypoactive EEG)¶

A high theta-beta ratio defines a separate EEG ADHD subtype.¹⁶⁵ This subtype has been described in 24.5% of people with ADHD.¹⁶⁶

• Total power increased overall¹⁶⁶
• Relative theta increased, especially frontal¹⁶⁶
  • Increased theta frontal has been found in several EEG studies in ADHD¹⁶⁷
  • This is considered representative of frontal lobe problems, especially hyperactivity¹⁶⁸
• Relative and absolute theta increased¹⁶⁹
• Beta activity reduced overall¹⁶⁶
  • Lower amplitude at relative beta, measured at the electrode derivation points Cz on Pz-O1 and Pz-O2 as well as paramedian¹⁶⁹
• Consequences: Theta-beta ratio increased (theta high, beta low)¹⁷⁰
• Delta central and posterior reduced¹⁶⁶
• Alpha front and rear reduced¹⁶⁶
• Increased slow waves, reduced fast waves¹⁷¹
• Type of behavior¹⁶⁶
  • Most typical ADHD symptom pattern of all EEG subtypes
  • Hyperactivity
  • Pleasurable
  • Less anxious

Therapy goals:

• Increase SMR (12 to 15 Hz)
• Reduce theta (4 to 8 Hz)
• Reduce theta while increasing beta: addresses tonic aspects of cortical activation to achieve an alert, focused yet calm state¹⁷²

Effectiveness:

• Train theta down and (possibly simultaneously) alpha up
  The last two training methods mentioned (theta down, beta up or theta down / alpha up training) differed only slightly in their results for 7-10-year-olds. Both protocols alleviate the symptoms of ADHD-HI in general (p <0.001) as well as the symptoms of hyperactivity (p <0.001), inattention (p <0.001) and omission errors (p <0.001), but not the oppositional and impulsive symptoms.¹⁷³
• Of 19 participants with ADHD-HI according to DSM III-R 12, 11 responded very well to neurofeedback training in which beta was trained up and theta down (40 sessions). The other 7 showed less improvement. In the responders, the IQ improved by 10 points (from 112 to 122) in addition to the symptoms. However, N = 19 is too small for a reliable statement.¹⁷⁴

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

The beta subtype is said to be present in around 23.2%¹⁷⁵ of people with ADHD.

Findings:¹⁷⁶¹⁷⁷

• Amplitude of beta (13 to 30 Hz)¹⁷⁸ or (18-26 Hz) increased, frontal and at the back of the head
• Beta dominates relative and absolute power
• Occurrence in the entire cortex
  • Frontal¹⁶⁹
  • Posterior¹⁶⁹
• Increased overall frontal performance¹⁷⁵
• Increased beta activity over the entire top of the skull¹⁷⁵
• Theta activity reduced in the fronto-central regions¹⁷⁵
• Alpha activity in the frontal regions reduced¹⁷⁵
• Type of behavior¹⁷⁵
  • Symptomatic:
    • Increased aggressiveness
    • Increased vandalism
    • Increased antisocial behavior.
  • Subtype-specific:
    This neurological abnormality is not found in ADHD-I, but only in a subgroup of the mixed type, which is also distinguished from the rest of ADHD-C by a greater tendency towards other symptoms ¹⁷⁹¹⁷¹
    • Tantrums
    • Mood swings
    • Increased delinquency

However, people with ADHD with excessive beta are not hyperactive. Compared to non-affected people, this is typical:¹⁸⁰

• Beta increased overall
• Delta is significantly reduced centrally posteriorly
• Alpha is reduced overall
• Significantly reduces the overall posterior performance
• The theta / beta ratio is reduced overall.
• The skin conductance is significantly reduced (just like in a person with ADHD with excessively elevated theta)

From this, the authors conclude that the theta/beta ratio is not associated with arousal.

Therapy goals:

• Increase SMR (12 to 15 Hz)
• Reduce Beta 2 (21 to 35 Hz)
• Reduce gamma (35 to 45 Hz)

A renowned group of researchers reported that people with ADHD with very low EEG theta values were more often non-responders to stimulants.¹⁸¹ However, we know of people with ADHD of the beta type who benefited greatly from methylphenidate and even more from amphetamine medication.

2.3.2. ADHD-I subtypes in the EEG¶

EEG abnormalities in ADHD-I are said to occur primarily in the PFC and in the frontal-paretic area.¹⁶⁴

2.3.2.1. Delta and theta increased, beta decreased¶

One study found this subtype in 24.5% of people with ADHD.¹⁸² Characteristic is:

• Delta increased overall¹⁶⁹¹⁸²
• Total theta increased¹⁶⁹¹⁸²
• Abnormal increase in slow frequencies (delta/theta) primarily in central and centro-frontal areas¹⁸³
• Alpha reduced overall¹⁸²
• Beta reduced¹⁶⁹
• Total posterior power reduced¹⁸²
• Type of behavior¹⁸²
  • Enthusiastic
  • Impulsive
  • Requires close supervision to complete tasks
  • Less need for sleep
  • Swears, uses obscene language
  • No Disorder of social behavior (Conduct Disorder, CD)
  • Prefers to surround himself with younger children
  • Developmental delay
• People with ADHD with high front-midline theta often showed
  • High and steep power peaks when discharged to Fz
  • With high FMT activity in the higher FMT frequencies:
    • Problems with emotion regulation and memory control.
  • With high FMT activity in the lower FMT frequencies:
    • Learning difficulties or memory problems.
  • States of anxiety
  • Affect breakthroughs

Therapy goals:

• Increase beta 1 (15 to 21 Hz)
• Reduce theta (4 to 8 Hz)

Kühle¹⁶⁹ describes that delayed brain development is often found in ADHD-I. As far as we know, the maturation of some areas of the brain is delayed in all ADHD subtypes. However, whether this represents a neurological deficit or even just a neurological correlate (= image) of ADHD is questionable. The maturation delay in people with ADHD corresponds quite exactly to the brain maturation delay in giftedness.
Find out more at ⇒ Giftedness and ADHD

2.3.2.2. Only alpha activity increased¶

This type is said to occur in around 16.8%¹⁷¹ of people with ADHD.

• Excessive alpha activity¹⁸⁴¹⁷¹
  • Posterior¹⁸⁵
  • Central¹⁸⁶
  • Fronto-central¹⁷¹
  • Sometimes also head-on¹⁸⁴
• Delta reduced overall¹⁷¹
• Theta fronto-central reduced¹⁷¹
• Type of behavior¹⁷¹
  • Hyperactive, fidgety
  • Confused, feels like in a fog
  • Slightly obsessive
  • Perfectionist, sets high goals
  • Only deals with one or two ideas or activities

The type of behavior described above, which is reminiscent of compulsiveness, is said to be reflected in studies of people with autism, in which very high alpha values were also found.¹⁸⁷¹⁸⁸

The alpha activity occurs as a μ-rhythm (also called monkey face (Mu-rhythm)) centrally over the entire cortex in the posterior temporal and/or temporal area.

A study of girls with ADHD-I only found significant differences in the alpha 2 band compared to non-affected girls.¹⁸⁹

2.3.2.3. Theta posterior increased, alpha and beta decreased¶

This type is said to occur in around 11%¹⁷¹ of people with ADHD.

• Total frontal power significantly increased¹⁸⁰
• Theta significantly increased¹⁸⁰
  • Especially posterior
• Theta / beta ratio significantly increased¹⁸⁰
• Alpha reduced across the entire skullcap¹⁸⁰
• Beta reduced across the entire skullcap¹⁸⁰
• Delta activity reduced centrally.¹⁸⁰
• Type of behavior¹⁸⁰
  • Outgoing
  • Cheerful
  • Fewer behavioral problems than other people with ADHD
  • Significantly less hyperactivity
  • Age-appropriate behavior (no developmental delay)
  • No increased anxiety
  • No increased antisocial behavior
  • No ritualized behavior

2.3.2.4. Only theta frontal midline (FMT) increased¶

• Abnormal increase in frontal midline theta (FMT) (5.5 to 8 Hz),¹⁹⁰¹⁹¹ especially under task load
• Dysfunction: hippocampus, anterior cingulate cortex (ACC)¹⁹²
• Medication recommendation: No medication; low doses of methylphenidate¹⁹²
• Unaffected people barely have FMT at rest
• People with ADHD with a high FMT often show
  • High and steep power peaks when discharged to Fz
  • With high FMT activity in the higher FMT frequencies:
    • Frequent problems with emotion regulation and memory control
  • With high FMT activity in the lower FMT frequencies:
    • Often learning difficulties or memory problems
  • States of anxiety
  • Affect breakthroughs

2.4. ADHD subtypes according to QEEG¶

A study with 69 participants found three QEEG subtypes:¹⁹³

• increased absolute and relative beta performance
  • K-ARS: 25.31
• increased relative fast alpha and beta performance
  • K-ARS: 21.67
• increased absolute slow frequency (delta and theta power)
  • K-ARS: 12.64 and thus barely stronger than non-affected persons with 11.07
  • WURS: 55.82 significantly higher than non-affected persons with 42.81

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

One study found:¹⁹⁴

• an age-dependent decrease in qEEG power in children with ADHD
• significant differences between children with ADHD and non-affected children in the theta/beta ratio and theta activity in the frontal area
• remarkable trend towards an increase in beta activity in the age groups 6-10 years and > 10 years
• in younger children with ADHD
  • Correlation between qEEG power and hyperactivity
  • Correlation between frontal theta activity and hyperactivity
• The qEEG power of children with ADHD gradually decreased with increasing age, corresponding to the decrease in symptoms

2.5. Functional differences in nerve conduction pathways in the brain (?)¶

Studies suggesting specific functional differences in the neural pathways in the brain for ADHD-HI and ADHD-I,¹⁹⁵¹⁹⁶ suffer from very low case numbers (n < 50), which affects the robustness of the results (for more on this, see: ⇒ Studies prove - sometimes nothing at all).

2.6. Subtypes / forms of presentation and serotonin¶

Furthermore, different serotonin levels are discussed in the different subtypes, which are thought to be associated with the 5-HT 1B receptor in ADHD-I and with the 5-HT 2A/C receptors in ADHD-HI.¹⁹⁷

2.7. Neuro-auditory profiles of the subtypes / forms of presentation¶

One study showed 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 showed reduced gray matter volumes in the left Heschl’s gyrus, and thus reduced 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 controls.
ADHD-HI showed left-right asynchrony, while ADHD-I and controls showed balanced hemispheric response patterns.¹⁹⁸

2.8. Amplitude of low-frequency fluctuation (ALFF) and functional connectivity (FC)¶

The amplitude of the low-frequency fluctuation (ALFF) measures how strongly an area of the brain oscillates at a low frequency. High ALFF values represent a stronger local metabolism and more spontaneous neuronal activity, low ALFF values a lower local activity.

A study found using functional near-infrared spectroscopy at rest (fNIRS) in children with ADHD-C compared to ADHD-I:¹⁹⁹

• increased amplitude of the low-frequency fluctuation (ALFF) in some brain regions
• reduced functional connectivity (FC)

2.9. Phase-amplitude coupling¶

Phase-amplitude coupling describes how the phase of a slow brain oscillation systematically influences the amplitude of a faster oscillation. It is an important mechanism of neuronal communication and is involved in attention, sensory processing and working memory.
One study investigated intra- and inter-channel PAC differences across different spatial scales and analyzed PAC-based brain network properties:²⁰⁰
ADHD-I, and even more so ADHD-C, shows a stronger α-γ-PAC than healthy controls.
ADHD-I showed mainly intrahemispheric changes
In ADHD-C, the left hemisphere and occipital regions are particularly affected.
In ADHD-C, PAC was significantly higher in the α-β band than in ADHD-I, especially in the left hemisphere.
ADHD-I also showed increased interchannel δ-β-PAC with widespread distribution compared to healthy controls.
The authors conclude from this that there are compensatory hyperactivation mechanisms in ADHD, especially in ADHD-C.

2.10. ACC-PI signal path¶

The ACC-PI signaling pathway (from the ACC to the posterior insula, PI) controls central (pain) sensitization mechanisms. ADHD-induced ACC-PI activity can increase or decrease pain sensitivity and possibly trigger overactivity (ergomania).²⁰¹

• 6-OHDA mice, a model animal for ADHD, show increased spontaneous activity of the ACC-PI signaling pathway²⁰²
• 6-OHDA mice show a sex-specific neuroinflammatory response to dopamine neuron loss by 6-OHDA:²⁰³
  • Males: Dopamine loss triggered inflammation only in the ACC
    • Consequences:
      • Hyperactivity
      • No increased sensitivity to pain (no hyperalgesia)
  • Females: Dopamine loss triggered inflammation in the ACC-PI signaling pathway
    • Consequences:
      • No hyperactivity
      • Increased sensitivity to pain (hyperalgesia)

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

One study compared the pregnancies of 7,103 mothers with ADHD-HI or ADHD-C and 2,928 mothers with ADHD-I.
Mothers with ADHD-HI / ADHD-C were / had compared to mothers with ADHD-I:²⁰⁴

• more often younger than 25 years
• more often a black skin color
• more frequently from a lower income quartile
• 32.3 % more smoked tobacco during pregnancy (25.8 % vs. 19.5 % in ADHD-I)
  • 526 % more than without ADHD (there 4.9 %)
• used illegal drugs more frequently
• 19 % more frequent hypertensive pregnancy disorders
• 19 % more frequent premature births
• 39 % more frequent maternal infections
• 33% more often newborns too small for gestational age

3. ADHD-HI/ADHD-C and ADHD-I as stress phenotypes¶

See also ⇒ Stress theories and stress phenotypes: a possible explanation of ADHD subtypes In the chapter ⇒ Stress

4. The problem of subdivision into subtypes / forms of presentation¶

One problem with the subdivision into subtypes / forms of presentation is that some people with ADHD transfer brain activities from affected brain areas to other brain areas, i.e. “misappropriate” brain areas in order to substitute the abilities of the affected brain areas.

This makes diagnosis by means of questionnaires and tests more difficult.

A more objective determination of the particular ADHD subtype/presentation could be made by taking a more detailed history using EEG or QEEG measurement and stress system reactance using the dexamethasone/ACTH/CRH test.

5. ADHD variants according to dopamine level?¶

Most of the literature links ADHD with reduced dopamine levels. This description may also include the fact that the dopamine level is neutral but the sensitivity of receptors is reduced, or that dopamine is broken down too quickly. As a result, too little dopamine (effect) is present.
Apart from the fact that this description usually does not differentiate more precisely in which brain region the dopamine deficit exists and whether it is a deficit of the tonic or phasic dopamine output or the basal dopamine level, there is conflicting evidence that an excess of dopamine can also cause ADHD symptoms. See, among others, ⇒ ADHD in animal models In the chapter ⇒ Neurological aspects.
This is consistent with the inverted-U model, according to which an excess as well as a deficit of a neurotransmitter can cause confusingly similar symptoms, because optimal signal transmission is dependent on a certain (“mean”) neurotransmitter level. Signal transmission is equally impaired by excessive and reduced neurotransmitter levels.

As long as ADHD is defined and diagnosed purely on the basis of symptoms, this will inevitably lead to people with ADHD being treated in the same way as those with dopamine deficiency (even if we assume that the latter are rare or at least less common). Against this background, the question arises as to whether it would not make sense to either

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

Contrary to our initial expectations, however, findings on the effect of ADHD drugs on hypodopaminergic and hyperdopaminergic animal models show that the drugs primarily used to date appear to have comparable effects on both variants.
Stimulants act primarily as dopamine reuptake inhibitors and thus increase the dopamine level available in the synaptic cleft. Nevertheless, stimulants reduce hyperactivity even in animal models with dopamine excess, 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 dopamine excess. Cognitive impairments such as inattention and learning deficits appear to be improved by stimulants as well as atomoxetine in dopamine excess.
More on this at ⇒ ADHD in animal models In the chapter ⇒ Neurological aspects.

Even though the medications used to date appear to work equally well for dopamine deficiency and dopamine excess, we thought it would be desirable to distinguish between these different ADHD variants more consciously. The fact that the medications used to date work equally in both cases could also be the result of the fact that the effects of medications have not yet been assessed separately for the two variants. It is quite conceivable that, with appropriate differentiation, it could turn out that individual medications that were previously devalued due to their lower efficacy (compared to the stimulants primarily used to date) prove to be effective for one of the variants and ineffective for the other - as appears to be the case with atomoxetine in relation to hyperactivity. In this case, the efficacy would have to be re-evaluated in relation to the area of application.

The question of ADHD variants (hypodopaminergic/hyperdopaminergic) is unlikely to gain any practical significance in practice as long as there is no inexpensive, reliable and side-effect-free method of determining the dopamine (effect) level in certain regions of the brain in people with ADHD. However, we would like to see greater consideration of this aspect in the scientific study of ADHD and in a more in-depth examination of drug treatment of ADHD, as well as a consistent differentiation of study results according to subtypes / forms of presentation.