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In ADHD, the subtypes ADHD-HI (predominant hyperactivity), ADHD-C (attention problems and hyperactivity in equal measure) and ADHD-I (predominant inattention) are distinguished. The pure ADHD-HI type is usually diagnosed up to the age of 6, 7 years at the longest, exceptionally up to 14, 15 years. This is probably mainly due to the fact that inattention symptoms can only be reliably diagnosed from this age. ADHD-C could therefore be referred to as ADHD-HI type in later development. In adults with ADHD, attention problems may also remit significantly or disappear, although they remit considerably less frequently than hyperactivity problems: ⇒ ADHD in adults.
The ICD distinguishes between Simple Activity and Attention Disorder (F90.0) and Hyperkinetic Disorder of Social Behavior (F90.1), for which a social behavior disorder is additionally required. The latter is considered (rightly in our opinion) as a comorbidity according to DSM.
The ADHD-HI, ADHD-I, and ADHD-C subtypes have been shown to be valid, whereas the evidence for a subtype of hyperkinetic disorder of social behavior is insufficient1
SCT is no longer considered a subtype of ADHD. However, because SCT appears to be closely related and highly comorbid to ADHD, we have devoted a separate page to SCT: ⇒ SCT - Sluggish Cognitive Tempo.
In adults, a sex-independent frequency distribution of subtypes was found, from:
The question of whether the subtypes differ by different (genetic) causes or neuro(physio)logical processes has been studied many times. The causes and neuro(physio)logical processes are very similar in all subtypes. To date, few truly reliable distinguishing criteria are known. The most relevant difference is the endocrine response to acute stress. Since stress-induced neurotransmitter releases (especially norepinephrine) appear to parallel these subtype-specific cortisol responses to acute stress, this may explain some differences of ADHD-HI/ADHD-C and ADHD-I.
We consider the ADHD subtypes as different (psychological) forms of reaction to one and the same genetic / neurological source of disturbance, where essentially the personality traits are
Extrovert / introvert
as well as next to it
The personal way of processing stress (Bis/Bas) as a phenotypic stress response, and
The learned way of dealing with stress (role model)
determine which subtype an ADHD sufferer develops. These are neurophysiologically reflected in the cortisol stress response. More on this below under 220.127.116.11.
The subtype expression of the affected person is not necessarily stable over the whole life.4 We know quite a few affected persons who report a clear change of subtype.
The literature primarily names 3 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 likely to be merely an early form of the mixed type, Sluggish Cognitive Tempo (SCT) is increasingly emerging as an independent disorder. The occasional forms described further are unlikely to represent true subtypes and are mentioned only for the sake of completeness.
Regardless of the typing of ADHD-I, ADHD-HI, and ADHD-C based on observed symptoms, there is a typing based on the different EEG patterns measured ⇒ ADHD subtypes according to EEG. This has not yet gained acceptance, although it may be measurable by objective biomarkers. To date, there is a lack of experience on the different symptomatology of the EEG subtypes and how they respond to specific treatments. An attempt to automatically distinguish the subtypes based on their EEG patterns using AI failed.5 It was also only possible to distinguish 84% of ADHD sufferers from non-affected individuals.
Lethargic states (to be distinguished from depression)17
A significant subset of ADHD-I are reported to have slowed thinking (Sluggish)16
We think the term “slowed thinking” is inaccurate and inappropriate. We see slowed decision making. The ability to think quickly is basically given; we suspect an overabundant blockade of the PFC by noradrenaline and possibly other neurotransmitters via the alpha-1-adrenoceptor. SCT is no longer considered a subtype of ADHD, nor is it considered ADHD-I specific.
More frequent allergies due to the excess cortisol reaction. Cortisol promotes the immune defense against external stresses.
A high cortisol response to acute stress, typical of ADHD-I, correlates with poorer memory performance when learning vocabulary after exposure to stress - but only in men. Females might 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 retrieval of declarative (explicit) memory via glucocorticoid receptors (GR) in the PFC and hippocampus. Nondeclarative (implicit, intuitive) memory is not affected.20 This could explain the more frequent thinking and memory blocks seen in ADHD-I, and likewise why ADHD-I sufferers often seem to have higher intuition. That the shift in the focus of memory skills leads to a shift in problem-solving patterns would be obvious in any case. Trappmann-Korr calls this “holistic” perception.
It is likely that not only retrieval (remembering) but also acquisition (learning) and memory consolidation (long-term storage) of information are impaired. Consolidation occurs especially 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 administration.20
Externalizing behavior disorders and aggressive behavior are atypical in ADHD-I and indicate the ADHD-HI subtype.22.
Less frequent symptoms of aggressive or oppositional defiant behavior2324
ADHD-I is therefore less frequently diagnosed because it is less likely to be unpleasantly noticed 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 outcomes by subtype and, in particular, do not distinguish ADHD-C from ADHD-I type.
Less frequent comorbid oppositional defiant behavior than ADHD-HI subtype.8
Lower proportion of smokers than ADHD-HI subtype.(The pathways of action of nicotine and methylphenidate are similar)16
Less frequent inflammatory reactions such as neurodermatitis due to the overshooting cortisol response. Cortisol inhibits the inflammatory processes initiated by CRH and instead promotes defense against foreign bodies, which can show up as allergies when overshot
Underactivation of the PFC in ADHD-I is explained by correlating stress responses of cortisol, norepinephrine, and dopamine in the brain. See more at ⇒ Neurotransmitters in stress
* A large increase in norepinephrine / dopamine shuts down the PFC. This deactivation of the PFC occurs through alpha 1-adrenoceptors, which have lower norepinephrine and cortisol affinity than alpha 2-adrenoceptors and are therefore only addressed at very high norepinephrine and cortisol levels.2627282930
Thus, a particularly large increase in DA and NE during severe stress could lead to (frequent) underactivation of the PFC, as is typical in ADHD-I.
This background could explain Raynaud’s and hypertension problems in some ADHD-I sufferers, which are also mediated by alpha-1-adrenoceptors.
The question is whether alpha-1-adrenoceptor antagonists, which have been used successfully against Raynaud’s disease and hypertension, might not also be helpful against the PFC blockades in ADHD-I.
To date, only alpha-2-adrenoceptor agonists have been used and are likely to be considered third-line agents. Guanfacine addresses alpha-2-A and alpha-2-D, while yohimbine addresses alpha-2-B adrenoceptors. Agonization of the more affine alpha-2 receptors is contrary in effect to antagonization of alpha-1 receptors. As with the cortisol receptors, the lower affinity receptor is responsible for shutting down the system and is only addressed at very high levels of neurotransmitter. If the more affine receptors are too strong, the less affine shut-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 thus more easily addressed.
CRH also affects the PFC and, at high levels of CRH, can impair it.
Increased cortisol responses to a stressor correlate with increased variance in response time.31 Increased variance in response times could be explained by an impairment in the performance of the PFC, as is particularly pronounced in the ADHD-I subtype. This impairment could be explained by norepinephrine responses to acute stress that are also elevated, analogous to the cortisol response. Some diagnosticians pay particular attention to this variance in response times in an ADHD-I diagnosis. Cortisol leads to a decrease in cortisol and norepinephrine
This negative feedback is the result of cortisol (it shuts down the HPA axis again) and is independent of the synchronicity of the release of cortisol and norepinephrine on stress
The dopamine D4 receptor (DRD4) has a special role in PFC, which is why Diamond32 assumes that disruption of the DRD4 7R gene is associated with ADHD-I. We do not believe this to be true.
Noble found that the A1, B2, and intron 6 1 gene polymorphisms of DRD2, as well as the DRD4 7R polymorphism, were associated with an elevated Novelty Seeking (Sensation seeking) Score. However, none of these polymorphisms correlated with a high Harm Avoidance Score (BIS), which 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, whereas impulse control problems are atypical for ADHD-I and more typical for ADHD-HI.
In ADHD-I, there is often said to be a deficiency of serotonin.35
See below under “Subtypes in ADHD according to EEG”.
1.1.6. Sluggish Cognitive Tempo (SCT) - stand-alone disorder¶
SCT is now considered a separate disorder independent of ADHD, although SCT and ADHD are very often comorbid. However, there are SCT sufferers without ADHD.
More about SCT at ⇒ SCT - Sluggish Cognitive Tempo.
Stress intolerance Cortisol inhibits locus coeruleus, thereby decreasing norepinephrine release in CNS
Low cortisol response results in impaired norepinephrine inhibition = elimination of important stress brake Hypocortisolism thereby causes stress intolerance, irritability, sensitivity to sensory stimuli (noise, etc.) Hypocortisolism could promote emergence of intrusions as observed in PTSD46
Negative symptom delineation in ADHD-HI:
If inattention and hyperactivity (the latter also as inner drive) exist, the so-called ADHD-C is present.
Inattention can usually only be detected between the ages of 6 and 15. ADHD-HI (with hyperactivity without attention problems) can therefore be considered an early form of the later mixed type.4147
The question of whether ADHD exists entirely without inattention has not been conclusively answered. We tend to assume this, although this is likely to be a rather rare manifestation.
The higher the aptitude, the better the coping mechanisms. The older the affected individuals are, the more remitted individual symptoms may be, which is why a lack of (well-concealed) inattention in test settings does occur. Similarly, a high intrinsic interest of affected individuals in the tests leads to an equalization of test performance compared to nonaffected individuals. This is plausible when the stress benefit and thus the mechanisms of the stress symptom inattention are considered.
In ADHD-HI, allergies appear to occur less frequently than in the ADHD-I subtype because of the more frequently flattened cortisol response to stress. Cortisol increases the immune response to external stresses such as allergens.
1.2.3. Neurophysiological peculiarities in ADHD-HI¶
In ADHD-HI (with hyperactivity/impulsivity) and likewise in correlated aggression, the release of catecholamines and cortisol in response to acute stressors is often decreased or absent compared with nonaffected individuals, whereas the cortisol stress response is typically increased in ADHD-I affected individuals compared with nonaffected individuals.
18.104.22.168. Flattened cortisol stress response in ADHD-HI¶
ADHD-HI is often associated with a flattened cortisol response to acute stress. ⇒ Cortisol in ADHD
22.214.171.124. Deficient HPA axis disconnection in ADHD-HI¶
126.96.36.199. Decreased norepinephrine depletion in ADHD-HI?¶
Cortisol further causes a breakdown of norepinephrine.
A too low cortisol response to acute stress and a consequently too low norepinephrine depletion could possibly explain a permanent overactivation of the PFC in ADHD-HI/ADHD-C.
A slightly increased (dopamine and) norepinephrine level in the PFC increases its activation and causes improved cognitive performance.4849505152 Only a strong increase in norepinephrine / dopamine shuts down the PFC.2627282930
A fairly large study reported decreased hippocampal volume in ADHD-HI as opposed to ADHD-I and nonaffected individuals.
* ADHD-HI: reduction in hippocampal areas53
* Molecular layer
* Granule cell band of the dentate gyrus
* Hippocampal tail
* Other hippocampal regions were not reduced in size
* ADHD-I: no reliable differences in hippocampal volume to controls53
* Finally, reduced 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.53
In ADHD-HI sufferers with comorbid depressive symptoms, one study found significantly higher morning than evening levels of indole acetic acid. MPH reduced this by 50%. MPH simultaneously reduced morning levels of indolepropionic acid and returned the diurnal profile to that of healthy control subjects.54
SHR exhibit behavioral subgroups corresponding to ADHD-HI and ADHD-I
One study found SHR (Spontaneous(ly) hypertensive rat) subgroups that differed significantly with respect to impulsivity. Impulsive SHR, compared with non-impulsive SHR and WKY (as controls; no behavioral subgroups were found in the latter), showed55
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
Acute administration of a cannabinoid agonist reduced impulsivity in impulsive SHR, with no change in WKY
Hyperactivity (in children; in adults; inner restlessness)
Problems with sustained attention (ADHD-C and ADHD-I)
Fewer problems with selective attention (ADHD-I subtype only)21
Corresponds largely 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 symptomatology was simultaneously evident in brain structure changes measurable by fMRI in brain systems known to be involved in these cognitive functions.56
A small study replicated previous research that frontal delta and theta power are higher in ADHD-C than in ADHD-I and TD groups.57
1.3.1. ADHD-C with inhibition deficits, without reward deficits¶
Inhibitory deficits means deficits in executive functions and inhibitory cognitive functions.
Different frontal lobes
in the inhibition of motor responses
Of the posterior default mode
In the ventral striatum
during error handling.
Executive function deficits also show up in other studies58596061
Pre-supplementary motor area (pre-SMA)
Middle frontal gyrus
Precentral frontal gyrus
Hyperfunction in the
Inferior frontal gyrus
1.3.2. ADHD-C with inhibition deficits and reward deficits¶
Mostly non-overlapping cortical and subcortical regions
during error processing as well as
Overactivated amygdala regions and
Overactivated ventral striatal 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 frequent subgroup. According to the absence of the mentioned particular symptoms, no neurological abnormalities were found
We do not consider the “subtypes” mentioned below, which have been mentioned sporadically in the literature, to be true subtypes of ADHD.
1.4.1. ADHD with oppositional behavior disorder (?)¶
Oppositional behavior disorder, in our opinion, is a comorbidity that occurs primarily in ADHD-HI type and is not a subtype of ADHD-HI.
Significantly, even among those who hypothesize subtypes of ADHD with oppositional behavior disorder, it is described only in association with the ADHD-C and ADHD-HI types, but not with the (stress phenotypically introverted) ADHD-I type.
The residual type is occasionally referred to as a partially regressed ADHD that is no longer fully developed but is still present.
This is not a subtype of ADHD, but may explain why there are sometimes ADHD sufferers who lack individual leading symptoms (e.g., with a largely full symptom picture without attention problems).
1.4.4. ADHD adult subtype pair according to Reimherr¶
Reimherr et al, in 8 replication studies of 1,490 ADHD-affected adults, found two clusters, the inattentive adult subtype and the emotionally dysregulated adult subtype.63. The finding is consistent with an earlier study by the authors.64
Both subtypes benefited equally from MPH treatment.
Volk et al defined seven subtypes.6667 They are presented according to frequency (% in parentheses). In addition, the frequency of the comorbidities depression, ODD (Oppositional Defiant Disorder) and CD (Conduct Disorder) within the respective group is given.
This section deals with the question whether different subtypes (according to symptom expression) correlate with certain dopamine (effect) levels. The question whether dopamine deficiency and dopamine excess are possibly different disorders or at least distinguishable variants of ADHD is addressed at the end of this chapter.
2.1.1. Hyperactivity, impulsivity: dopamine deficiency or excess in the striatum¶
Hyperactivity and impulsivity, as exhibited by the ADHD-HI subtype (without inattention) or ADHD-C (with inattention), are caused (with respect to ADHD) primarily by deviations of dopamine levels from optimal dopamine levels in the right hemispheric striatum (involving the frontostriatal loop consisting of the PFC, caudate nucleus, and globus pallidus, but not the putamen).686970
According to the prevailing opinion in the literature, 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. See ⇒ For more information ADHD in animal models in the chapter ⇒ Neurological aspects. As long as ADHD is not defined (and diagnosed) neurobiologically as a dopamine deficit in the striatum (and/or PFC) but is diagnosed on the basis of symptoms alone, both variants must be considered. Excess as well as deficiency of neurotransmitters cause almost the same symptoms according to the inverted-U-model, because the functionality of signal transmission is only given at optimal neurotransmitter levels. However, the evidence for a deficiency of phasic dopamine in the striatum in ADHD is by far in the majority.
Because dopamine degradation in the striatum occurs primarily via DAT, whereas dopamine degradation in the PFC occurs primarily via NET and COMT rather than DAT, the DAT-10R gene variant correlated strongly with hyperactivity and impulsivity, but not with inattention.7168
2.1.2. Hyperactivity, impulsivity: dopamine excess in the PFC¶
In healthy individuals, a high level of dopamine in the PFC appears to lead to a low level of dopamine in the striatum and vice versa.
A fully utilized PFC (high dopamine level) simply does not seem to need any stimuli from the reinforcement/motivation center and therefore signals to it: “closed due to overcrowding - give it a rest”. The striatum then sulks silently (underactivated = low dopamine). This is a normal, healthy control loop.
Prolonged tonic dopamine deficiency in the striatum leads to upregulation of D2 autoreceptors (due to very prolonged dopamine excess in the PFC), which in turn leads to upregulation of dopamine transporters in the striatum. See ⇒ Up- and downregulation of the dopamine transporter In the article ⇒ Dopamine in the chapter ⇒ Neurological aspects. This could explain DAT overactivity, which would help explain or enhance the tonic dopamine deficiency in the striatum hypothesized in ADHD. .
Since hyperactivity can be mediated by a deficiency 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 ADHD-I-typical underactivation of the PFC should rather cause a dopamine excess in the striatum due to the associated dopamine deficiency in the PFC. Studies show a dopamine deficiency in the striatum in ADHD, but do not differentiate between subtypes.72
In the ADHD literature, it is often argued that there are too many / overactivated dopamine transporters (DAT) in ADHD. If in ADHD-HI a prolonged dopamine excess in the PFC causes a prolonged dopamine deficiency, which in turn triggers an upregulation of the dopamine transporters - just as dopamine excess due to amphetamine abuse probably triggers a downregulation73 - the dopamine transporters in ADHD-I should consequently be less increased / overactive than in ADHD-HI. Surprisingly, there are few studies on the number / activity of DAT in the different ADHD subtypes. However, these have a fairly clear tenor: ADHD-HI is much more strongly associated with increased numbers of DAT than ADHD-I.
Studies on DAT differences among subtypes
In a SPECT study 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 ADHD-I sufferers compared with nonaffected individuals. Smoking significantly decreased DAT to or below the level of nonaffected individuals in both subtypes.74 One study compared DAT in the Spontanuous(ly) hypertensive rat (SHR), which is a validated model of the ADHD-HI 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.75
Another study compared rats that are ADHD-HI models, ADHD-I models, and unaffected models. It found that ADHD-HI rats had significantly lower dopamine levels in the dorsal striatum, whereas some of these levels were the same, and some were even higher, in ADHD-I rats than in unaffected rats. Similarly, ADHD-HI rats had faster dopamine uptake in the ventral striatum and nucleus accumbens, and ADHD-I rats had faster dopamine uptake only in the nucleus accumbens, both compared with unaffected rats.76 Another study also found lower dopamine levels (and slightly higher norepinephrine levels) in the striatum in ADHD-HI rats compared with unaffected rats.77
MPH, which significantly reduces DAT, is reported to be far less effective in ADHD-I than in ADHD-HI, according to one study.78 Another study reports a good effect of MPH in ADHD-I.79
SCT sufferers (we had previously considered SCT to be an extreme form or subtype of ADHD-I) are particularly likely to be MPH nonresponders. In particular, elevated SCT Sluggish / Sleepy factor scores indicate MPH nonresponding. Neither elevated SCT daydreamy symptoms, nor ADHD subtype (ADHD-HI or ADHD-I) differed in MPH responding rates. The latter supports that SCT is not a subtype of ADHD-I.25
Genetic differences between subtypes in ADHD-associated polymorphisms of the DAT1 gene are thought to suggest an association between DAT1 gene polymorphisms and ADHD-HI, but not with ADHD-I.80 However, another study could not confirm this.81 Another study found an association of DAT1 10/10 with ADHD-I, where DAT1 10/10 is thought to represent increased DAT expression as well as decreased dopamine uptake. The results of this study do not fit with any of the findings known to date on this side in other respects.82 In turn, another study found that DAT1 10/10 was as prevalent in ADHD sufferers in Indonesia as in nonaffected individuals.
However, it is questionable whether DATs actually regulate dopamine levels in the way that has been assumed so far.73
2.2. Exaggerated and flattened endocrine stress responses of subtypes¶
In ADHD-I, the endocrine stress responses appear to be much stronger than in ADHD-HI and ADHD-C.
An endocrine stress response is the amount of hormone (and neurotransmitter) release in response to an acute stressor.
The ADHD-I subtype often shows a hypercortisol stress response, whereas 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, whereas 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
Because hypocortisolism may represent a long-term sequential response to hypercortisolism when downregulation (⇒ upregulation) occurs because of persistently elevated cortisol levels Downregulation/Upregulation; ⇒ Altered hormone and neurotransmitter levels according to stress phase in the article ⇒ The stress systems of humans - basics of stress In the chapter ⇒ Stress) of the glucocorticoid (cortisol) receptor systems occurs, 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 represent 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, in disorders with internalizing symptoms - depression, anxiety, etc. - the cortisol responses are regularly elevated.
Increases in cortisol are associated with stress-induced release of norepinephrine and α1-adrenergic receptor activation.8384 Parallel to the neurotransmitter-norepinephrine and cortisol correlation issue discussed here, there is a correlation between cortisol and dopamine release.85Cortisol levels correlate positively with AMPH-induced dopamine release in the left ventral striatum and dorsal putamen.
We assume that the cortisol, epinephrine, norepinephrine and dopamine responses in the brain to acute stress correlate, so that a high cortisol response to acute stress is accompanied on the one hand by high (hormone) norepinephrine release in the sympathetic nervous system and on the other hand by high (neurotransmitter) norepinephrine and dopamine release in the central nervous system (= brain). Low levels are also likely to correlate. This could conclusively explain quite a few patterns of ADHD subtypes.
For (hormone-)norepinephrine in the sympathetic nervous system to cortisol such a correlation was observed based on alpha-amylase measurements.8687 however, (hormone-)noradrenaline from the adrenal medulla crosses the blood-brain barrier only to a small extent and therefore cannot significantly influence the (neurotransmitter-)noradrenaline level in the brain.
In favor of our hypothesis is that the HPA axis (which secretes cortisol) and the locus coeruleus (which secretes norepinephrine) are activated by the same instances, which makes a parallelism of the intensity of the reactions seem conceivable, namely:
Mesocortical / mesolimbic system (dopaminergic)
Amygdala (serotonergic, acetylcholinergic)
Hippocampus (serotonergic, acetylcholinergic)
Details of the hypothesis of a correlation of the cortisol response and neurotransmitter-norepinephrine response to stress
Measurements of (neurotransmitter) norepinephrine are only possible in spinal fluid (since the hormone norepinephrine of the body produces the same metabolites (breakdown products) and can cross the blood-brain barrier only to a small extent). Cortisol can cross the blood-brain barrier, which is why cortisol can alternatively be measured in blood or saliva.
Results related to stress:
Stress simultaneously increases (neurotransmitter) norepinephrine and cortisol levels in the brain.888384 A rise in cortisol is associated with stress, a rise in norepinephrine with increased arousal.
Outcomes in ADHD:
Unfortunately, only one study on (neurotransmitter) norepinephrine in ADHD could be found so far, which furthermore does not consider cortisol. In the spinal fluid of hyperactive ADHD-HI sufferers, the serotonin degradative 5-hydroxyindoleacetic acid (5-HIAA) correlated positively with aggression (unexpectedly), the dopamine and norepinephrine degradative homovanillic acid (HVA) correlated positively with hyperactivity, and the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) correlated with aggression, delinquency, and behavioral problems. The ADHD-I subtype was not included. The results were also unexpected by the authors.89
In the case of mental disorders or psychological stress, a positive correlation between (neurotransmitter) norepinephrine and cortisol response to the stressor was found almost unanimously. Physical stress (hypoglycemia), on the other hand, follows a different control pattern.
Nevertheless, the question of a positive, negative or missing correlation could be disorder-specific. Only studies of ADHD sufferers will be able to provide certainty, whereby a distinction must be made according to subtypes.
A positive correlation of neurotransmitter norepinephrine and cortisol has been found in several studies:
In rhesus monkeys, early stress from 4-day separation from the mother causes an increase in the norepinephrine metabolite MHPG in the spinal fluid as well as a rise in cortisol in the blood.90
The results of an elaborate study of cortisol, norepinephrine, and CRH levels in spinal fluid (in which, by its nature, hormonal norepinephrine from the body cannot be present) found correlating (elevated) cortisol and norepinephrine neurotransmitter levels in depression, with the correlation persisting through circadian changes over the day. In contrast, CRH levels in spinal fluid did not correlate with cortisol levels.91
Another study of 140 depression sufferers confirmed the correlation between the norepinephrine metabolite MHPG in spinal fluid and blood cortisol on dexamethasone.92
In dogs, a correlation between cortisol, norepinephrine, ACTH, and β-endorphin in spinal fluid to physical exertion was found.93
In PTSD, an increase in norepinephrine in the spinal fluid correlates with symptom severity.94 The cortisol response to acute stress as well as to dexamethasone is also increased in PTSD.95 In a study (much too small at n = 8) of PTSD sufferers (war victims), norepinephrine levels in spinal fluid increased when watching a trauma-inducing video, whereas CRH and cortisol blood levels were (unexpectedly for the authors) lower when watching the trauma-inducing video than when watching a neutral video. ACTH remained unchanged.96 The results of basal cortisol levels in PTSD are contradictory (not increased or decreased).97
In monkeys, increased levels of norepinephrine, cortisol, and corticotrophin in spinal fluid correlate with aggressiveness, while 5-hydroxyindoleacetic acid (a metabolite of serotonin) was decreased.98
The elevated spinal fluid CRH levels in AD correlate significantly with elevated blood cortisol levels as well as elevated cortisol responses (lack of cortisol suppression in 6 of 10 subjects) to dexamethasone testing.99
In severe and mild AD, basal cortisol and norepinephrine levels correlate in spinal fluid. Unexpectedly, this correlation was not found in unaffected individuals.100
In fish, specimens defeated in fights show a long-lasting increase in cortisol and norepinephrine.101
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 spinal fluid, while increasing norepinephrine levels in the blood (norepinephrine as a body hormone).102
In any case, our understanding of a correlation of cortisol and neurotransmitter norepinephrine is not contradicted by the fact that cortisol inhibits the locus coeruleus and thus reduces the release of norepinephrine in the CNS,18 because this merely describes the effect of the already released cortisol, which also inhibits the HPA axis and thus itself. Moreover, norepinephrine is released in the sympathetic nervous system, as in the brain, in response to acute stress, temporally before cortisol.
Our assumption is also not contradicted by the fact that dexamethasone in ADHD-HI rats increases only dopamine, but not noradrenaline levels in the PFC (and dopamine and noradrenaline levels in the striatum), whereas in unaffected rats, dopamine and norepinephrine levels in the PFC remained unchanged and only dopamine increased in the striatum,77 because a response to cortisol, which is released temporally after norepinephrine in the PFC during stress, is also described here.
It should be noted that in ADHD-HI (also in SHR rats) the cortisol response to dexamethasone is flattened compared to non-affected individuals. Nevertheless, dexamethasone shows positive effects on ADHD-HI symptoms in ADHD-HI rats. Here, in the PFC, the effect of dexamethasone predominated over the ADHD-HI phenotype, whereas in the striatum, the phenotype showed stronger influences than the medication.
The hypothesis is also not contradicted by the results of investigations, according to which cortisol and catecholamineblutwerte Do not form a correlation.103Catecholamines in the blood only represent the hormonal noradrenaline levels of the body, but not the levels of neurotransmitters in the CNS, which are to be separated from each other due to the blood-brain barrier. What would be needed are measurements of vanillic mandelic acid in urine, which is a metabolite of norepinephrine in the brain.104
Independently, measurements of cortisol and alpha-amylase to acute stress that are temporally small-scale (2-minute rhythm) showed that, depending on the affected individual, the cortisol maximum occurs temporally up to 14 minutes before or up to 14 minutes after the alpha-amylase maximum, so that a correlation between these two values by single fixed measurements occurring x minutes after the stressor would be misleading.105
Studies found correlations between basal cortisol and vanillin mandelic acid levels (the latter as a norepinephrine neurotransmitter metabolite) in cluster headache,106 and as responses to stressors such as the dexamethasone test in PTSD,107 depression108109 or post rape.110
In contrast, no correlation was found between (basal) blood cortisol levels and plasma MPHG as a norepinephrine neurotransmitter metabolite in panic attack sufferers.111 Further, no correlations of basal cortisol and norepinephrine levels were found in a (with n = 10 much too small) study.112 When evaluating the measurement of MHPG and vanillic mandelic acid in blood or urine, it should be noted that only 20% of MHPG results from metabolism of neurotransmitter norepinephrine in the brain, so that the vast majority of MHPG results from hormone norepinephrine in the body. In addition, more than half of MHPG is converted to vanillin mandelic acid.113114 As a result, by blood or urine levels of metabolites, neurotransmitter norepinephrine (in the brain) cannot be measured independently of hormone norepinephrine (in the body).
On the other hand, levels of norepinephrine in cerebrospinal fluid have been found to correlate with levels of (cortisol and) norepinephrine in blood and norepinephrine metabolites in urine.92 However, this is a correlation and not an identity.
A very large increase in norepinephrine / 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.77
The PFC is very sensitive to its neurochemical environment. Too little (drowsiness) as well as too much (severe stress) catecholamine release in the PFC weakens the cognitive control of behavior and attention.115is the PFC remains permanently activated in ADHD-HI and ADHD-C - which is just too much at some point.
ADHD-I patients, on the other hand, suffer from an endocrinological overreaction to acute stress. Assuming the hypothesis that in ADHD-I not only the cortisol stress response but also the norepinephrine release in the brain to acute stress is excessive, the established finding that strongly increased norepinephrine levels block the PFC would explain why ADHD-I often suffer from thought blockades and excessive demands when making decisions.
The strong stress-cortisol response in ADHD-I, which occurs on the 3rd stage of the HPA axis some time after the noradrenaline release, leads to a strong brake of the noradrenaline release. The norepinephrine brake of the PFC is therefore relaxed again in ADHD-I and the PFC ramps up again after some time. Thus, the PFC does not remain permanently in a dysfunctional state (as in ADHD-HI/ADHD-C). Thus, a mere temporary underfunction of the PFC does not lead to a permanent dopamine surplus in the striatum, which is why striatal problems are not as severe in ADHD-I. (Excess as well as deficiency each cause disturbances in the communication of the nerves and can therefore cause different or almost the same symptoms in the same brain region, because only with optimal neurotransmitter levels is the communication of signals in the brain functioning properly).
The various subtypes can also be conclusively described as stress phenotypes, in agreement with the endocrinological / neurological characteristics described.
Stress phenotypes means a typed response to stress.
More on this below under 6.
PFC deactivation occurs through alpha 1-adrenoceptors, which have lower norepinephrine and cortisol affinity than alpha 2-adrenoceptors and are therefore only addressed at very high levels of norepinephrine and cortisol.
On this side, a strong dopamine/norepinephrine increase is thought to be the cause of the ADHD-I-typical underactivation of the PFC.
Since in ADHD-HI (and ADHD-C) there is a flattened cortisol response to an acute stressor, a parallel flattened norepinephrine/dopamine release would result in a permanent mild stress state that does not shut down the PFC but permanently overactivates it.
In any case, due to a weaker cortisol response to acute stress, cortisol levels at the end of a stress response in ADHD-HI and ADHD-C (and independent of the hypothesis on this side of a correlation of release levels) are worse able to shut down the stress systems of the HPA axis and norepinephrine release in the brain again.
Most studies find different EEG subtypes in ADHD sufferers.
Externalizing characters show a flattened error-related negativity (ERN), internalizing characters an increased ERN.116 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 above the PFC.
An attempt to automatically distinguish 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, whereas internalizing symptoms (ADHD-I) were associated with increased activity in the alpha and beta bands.117 In contrast, a study of 94 boys aged 6 to 9 years uniformly found increased total alpha activity with decreased alpha peak frequency, decreased alpha bandwidth, and decreased alpha amplitude suppression magnitude, as well as an increased alpha1 / alpha2 (a1 / a2) ratio, despite differentiation by subtype.118
Most typical ADHD symptom picture of all EEG subtypes
Increase SMR (12 to 15 Hz)
Decrease theta (4 to 8 Hz)
Decrease theta while increasing beta: addresses tonic aspects of cortical activation to achieve attentive, focused, yet serene state126
Theta down and alpha up (at the same time, if necessary)
The latter two training methods (train down theta, train up beta or train down theta / train up alpha) differed little in their results in 7-10 year olds. Both protocols alleviate symptoms of ADHD-HI in general (p <0.001) as well as symptoms of hyperactivity (p <0.001), inattention (p <0.001), and omission errors (p <0.001), but not oppositional and impulsive symptoms.127
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 was trained down (40 sessions). The other 7 showed smaller improvements. In the responders, IQ improved by 10 points at the same time as symptomatology (from 112 to 122). However, N = 19 is too small for a reliable statement.128
This neurological abnormality is not seen in ADHD-I, but only in a subgroup of the mixed type, which is also said to differ from the rest of ADHD-C by a greater tendency to develop other symptoms 132125
Moody mood swings
However, ADHD sufferers with excessive beta are not hyperactive. Compared to non-affected individuals, be typical:133
Beta increased overall
Delta is significantly reduced centrally posteriorly
Alpha is reduced overall
Significantly reduces the overall posterior power
Reduces the theta / beta ratio overall.
Skin conductance is significantly reduced (just as in sufferers with excessively elevated theta)
From this, the authors conclude that the theta / beta ratio is not associated with arousal.
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 ADHD sufferers with very low EEG theta values were more often nonresponders with respect to stimulants.134 However, we know beta-type sufferers who benefited greatly from methylphenidate and even more from amphetamine medication.
No social behavior disorder (Conduct disorder, CD)
Prefers to surround himself with younger children
ADHD sufferers with high front-midline theta often showed
High and steep power peaks when discharged to Fz
At high FMT activity in the higher FMT frequencies:
Problems with emotion regulation and memory control.
At high FMT activity in the lower FMT frequencies:
Learning difficulties or memory problems.
Increase beta 1 (15 to 21 Hz)
Decrease theta (4 to 8 Hz)
Kühle124 describes that in ADHD-I, delayed brain development is often found. As far as we know, the brain maturation of some areas is delayed in all ADHD subtypes. Whether this is a neurological deficit or only a neurological correlate of ADHD is questionable. The maturation delay in ADHD patients corresponds quite exactly to the brain maturation delay in giftedness.
See more at ⇒ Giftedness and ADHD
A study of 69 participants found three QEEG subtypes:146
increased absolute and relative beta performance
increased relative fast alpha and beta performance
increased absolute slow frequency (delta and theta power)
K-ARS: 12.64, barely higher than non-affected at 11.07
WURS: 55.82 significantly higher than non-affected at 42.81
Consequently, the third group can 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).
2.5. Functional differences of nerve conduction pathways in the brain (?)¶
Studies suggesting specific functional differences in brain nerve conduction pathways for ADHD-HI and ADHD-I,147148 suffer from very low case numbers (n < 50), which affects the robustness of the results (for more details, see: ⇒ Studies prove-sometimes nothing at all).
One study demonstrated differences between ADHD-HI, ADHD-I, and controls in auditory brain regions, the Heschl’s gyrus (HG) and the planum temporale (PT). ADHD-HI and ADHD-I revealed 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, whereas ADHD-I did not differ from controls. ADHD-HI showed left-right asynchrony, whereas ADHD-I and controls showed balanced hemispheric response patterns.150
3. ADHD-HI/ADHD-C and ADHD-I as stress phenotypes¶
One problem with subtyping is that some ADHD sufferers outsource brain activities from affected brain areas to other brain areas, that is, they “misappropriate” brain areas to substitute for the abilities of the affected brain areas.
This correlates with the fact that one genetic disposition (DAT 10-repeat-allele of the dopamine transporter genotype (40-bp 30 VNTR of DAT, SLC6A3) associates high BAS with high ventral striatum activity, whereas in other genetic dispositions (DAT 9-repeat-allele), high BAS does not correlate with high striatum activity.151
Similarly, one polymorphisms of the THP2 and 5-HTTLPR genes show a high positive correlation between a high BIS and amygdala-hippocampus connectivity, whereas other polymorphisms of these genes show a high negative correlation between a high BIS and amygdala-hippocampus connectivity.152
This makes diagnosis by means of questionnaires and tests more difficult.
A more objective determination of the particular ADHD subtype could be made by a more accurate history by EEG or QEEG measurement and stress system reactance by the dexamethasone/ACTH/CRH test.
Assuming our thesis that the subtypes of ADHD are defined by the natural disposition of the respective affected person with regard to his stress response type (fight/flight/freeze, where fight is understood as the 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 subjects according to fight/flight/freeze characteristics be included in the QEEG comparison databases in order to be able to match the specific activities of the individual brain areas with the respective matching comparison values of healthy subjects.
We are not aware of QEEG databases containing information on this.
Most voices in the literature link ADHD to decreased dopamine levels. This description is likely to include that the level of dopamine is neutral but the sensitivity of receptors is decreased, or that the breakdown of dopamine is too rapid. The result is that there is too little dopamine (action).
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 tonic or phasic dopamine output or of basal dopamine levels, there is contrary evidence that dopamine excess 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 depends on a certain (“mean”) neurotransmitter level. Signal transmission is equally affected by excessive as well as decreased neurotransmitter levels.
As long as ADHD is defined and diagnosed purely on the basis of symptoms, this will inevitably lead to sufferers with dopamine deficiency being treated in the same way as sufferers with dopamine excess (even if the latter are likely to be rare, or at least rarer, according to our conjecture). Against this background, the question arises whether it would not make sense to either
To define ADHD neurobiologically as a dopamine (effect) deficit and to name all forms (even with similar symptoms) with a dopamine excess differently,
ADHD neurobiologically to be divided into two dopaminergic variants*, the hypodopaminergic variant (dopamine deficiency) and the hyperdopaminergic variant (dopamine excess).
*We deliberately chose the term variant to continue to reserve the term subtype for the different symptom forms (predominantly hyperactive, predominantly inattentive, ADHD-C).
However, contrary to our initial expectation, findings on the effects of ADHD medications in both hypodopaminergic and hyperdopaminergic animal models indicate that the primary medications used to date appear to have comparable effects in both variants.
Stimulants act primarily as dopamine reuptake inhibitors, thereby increasing the level of dopamine available in the synaptic cleft. Nevertheless, stimulants 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 ameliorated by stimulants as well as atomoxetine in the presence of dopamine excess.
See more at ⇒ ADHD in animal models In the chapter ⇒ Neurological aspects.
Even though the medications used so far seem to work equally well for dopamine deficiency and dopamine excess, we thought it would be desirable to distinguish more consciously between these different ADHD variants. 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 previously been assessed separately for the two variants. It is quite conceivable that, with appropriate differentiation, individual medications that have so far been devalued because of a lower efficacy (compared to the stimulants primarily used so far) could prove to be effective for one of the variants and ineffective for the other - as seems to be the case with atomoxetine with regard to hyperactivity. In this case, efficacy would need to be re-evaluated in relation to the area of use.
The question of the ADHD variants (hypodopaminergic/hyperdopaminergic) is not likely to gain practical importance as long as there is no inexpensive, reliable and side-effect-free method to determine the dopamine (effect) level in certain brain regions of affected persons. However, in the scientific study of ADHD and in a more in-depth study of drug treatment of ADHD, we would like to see more consideration of this aspect as well as a consistent differentiation of study results according to subtypes.