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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 and occurs mainly in childhood and adolescence. 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.
In adults, a gender-independent frequency distribution of subtypes / forms of presentation was found, from:
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. The most relevant difference appears to be the endocrine response to acute stress. As the stress-induced neurotransmitter releases (particularly noradrenaline) appear to run parallel to 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.4 We know quite a few people with ADHD who report a significant change in subtype.
1. Presentation forms (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 sporadically further described forms 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.5 In addition, only 84% of people with ADHD could be distinguished from those not affected.
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.
Lethargic states (to be distinguished from depression)17
A significant subsection of ADHD-I is said to have slowed thinking (Sluggish)16
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.
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.19Cortisol 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.20 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.20
Externalizing behaviour disorders and aggressive behaviour are atypical in ADHD-I and indicate the ADHD-HI subtype.22.
Less frequent symptoms of aggressive or oppositional defiant behavior2324
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.8
Lower proportion of smokers than with ADHD-HI subtype (the pathways of action of nicotine and methylphenidate are similar)16
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 itself as allergies if excessive
According to one view, a noticeable proportion of methylphenidate non-responders (MPH does not work). If MPH is effective, low doses are often sufficient.16
According to another opinion, ADHD-HI and ADHD-I do not differ in the MPH response rate.25
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¶
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.2627282930
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.
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.31 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
The dopamine D4 receptor (DRD4) has a special significance in the PFC, which is why Diamond32 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.33
High Novelty Seeking / Sensation Seeking rates are associated with high aversion to boredom and correlate with impulse control disorders.34 Boredom is a cause of inattention in ADHD-I, while impulse control problems are atypical of ADHD-I and more typical of ADHD-HI.
In ADHD-I, there is often said to be a lack of serotonin.35
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.36
The 5-HTTLPR-L/L genotype correlates with hyperactive symptoms.37
One study reports a correlation between the presence of a 5-HTTLPR-S allele and inattention.38
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.
Good response to methylphenidate.
The non-responder rate (MPH does not work) should be 10 %.43
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.16
Higher proportion of smokers than in the ADHD-I subtype. (Nicotine acts as a stimulant like methylphenidate)16
Hyperactive/impulsive type often only a precursor in childhood/adolescence for later ADHD-C4445
Boys are affected 5 times more frequently than girls46.
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 are18
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)
Stress intolerance Cortisol inhibits locus coeruleus and thus reduces the release of noradrenaline in the CNS
A low cortisol response results in 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 PTSD49
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.4450
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 intrinsic interest of the person with ADHD in the tests 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. 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¶
1.2.3.3. 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.5152535455 Only a strong increase in noradrenaline / dopamine reduces the PFC.2627282930
1.2.3.4. 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 areas56
* 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 controls56
* 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.56
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.57
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)58
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
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)21
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.60
A small study replicated previous research that frontal delta and theta power is higher in ADHD-C than ADHD-I and TD groups.61
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 studies62636465
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
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:
the worst overall performance in the global neurocognitive index6768
poorer neurocognitive index than SCT (p < 0.001)68
significantly increased proportion with a DRD4-7 repeat allele67
attention-related posterior brain regions (especially temporal-occipital areas) activated more strongly for go and no-go cues than for controls and ADHD-I67
only SCT was independently associated with poorer overall memory performance68
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.
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.70. The result is consistent with an earlier study by the authors.71
Both forms of presentation (subtypes) benefited equally from MPH treatment.
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:72
“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.7374 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:69
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:75
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.76
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).
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 different variants of ADHD 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).767778
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 model7980 , 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 by far in the majority.
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.8176
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.36
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,82 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).82
In the ADHD literature, it is often argued that too many / overactivated dopamine transporters (DAT) are present in ADHD. If a long-lasting excess of dopamine in the PFC causes a long-lasting dopamine deficiency in ADHD-HI, which in turn triggers upregulation of the dopamine transporters - just as excess dopamine due to amphetamine abuse probably triggers downregulation83 - the dopamine transporters in ADHD-I should consequently be less strongly increased / overactive than in ADHD-HI. Surprisingly, there are only a few studies on the number / activity of DAT in the different ADHD subtypes. These have so far tended to show that ADHD-HI is much more strongly associated with an increased number of DAT than ADHD-I.
2.1.3. DAT differences in the forms of presentation (subtypes)¶
Various studies indicate 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.84 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.85
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.86 Another study also found lower dopamine levels (and slightly higher norepinephrine levels) in the striatum in ADHD-HI rats compared to unaffected rats.87 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.88 Another study reports a good effect of MPH in ADHD-I.89
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.25
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.9076 However, another study was unable to confirm this.91 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.92 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.36
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 girls93
However, it is questionable whether DAT actually regulates dopamine levels in the way previously assumed.83
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.9596 Parallel to the issue of the correlation of neurotransmitter noradrenaline and cortisol discussed here, there is a correlation between cortisol and dopamine release.97Cortisol 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.
Such a correlation was observed for (hormone) noradrenaline in the sympathetic nervous system to cortisol on the basis of alpha-amylase measurements.9899 however, (hormone) noradrenaline from the adrenal medulla only crosses the blood-brain barrier to a small extent and therefore cannot significantly influence the (neurotransmitter) noradrenaline level in the brain.
Our hypothesis is supported by the fact that the HPA axis (which secretes cortisol) and the locus coeruleus (which secretes noradrenaline) are activated by the same instances, which makes a parallelism of the intensity of the reactions conceivable, namely:
Mesocortical / mesolimbic system (dopaminergic)
Amygdala (serotonergic, acetylcholinergic)
Hippocampus (serotonergic, acetylcholinergic)
Details on the hypothesis of a correlation between the cortisol response and the neurotransmitter norepinephrine response to stress
The measurement of (neurotransmitter) noradrenaline is only possible in the spinal fluid (as the body’s hormone noradrenaline produces the same metabolites (degradation products) and can only cross the blood-brain barrier to a limited extent). Cortisol can cross the blood-brain barrier, which is why cortisol can alternatively be measured in blood or saliva.
Results in relation to stress:
Stress simultaneously increases (neurotransmitter) noradrenaline and cortisol levels in the brain.1009596 An increase in cortisol is associated with stress, while an increase in noradrenaline is associated with increased arousal.
ADHD outcomes:
Unfortunately, only one study on (neurotransmitter) noradrenaline in ADHD has been found so far, which also does not take cortisol into account. In the cerebrospinal fluid of hyperactive people with ADHD-HI, the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) correlated positively with aggression (unexpected), the dopamine and noradrenaline metabolite homovanillic acid (HVA) positively with hyperactivity and the noradrenaline metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) with aggression, delinquency and behavioral problems. The ADHD-I subtype was not included. The results were unexpected even for the authors.101
A positive correlation between the (neurotransmitter) noradrenaline and cortisol response to the stressor was found almost unanimously in the case of psychological disorders or psychological stress. Physical stress (hypoglycaemia), on the other hand, follows a different control pattern.
Nevertheless, the question of a positive, negative or no correlation could be disorder-specific. Only studies of people with ADHD will be able to provide certainty, whereby a distinction must be made between forms of presentation (subtypes).
A positive correlation between neurotransmitter norepinephrine and cortisol has been found in various studies:
In rhesus monkeys, early stress caused by a 4-day separation from the mother causes an increase in the noradrenaline metabolite MHPG in the cerebrospinal fluid as well as an increase in cortisol in the blood.102
The results of an elaborate study of cortisol, noradrenaline and CRH levels in the spinal fluid (which by its nature cannot contain hormonal noradrenaline from the body) found correlating (elevated) cortisol and noradrenaline neurotransmitter levels in depression, with the correlation persisting across circadian changes throughout the day. CRH levels in the spinal fluid, on the other hand, did not correlate with cortisol levels.103
Another study with 140 persons with ADHD confirmed the correlation between the noradrenaline metabolite MHPG in the cerebrospinal fluid and blood cortisol on dexamethasone.104
In dogs, a correlation between cortisol, noradrenaline, ACTH and β-endorphin in the cerebrospinal fluid and physical exertion was found.105
In PTSD, an increase in noradrenaline in the spinal fluid correlates with the severity of the symptoms.106 The cortisol response to acute stress and to dexamethasone is also increased in PTSD.107 In a study (with n = 8, far too small) of people with ADHD (war victims), noradrenaline levels in the cerebrospinal fluid increased when watching a traumatizing video, whereas CRH and cortisol blood levels were (unexpectedly for the authors) lower when watching a traumatizing video than when watching a neutral video. ACTH remained unchanged.108 The results of basal cortisol levels in PTSD are contradictory (not increased or decreased).109
In monkeys, increased levels of noradrenaline, cortisol and corticotrophin in the cerebrospinal fluid correlate with aggressiveness, while 5-hydroxyindoleacetic acid (a metabolite of serotonin) was reduced.110
The increased CRH levels in the cerebrospinal fluid in Alzheimer’s disease correlate significantly with increased blood cortisol levels and increased cortisol responses (lack of cortisol suppression in 6 out of 10 subjects) to the dexamethasone test.111
In severe and mild Alzheimer’s, basal cortisol and noradrenaline levels in the spinal fluid correlate. Unexpectedly, this correlation was not found in unaffected people.112
In the case of fish, specimens that are defeated in fights show a long-lasting increase in cortisol and noradrenaline.113
No positive correlation between neurotransmitter norepinephrine and cortisol was found during physical stress (hypoglycemia):
Hypoglycemia (low blood sugar) caused by insulin administration increases cortisol and decreases norepinephrine (as a neurotransmitter) in the cerebrospinal fluid, while norepinephrine levels in the blood (norepinephrine as a body hormone) increase.114
In any case, the fact that cortisol inhibits the locus coeruleus and thus reduces the release of noradrenaline in the CNS does not contradict our understanding of a correlation between cortisol and the neurotransmitter noradrenaline,18 because this merely describes the effect of the cortisol that has already been released, which also inhibits the HPA axis and thus itself. In addition, noradrenaline is released in the sympathetic nervous system and in the brain in response to acute stress before cortisol.
Our assumption is also not contradicted by the fact that dexamethasone only increases the dopamine, but not the noradrenaline level in the PFC (and the dopamine and noradrenaline level in the striatum) in ADHD-HI rats, while the dopamine and noradrenaline levels in the PFC remained unchanged in unaffected rats and only dopamine increased in the striatum,87 because a reaction to cortisol is also described here, which is released after the noradrenaline in the PFC during stress.
It should be noted that the cortisol response to dexamethasone is flattened in ADHD-HI (also in SHR rats) compared to non-affected individuals. Nevertheless, dexamethasone has a positive effect on ADHD-HI symptoms in ADHD-HI rats. The effect of dexamethasone on ADHD-HI phenotype was predominant in the PFC, while in the striatum the phenotype showed stronger influences than the medication.
The hypothesis is also not contradicted by the results of studies according to which cortisol and catecholamineblood levels Do not form a correlation.115Catecholamines in the blood only reflect the body’s hormonal noradrenaline levels, but not the levels of neurotransmitters in the CNS, which can be separated from each other due to the blood-brain barrier. Measurements of vanillin mandelic acid in urine, which is a metabolite of noradrenaline in the brain, would be necessary.116
Independently of this, measurements of cortisol and alpha-amylase in response to acute stress, which are carried out at small intervals (2-minute rhythm), showed that, depending on the person with ADHD, the cortisol maximum occurs up to 14 minutes before or up to 14 minutes after the alpha-amylase maximum, so that a correlation between these two values using individual fixed measurements taken x minutes after the stressor would be misleading.117
Studies found correlations between basal cortisol and vanillic mandelic acid levels (the latter as a noradrenaline neurotransmitter metabolite) in cluster headaches,118 and as responses to stressors such as the dexamethasone test in PTSD,119 depression120121 or post-rape.122
In contrast, no correlation was found between (basal) cortisol blood levels and plasma MPHG as a norepinephrine neurotransmitter metabolite in people with ADHD.123 Furthermore, no correlations of basal cortisol and noradrenaline levels were found in a study (with n = 10, far too small).124 When evaluating the measurement of MHPG and vanillin mandelic acid in blood or urine, it should be noted that only 20% of MHPG results from the metabolism of the neurotransmitter noradrenaline in the brain, so that the vast majority of MHPG results from hormone noradrenaline in the body. In addition, more than half of MHPG is converted into vanillinmandelic acid.125126 As a result, the neurotransmitter norepinephrine (in the brain) cannot be measured independently of the hormone norepinephrine (in the body) by blood or urine levels of metabolites.
On the other hand, it was found that the levels of noradrenaline in the cerebrospinal fluid correlate with the levels of (cortisol and) noradrenaline in the blood and noradrenaline metabolites in the urine.104 However, this is a correlation and not an identity.
A very strong increase in noradrenaline / dopamine shuts down the PFC and shifts behavioral control to posterior brain regions.2627282930 There are connections between cortisol and the stimulation of D1 receptors.87
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.127is 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 on this side of a correlation of the amounts released) less able to shut down the stress systems of the HPA axis and the release of noradrenaline in the brain again.
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.128 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.5
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.129 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.130
Most typical ADHD symptom pattern of all EEG subtypes
Hyperactivity
Enjoyable
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 state139
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.140
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.141
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 146138
Tantrums
Mood swings
Increased delinquency
However, people with ADHD with excessive beta are not hyperactive. Compared to non-affected people, this is typical:147
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.148 However, we know of people with ADHD of the beta type who benefited greatly from methylphenidate and even more from amphetamine medication.
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)
Kühle136 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
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.154155
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.156
2.3.2.3. Theta posterior increased, alpha and beta decreased¶
This type is said to occur in around 11%138 of people with ADHD.
A study with 69 participants found three QEEG subtypes:160
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).
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,162163 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, a different serotonin level in the different subtypes is discussed, which is thought to be related to the 5-HT 1B receptor in ADHD-I and to the 5-HT 2A/C receptors in ADHD-HI.164
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.165
3. ADHD-HI/ADHD-C and ADHD-I as stress phenotypes¶
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 correlates with the fact that a genetic disposition (DAT 10-repeat-allele of the dopamine transporter genotype (40-bp 30 VNTR of DAT, SLC6A3) links a high BAS with a high activity of the ventral striatum, while in other genetic dispositions (DAT 9-repeat-allele) a high BAS does not correlate with a high activity of the striatum.166
Similarly, some polymorphisms of the THP2 and 5-HTTLPR genes show a high positive correlation between high BIS and connectivity between the amygdala and hippocampus, while other polymorphisms of these genes show a high negative correlation between high BIS and connectivity between the amygdala and hippocampus.167
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.
Assuming our hypothesis that the subtypes / presentation forms of ADHD are defined by the natural disposition of the respective person with ADHD with regard to their stress response type (fight/flight/freeze, whereby fight is understood as a type of the hyperactive-impulsive subtype (ADHD-HI) and freeze as a synonym of the purely inattentive subtype (ADHD-I), according to the FF(F)S model of Connor), a QEEG analysis would require that a statistically valid number of healthy individuals with fight/flight/freeze characteristics be included in the QEEG comparison databases in order to be able to compare the specific activities of the individual brain areas with the respective matching comparison values of healthy individuals.
We are not aware that QEEG databases contain any information on this.
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).
*We have deliberately chosen the term variant in order to continue to reserve the term subtype / presentation form for the different symptom forms (predominantly hyperactive, predominantly inattentive, ADHD-C).
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 effect of medications has 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 have so far been 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.
