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We hypothesize that the different ADHD subtypes (especially the two poles ADHD-HI and ADHD-C (with hyperactivity) and ADHD-I (without hyperactivity)) can be described or explained as phenotypically different stress responses.
1. Typical stress response patterns in mammals and humans¶
Mammals respond to stress with different patterns that are randomly distributed within a population.
According to the Fight/Flight stress response model (Fight/Flight System, FFS) by Cannon, 1932 (later also Gray), a part of the population tends to react to stress with aggression or attack (Fight), i.e. an outward (extroverted) reaction.
The other part of the population tends to react to stress by running away (Flight) or “pretending not to be there” (Freeze), i.e. with an inward (introverted) reaction.
2. Stress reaction patterns based on the BIS/BAS/FFFS system according to Grey¶
Mammalian responses to stress are not uniform.
According to the fight/flight stress model (by Connor (1932) and later Gray, who combined it with the BIS/BAS model → RST of 1990, revised 2000), there are 2 to 3 main groups of stress responses:
The BAS type reacts to stress with attack.
The FFFS type reacts to stress by running away or playing dead.
According to Gray’s (2000) revised Reinforcement Sensitivity Theory (RST), the BIS system no longer responds to stimuli from the outside, but only becomes active when the BAS and FFFS systems have both been activated. The BIS system is responsible for the trade-off between BAS and FFFS.
Benefits of different stress phenotypes
These reaction models are very deeply rooted. The survival probability of a “stone-age” group of Homo sapiens has always been higher if the group had members with different stress phenotypes. Modern industrial psychology knows that groups with different characters are more successful than homogeneous groups.
Examples
Quite banally: if all members of a group were night owls or early risers - how well would the primeval group have been protected from enemies if all group members slept at the same time?
Likewise, what is the likelihood that at least individual group members would have survived if an entirely new challenge arose in which either deliberate or spontaneous action was the optimal survival strategy?
In other words, it would run counter to the basic idea of evolution that groups with homogeneous character structure survive better than others.
The different stress response phenotypes are also evident in other creatures, e.g., guppies.1
Subsequently, it seems conclusive to us that the expression of the single individual as fight or flight type is a purely random variable that ensured that a population had enough members of the two types.
If we add “freeze” as an independent stress response phenotype (which after all could plausibly explain the phenomenon of sluggish thinking), there would be three stress phenotypes.
Put another way: Groups in which a single type has become genetically dominant have had less probability of survival, so that we are descendants of those who have passed on this trait with a high random distribution.
Similar: Farmer/Hunter hypothesis
In the Hunter/Farmer hypothesis picture, ADHD-HI subtype sufferers are phenotypically viewed as Hunter (hunters) and ADHD-I subtype sufferers are phenotypically viewed as Farmer (sedentary), with the ADHD symptoms of each subtype occupying an (unhealthy) extreme form of the two poles. Representation as extreme poles is conclusive.
Sometimes, however, an idealization or strangely justified “superiority” of ADHD is derived from the Hunter/Farmer hypothesis - we explicitly do not share this view. ADHD sufferers may be different from non-affected people, which may have disadvantages in some constellations and advantages in others - but a superiority cannot be derived from this. If one realizes that the standards of what is “right” and what is “wrong”, i.e. what is “sick” and what is “healthy”, are always defined by the majority and that in the case of a particularity the majority is by definition not affected by the particularity of minorities, this relativizes the valuation of a designation considerably anyway.
Our observation is that professional/entrepreneurial self-employment is the domain of the Type A personality and the ADHD-HI/mixed type. Type C personalities and people of the ADHD-I subtype are, according to our (purely subjective) impression, less or less successful as self-employed persons. This is especially true for SCT sufferers, who, according to our experience, are rather advised not to become self-employed.
Independence necessarily requires the ability to make quick decisions. While hasty or even ill-considered impulsive decisions may be disadvantageous for independence, decision-making difficulties seem to be an even greater stumbling block.
Conversely, according to our (purely subjective) impression, activities that require great empathy and patience, such as therapeutic professions, seem to be a strength of the more introverted types.
We understand the ADHD-HI subtype to be an ADHD sufferer who responds to stress with action and extroversion (fight, BAS, extroverted), whereas the ADHD-I subtype is an ADHD sufferer who responds to stress with flight or play dead (flight/freeze, introverted). Research confirms that the personal tendency to act out stress through externalizing reactions correlates with high BAS, while the personal tendency to internalize stress correlates with high flight/freeze. (According to Gray’s “old” RST definition before 2000, this would still be the BIS).2.
Several years after the first thoughts on this side about a connection between the BIS/BAS system and ADHD subtypes, we encountered a meta-analysis on cortisol and ADHD that had already discussed this idea.3
2.1.1. ADHD-HI/ADHD-C (with hyperactivity): high BAS¶
The ADHD-HI subtype (with hyperactivity) forms in ADHD sufferers with the stress response pattern Fight (aggression and attack). ADHD-C would then be a weakened form of the ADHD-HI subtype (with partially caught-up brain development).
Symptomatic:
Stress is externalized, acted out externally
More frequent aggressive behavior
More frequent impulsive behavior
More frequent motor hyperactivity
More conflicts with peers
Attention problem: easily distracted
Supporting the description of the mixed type as a relative of the ADHD-HI subtype is the fact that in both, cortisol levels to acute stressors fall and remain well below those of unaffected individuals, whereas in the ADHD-I subtype, the cortisol response to acute stressors rises above that of unaffected individuals. ⇒ The HPA axis / stress regulation axis
2.1.2. ADHD-I subtype (without hyperactivity): high FFFS¶
The ADHD-I subtype (without hyperactivity) is formed in ADHD sufferers with a tendency to high FFFS (according to the old RST: BIS) and the stress reaction pattern Flight (flight or playing dead, whereby playing dead is probably only the precursor to flight upon detection; playing dead is associated with very high internal tension).
Symptomatic:
Stress is internalized, acted out inwardly
Less aggressive behavior
Less impulsive behavior
Significantly fewer conflicts with peers
Attention problem: easily bored
The inner pressure (or stress) that triggers the reactions is the same for both types. However, the different way of dealing with the inner pressure leads to different symptoms.
According to this view, the different symptoms of ADHD-HI and ADHD-I are basically based in the method of coping with stress of the affected persons.
According to this view, the new RST could explain the phenomenon SCT (“sluggish cognitive tempo”) as a “switched off” BIS (due to particularly high norepinephrine and dopamine levels4?), which is thus particularly strongly inhibited in its decision making. This could explain why SCT sufferers can have above-average intelligence and yet be massively impaired in their decision-making.
According to this side hypothesis, in SCT, the BIS system, which (according to the new RST) has mainly deliberative tasks in the presence of simultaneously activated BAS and FFS, is also turned off by too high levels of norepinephrine and dopamine (which deactivate the PFC).
For character traits such as extraversion / introversion / neuroticism / harm avoidance as well as personality traits such as affective lability or social avoidance, family and twin studies have demonstrated hereditary causes.5
Comparably Huber6 and Trappmann-Korr7 describe a connection between ADHD subtypes and personal character traits of the affected persons.
Similarly, a study that distinguished comorbidities in ADHD by subtype found that hyperactivity/impulsivity (ADHD-HI) closely correlated with externalizing comorbidities, and predominant inattention (ADHD-I) clustered with internalizing comorbidities such as dysthymia and anxiety disorders including generalized anxiety disorder.8
Diamond9 described SCT as a subset of ADHD-I, which seemed plausible in the context of our differentiation matrix by stress response type, but is now considered refuted: SCT is now considered a disorder in its own right, even though it is very often comorbid along with ADHD.
We assume that the classical ADHD subtype poles ADHD-HI (with hyperactivity) and ADHD-I (without hyperactivity) represent different stress phenotypes, which show different stress reaction patterns to one and the same cause (ADHD). ADHD-HI tends to externalize stress, while ADHD-I tends to internalize stress.
Notice:
Gray’s BIS / BAS system, Connor and Gray’s FFFS system, and the distinction between the ADHD-HI and ADHD-I subtypes are accepted standard models. The explanation of the subtypes ADHD-HI and ADHD-I as stress phenotypes is a hypothesis developed by us.
Even in healthy people, there are typical differences in the cortisol response to stress to the extent that one group reacts with an increased cortisol response and one group reacts with a flattened cortisol response, although this is independent of the type of stressor. Sources for this under 4.4.
According to this view, this stress phenotype determines which ADHD subtype an ADHD sufferer develops. The stress phenotype, which is based on healthy people, ultimately uses only other terms instead of the ADHD subtypes commonly used for ADHD sufferers.
One study found that temperament could explain about 20% of ADHD-HI symptomatology.10 Unfortunately, the study did not distinguish between ADHD-HI and ADHD-I and apparently examined ADHD-HI subtype alone. Nevertheless, we think we can interpret the result as a tendential confirmation of a correlation between character traits and ADHD-HI subtype symptomatology.
A lot of anger, frustration or hostility when one’s wishes are not respected or one’s goals are not achieved19
More common abnormalities of lipid metabolism (hypertriglyceridemia) can be eliminated in the type A personality by ACTH administration, but not by cortisol administration.20
The described ACTH effect is consistent with the present understanding of underreactivity of the HPA axis in type-A.
Majority have an increased insulin response to glucose (hyperinsulinemia),20 which, although not caused by hypertriglyceridemia, may be related to it.
The HPA stress response in type A is thought to be mediated primarily by CRH.21.
This could indicate a pituitary weakness (and consequently a weak adrenal response) in type A and ADHD-HI, possibly due to a downregulation of CRH receptors in the pituitary due to prolonged stress-induced CRH release. However, this is contradicted by the fact that (however: in healthy type A humans) a flattened cortisol stress response also occurs after ACTH administration (see 4.1.1.2.).
The lower the social contacts and social support, the higher the resting pulse and the (basal = stressor-independent) urine adrenaline level in type A.22
A study of 58 sports students found no significant traits in Type A personalities.23 In our opinion, this could possibly be due to the fact that sports training increases stress resistance and therefore levels out differences.
4.1.1.2. Flattened cortisol stress response of type A personality¶
A flattened cortisol stress response is believed by this side to be a phenotypic biomarker of type A personality.
Type A correlates with a flattened cortisol stress response.24
Type A responded to ACTH injection with a flattened cortisol response. 40% showed no cortisol response at all or a depressed cortisol response.25
Basal ACTH levels are elevated in healthy type A personalities compared to healthy type B personalities.26
Likewise, the ACTH awakening response is increased.25
The elevated basal ACTH levels may be related to the flattened cortisol response in such a way that the sustained ACTH elevation has caused downregulation of ACTH receptors, and therefore the cortisol response is reduced.25
The typical characteristics of the Type A personality coincide with those of the ADHD-HI/mixed type
ADHD-HI sufferers (hyperactive, type A personality, active-coping), often respond to a stressor with a flattened cortisol response compared with nonaffected individuals (⇒ The HPA axis/stress regulatory axis) and a decreased epinephrine/norepinephrine response (⇒ The autonomic nervous system)
Insecurity and anxiety are defining characteristics attributed to the Type C personality.14
A higher sense of shame and lower body image correlate with a higher cortisol stress response.27
The Type C personality is described as somewhat more anxious.11 We consider the attribution of aggressiveness mentioned there to be questionable.
4.1.3.2. Excessive cortisol stress response in type C personality¶
Type C reacts to ACTH administration with an excessive cortisol response.25 Friedman contrasted type A only with type B, which deviates from the 3-level distinction used here (A and C as opposite-pole extremes, B as a balanced middle).
Although there are no other publications that have directly measured a pronounced cortisol stress response in type C personality, we nevertheless have little doubt that an exaggerated cortisol response is likely to represent a phenotypic biomarker of type C personality.
In addition, it is assumed that the stress response here is primarily mediated by vasopressin.28
After subjects completed the TSST several times in a row, only one third showed an elevated cortisol stress response (habituation effect). This third with elevated cortisol levels were more self-confident, less extroverted and tended to be more neurotic in personality questionnaires.29
ADHD-I sufferers (inattentive without hyperactivity, type C personality, passive-coping type) very often react with an increased cortisol response compared with nonaffected individuals (⇒ The HPA axis/stress regulatory axis) and increased epinephrine/norepinephrine response (⇒The autonomic nervous system).
ADHD-I sufferers are more likely to have the PFC shut down by high levels of norepinephrine due to the high endocrine stress response initiated by a high noradrenergic response. Because the PFC (in addition to the hippocampus) is able to control cortisol release,30 blockade of the PFC could lead to an uncontrolled cortisol stress response.
Although one meta-study found no correlation between ADHD and cortisol stress responses,31 this may be because only one of the included studies differentiated by subtype and the meta-study therefore looked at the ADHD population as a whole.
4.2. Cortisol stress responses and personality traits in healthy individuals¶
First, it should be noted that high or low cortisol responses already correlate with gender and with general personality traits. Significantly more formative, however, is the correlation of cortisol response and the orientation of the stress phenotype.
4.2.1. Personality traits in high cortisol stress response¶
Personality traits are associated with high cortisol responses to acute stressors:
Higher extraversion,50 while another study found a flattened cortisol stress response with low extraversion in men35
High neuroticism.513652 Another study found this only in women. Neuroticism was associated with high morning cortisol levels in another study.3553
The flattened cortisol stress response in neuroticism is explained by one publication to mean that individuals with higher neuroticism would experience higher levels of chronic stress, with chronic prolonged stressful experience leading to downregulation of both the autonomic nervous system and the HPA axis.36 It is true that chronic stress can trigger downregulation.525455 However, it should be doubted that the personality trait neuroticism alone triggers such high and chronic stress.
Higher anxiety in healthy people was surprisingly associated with low cortisol, ACTH, epinephrine, norepinephrine, and prolactin levels during psychosocial stress in a small-subject study.58
For more on typical character traits in relation to exaggerated or blunted cortisol stress responses, see ⇒ Stress response phenotypes in humans.
In general, healthy men show a higher cortisol response to stressors such as the TSST than healthy women. Healthy individuals with greater social affinity have reduced cortisol responses to the TSST. The cause is thought to be higher stress resilience with social affinity.34
A study of 120 healthy subjects found different cortisol stress responses in healthy adult men.59
One part of the subjects reacted to stress with an increase in cortisol, the other part with a decrease in cortisol (flattened cortisol stress response). Another study came to the same conclusion.60
Second graders showed elevated levels of cortisol on exam days and concomitant decreased levels of epinephrine and norepinephrine. Individual differences in secreted hormones were significantly related to personality variables observed in the classroom and to the effects of academic stress:61
Social approach behavior correlated with higher cortisol and adrenaline levels
Fidgetiness correlated with low adrenaline.
Aggressiveness correlated with high levels of norepinephrine.
Inattention correlated with low norepinephrine levels.
Novelty-seeking correlates with low basal cortisol levels and cortisol stress responses to the dexamethasone/CRH test and the TSST in healthy adults; low novelty-seeking correlates with high levels. There is no correlation with ACTH.62 In contrast, risk aversion (harm avoidance) and reward dependence did not correlate with cortisol levels in healthy adults,63 but did correlate with internalizing symptoms57 typical of ADHD-I.
Another study of 79 healthy women similarly showed a distribution into three groups with low, moderate, and high cortisol stress responses, even with prolonged stress induction. The lower and higher cortisol stress responses were correlated with more unbalanced and negative affect, such as sadness and increased internal tension.64
In the healthy women studied, a decreased cortisol stress response correlated with hostility and negative affect, and an increased cortisol stress response correlated with increased sadness and inner tension.64
The latter is completely consistent with our postulated picture of stress phenotypes:
Increased as well as flattened cortisol stress responses are
A sign of an imbalance in the stress systems and
Correlated with different stress phenotypes:
The externalizing stress phenotype with flattened cortisol stress response (ADHD-HI, atypical depression, bipolar, aggression disorders) tends to have more hostility and negative affect
The internalizing stress phenotype with an excessive cortisol stress response (ADHD-I, melancholic / psychotic depression) shows more sadness and inner tension
According to our understanding, this further means that the different cortisol stress responses in ADHD-I (and possibly SCT) (increased cortisol stress response) and ADHD-HI (flattened cortisol stress response) are initially patterns of a stress phenotype and not yet necessarily an expression of a pathological imbalance of the cortisol system or the HPA axis.
We hypothesize that the more intense skewing of stress systems is associated with more intense elevation or flattening of cortisol stress responses and correlates with increased likelihood of mental disorders. Unfortunately, there are no studies on this yet.
It also fits that in depression the result of the dexamethasone/CRH test, which measures the cortisol stress response, is on the one hand an indicator for the presence of depression and on the other hand, after the depressive symptoms have subsided, an indicator for the probability of a relapse. This could be interpreted to mean that the cortisol stress response is an indicator of disease vulnerability rather than an exclusive indicator of the disorder itself.
It could fit to this that a meta examination of 49 studies found a correlation of the cortisol and ACTH stress response with the subjective stress perception only in about 1/4 of the studies, in 2/3 a correlation of cortisol or ACTH stress response. The correlation between cortisol (as well as ACTH) stress response and subjective stress perception was not dominant, ranging from 0.3 to 0.5.65
Stress phenotypes have also been identified in animals. Animals with active responses to environmental threats have lower CRH and cortisol stress responses than animals with passive responses.66 On the other hand, mice with CRH overexpression throughout the central nervous system (but not with CRH overexpression in specific forebrain regions) show increased active stress scoping.67
4.2.3. Cortisol stress responses, basal cortisol levels, and personality traits¶
One study examined the correlation of personality traits with low/high cortisol stress response and low/high basal cortisol levels in healthy long-term unemployed individuals.24 The following personality traits correlated with the different groups:
We suspect that what we refer to as stress phenotypy is referred to by others as affective style.
According to Davidson68, affective styles are determined, among other things, by brain regions
DLPFC
Ventromedial PFC (vmPFC)
Orbitofrontal cortex (OFC)
Amygdala
Hippocampus
Anterior cingulate cortex (ACC)
Insular cortex
regulated.
5. ADHD-HI/ADHD-C and ADHD-I as stress phenotypes¶
Although ADHD is strongly genetically predisposed, there is no genetic correlation with relatives’ subtypes. In other words, ADHD is heritable and depends on genetic factors, but the subtype is not heritable and therefore probably does not depend on (ADHD-specific) heritable genetic factors.69
While ADHD-HI/ADHD-C tend to externalize stress, ADHD-I sufferers tend to internalize stress.
These different response patterns are not limited to humans.
Two different stress phenotypes have been demonstrated in rats across different populations:70
The acting-coping type shows an increased adrenaline and noradrenaline response to a stressor. This group showed a more active readiness to defend and escape and a more inflexible behavioral stereotype, as well as increased blood pressure and pulse.
The passive-coping type shows a lower adrenaline and noradrenaline response to a stressor. Typical stress symptoms here were freezing/deadlining, a lower readiness to defend and flee with simultaneously higher flexibility of the behavioral response, and a lower pulse rate.
Stress alters brain functions
In simplified terms, the stress hormones released in high amounts during high stress, especially norepinephrine and dopamine, reduce the activity of the PFC. Whereas low DA and NE increases due to mild stress usually enhance cognitive performance, high DA and NE levels cause developmentally younger brain regions, especially the frontal cortex, to shut down.4 Stress impairs prefrontal cortical function.71 Thus, norepinephrine levels, which are elevated during acute stress, disrupt prefrontal cortex function727374
This mechanism made sense to our ancestors, who mostly had to fight or flight when faced with existential stress, because the slow thinking of the PFC costs too much time in the race to be at least the second slowest. We are the descendants of the more successful of our ancestors, i.e. of those who (figuratively generalized) managed to run away faster than at least one other and were therefore spared by the lion, or could fight somewhat better than the respective opponent. In today’s existential stress situations - e.g. a divorce or insolvency - this reaction is rather a hindrance. Today, especially in such stressful situations, cognitively complex performances still have to be made.
If this model is now applied to ADHD sufferers, who by definition are particularly sensitive to stress, the various ADHD symptoms can be explained as individual phenotypes caused by different stress hormone and neurotransmitter responses to a stressor, thereby determining which brain regions are altered or impaired as a result of the stress load and how.
Even in healthy individuals, typical differences in the cortisol response to stress exist to the extent that one group responds with an elevated cortisol response and one group responds with a flattened cortisol response, although this is independent of the type of stressor.5960
Melancholic (endogenous) depression, and even more so psychotic depression, is characterized by an exaggerated cortisol stress response, as is the ADHD-I subtype. ⇒ Melancholic and atypical depression
Atypical depression is characterized by a flattened cortisol stress response, which is also common in ADHD-HI/ADHD-C.75 ⇒ Melancholic and atypical depression
In bipolar depression, a flattened cortisol stress response is found quite predominantly, otherwise a normal cortisol stress response, but never an exaggerated cortisol stress response.
In addition, the amylase stress response is excessive. ⇒Bipolar depression in the article Cortisol in other disorders
In post-traumatic stress disorder, phenotypically different stress responses to the same traumatization are reported.76
More on the different cortisol stress responses in ADHD-HI and ADHD-I: ⇒ Cortisol and other stress hormones in ADHD
For more on cortisol stress responses in several other mental disorders: ⇒ Cortisol in other disorders. We have not yet encountered a mental disorder with a typically normal, moderate cortisol stress response. However, not every affected individual has an elevated or depressed stress response. A normal cortisol stress response may occur in ADHD-HI or atypical depression, although the flattened cortisol stress response may be more common in both.
6. Temperament and character as symptom predictors¶
An interesting study on predicting symptom severity using AI / machine learning came to the surprising conclusion that the results of the “Temperament and Character Inventory Scale” (TCI) have a particularly high impact on predicting symptom variance of77
[Kirschbaum, Prüssner, Stone, Federenko, Gaab, Lintz, Schommer, Hellhammer (1995): Persistent high cortisol responses to repeated psychological stress in a subpopulation of healthy men. Persistent high cortisol responses to repeated psychological stress in a subpopulation of healthy men. Psychosom Med. 1995 Sep-Oct; 57(5):468-74.](https://www.ncbi.nlm.nih.gov/pubmed/8552738 ↥↥↥
