Aggression in ADHD - neurophysiological correlates

A distinction must be made between hot (impulsive) and cold (deliberate) aggression.

Aggression is controlled in the brain by a system of interacting brain regions.

The determining neurotransmitters are testosterone, cortisol and serotonin. A high testosterone level combined with a low cortisol level promotes aggression. A low serotonin level promotes impulsivity, which also promotes aggression. A low dopamine level also promotes aggression, although it must be questioned in which regions of the brain a reduced dopamine level causes this, as the dopamine level is not the same throughout the brain.

• 1. The 2 types of aggression
  • 1.1. Hot (reactive) aggression
  • 1.2. Cold (proactive) aggression
• 2. Brain system of aggression
• 3. Inhibition of aggression through serotonin
• 4. Aggression as a result of a high testosterone/cortisol ratio
• 5. Aggression, adrenaline and noradrenaline
• 6. Irritability and dopamine
• 7. Behavioral correlates of aggression
• 8. Further correlations

1. The 2 types of aggression¶

There are two types of aggression:

1.1. Hot (reactive) aggression¶

• Defense reaction in the event of an attack on oneself or another member of the group
• Reactive, impulsive, affect-driven aggression¹
• Signs of anger, activates sympathetic nervous system
• Brain region involved: Dorsal part of the central cavernous gray (periaqueductal gray)
• Reduced serotonin levels²
• Excessive reactivity of the amygdala³

1.2. Cold (proactive) aggression¶

• Reaction to attacks of other kinds
• Also known as targeted, proactive or instrumental aggression¹
• Prey behavior
• No anger/rage signs, efficient attack, no sympathetic activation
• Involved brain region: Ventral part of the central cavernous sinus
• Is associated with reduced emotionality (callous unemotional traits, reduced empathy)³
• No reduced serotonin level²
• Reduced reactivity of the amygdala³

Aggression must always be distinguished from dominance behavior.

Aggression in ADHD is typically hot aggression. Aggression correlates with ADHD-HI and ADHD-C, less so with ADHD-I.
Cold aggression is not a typical ADHD symptom.

The fact that aggression and impulsivity are different constructs can also be seen in mice with an Adgrl3 gene defect, which show increased impulsivity and reduced aggression.⁴

2. Brain system of aggression¶

Aggression is significantly regulated in the brain through the interaction of several brain regions:⁵

• Hypothalamus
• Amygdala
• Orbitofrontal cortex (OFC)
• Central cave gray (periaqueductal gray, PAG)

Both types of aggression are activated by different stimulation of the periaqueductal gray (central cave gray) in the midbrain. It is triggered by the hypothalamus and amygdala, while control is carried out by the PFC.⁶

Androgen receptors, which bind the androgenic steroid hormones testosterone and dihydrotestosterone, are frequently found in⁷

• Amygdala
• Hippocampus
• Cerebral cortex

Testosterone (especially in conjunction with low cortisol levels) increases responses in the brain’s aggression system (particularly in the amygdala) to angry faces shown.⁸⁹ Amygdala reactivity can be predicted (among other things) by salivary testosterone levels and a specific adrenoceptor gene polymorphism.¹⁰

A high cortisol response, on the other hand, dampens the amygdala, as cortisol, which is released at the end of the HPA axis response, not only inhibits the HPA axis, but also slows down the HPG axis, at the end of which testosterone is released. As a result, an acutely high exogenous cortisol level reduces aggression and anxiety.¹

Impulsive-aggressive sufferers show reduced connectivity between the amygdala and PFC.¹¹¹²
Neurofeedback could be suitable for improving such connectivity.

Reactive aggression in ADHD correlated with high activity in:¹³

• right insula
• Hippocampus
• middle and upper frontal areas

3. Inhibition of aggression through serotonin¶

Serotonin cannot cross the blood-brain barrier. The following illustration relates exclusively to serotonin in the brain.

Aggression inhibition is mediated by the PFC via serotonin at the 5-HT1A and 5-HT1B serotonin receptors.
A high serotonin level in the PFC causes low aggression. High serotonin levels reduce aggression and impulsivity.^1415161718

In male prisoners, aggression correlated with:¹⁹

• Tryptophan serum level reduced
• Kynurenine serum level reduced
• 5-HT serum level increased
• 5-HT/(Trp∗1000) ratio increased
  • Correlated with the number of severely aggressive acts (r=0.593, P<0.001)
• Increased impulsivity
• ADHD symptoms increased
• IQ reduced
• Global function values reduced
• Mood disorders more frequent
• Drug abuse/addiction more frequent
• Borderline more common
• Conduct disorder more common
• Antisocial behavior more frequent

Especially the 3 features

• 5-HT/(Trp∗1000) ratio increased
• Increased antisocial behavior
• Global function values reduced

were (jointly) predictors of aggressive behavior. The model combining these three predictors had an area under the ROC curve of 0.851 (95% CI 0.806-0.895).

However, Zuckermann’s theory that impulsivity is also associated with increased dopamine levels does not seem to be confirmed. Rather, Cloninger’s theory that impulsivity is promoted by low serotonin and low dopamine levels seems to be confirmed.²⁰ However, according to the inverted-U theory²¹²² , according to which excessive and reduced neurotransmitter levels in a brain region can cause very similar deficits, these two theories are not mutually exclusive. However, it is possible that the representation also differs according to tonic and phasic dopamine, which regulate each other.

A low serotonin level also correlates with lower social skills.
Destruction of the raphe nuclei, where serotonin is produced in the brain, indirectly triggers aggression via the serotonin deficiency in the PFC, which can no longer inhibit aggression and impulsivity due to the lack of serotonin.

A reduced number of (2A) serotonin receptors was found in impulsive-aggressive men and women.²⁴²⁵²⁶ More on this in Montova et al.²⁷

4. Aggression as a result of a high testosterone/cortisol ratio¶

A high ratio of testosterone to cortisol is thought to promote the development of hot aggression (reactive, impulsive, affect-driven aggression), while serotonin modulates between hot and cold aggression (cold: goal-oriented aggression).¹²⁸

Testosterone is the hormone of the last stage of the hypothalamic-pituitary-gonadal axis (HPG axis), while cortisol is the hormone of the last stage of the hypothalamic-pituitary-adrenal axis (HPA axis). These two stress axes influence each other by inhibiting each other.²⁹

Cortisol inhibits all stages of the HPG axis. Testosterone only inhibits the HPA axis at the (first) stage of the hypothalamus.³⁰³¹²⁹

This mutual interaction between the HPG and HPA axes easily swings towards a dominance of one of the two hormone systems (cortisol or testosterone). However, HPG dominance is much more common in men, as the production of sex hormones (such as testosterone) is only controlled by the HPG axis in men, whereas in women they are produced approximately equally by the HPG axis and the adrenal cortex (HPA axis),³² so the significance of this problem is considerably less in women.

A prolonged ratio of high testosterone to low cortisol also causes the expression of genes that promote social aggression and at the same time impairs cortical control.²

A high cortisol level causes CRH gene expression in the amygdala, which promotes anxiety/anxiety states and social phobia.³³³⁴ In line with this, high cortisol responses are associated with internalizing stress phenotypes (e.g. ADHD-I, more frequent anxiety) and low cortisol responses with externalizing stress phenotypes (e.g. ADHD-HI, less frequent anxiety).

D-amphetamine drugs such as lisdexamfetamine (Elvanse) increase the cortisol level, but not the testosterone level.³⁵

The following were increased

• Glucocorticoids (such as through methylphenidate)
  • Cortisol
  • Cortisone
  • Corticosterone
  • 11-Dehydrocorticosterone
  • 11-Deoxycortisol
• The androgens
  • Dehydroepiandrosterone
  • Dehydroepiandrosterone sulfate,
  • Δ4-androstene-3,17-dione (androstenedione)
• Progesterone (only for men)

The following remained unchanged

• Mineralocorticoids
  • Aldosterone
  • 11-Deoxycorticosterone
• The androgen
  • Testosterone

An increase in glucocorticoid plasma levels due to guanfacine is probable.³⁶ We are not yet aware of any studies on the effect of guanfacine on testosterone levels.

Stimulants (methylphenidate and amphetamine drugs) reduce the concentration of androgens.
There is a correlation between ADHD-HI and a polymorphism of the androgen receptor gene, which leads to its higher expression.³⁷

An increase in testosterone levels alleviates depression. This also applies to patients with a normal testosterone level.³⁸

5. Aggression, adrenaline and noradrenaline¶

• Aggression and outwardly directed anger correlate with increased noradrenaline³⁹
• Anxiety, on the other hand, correlates with increased adrenaline³⁹

6. Irritability and dopamine¶

Low dopaminergic activity in the PFC is thought to be a predictor of irritability.⁴⁰

7. Behavioral correlates of aggression¶

Aggression correlates with

• High urge for reward⁴¹
• Low sensitivity to punishment (prototypical for psychopathy)⁴¹⁴²
• Novelty seeking⁴³
• A large study compared the correlation of various symptoms with aggressiveness.⁴⁴
  Externalizing symptoms showed a significantly higher correlation to aggression than internalizing symptoms, which can, however, be present alongside aggression.
  Correlation to aggressiveness (descending):
  • Emotional reactivity: 65 %
  • Rule violations: 63 %
  • Social problems: 60 %
  • Emotional instability: 51 %
  • Hyperactivity with impulsivity: 51 %
  • ADHD: 45 %
    Here, ADHD-HI and ADHD-I do not appear to have been considered separately. If considered separately, we expect a significantly increased correlation with ADHD-HI and a significantly decreased correlation with ADHD-I.
  • Hyperactivity: 43 %
  • ODD: 43 %
  • Anxious-depressive: 43 %
  • Seclusion: 42 %
  • Cognitive problems / thinking disorders: 42 %
  • Inattention 39 % to 54 %
    Inattention appears to be independent of externalizing or internalizing tendencies. Thus, it is equally prevalent in ADHD-HI and ADHD-I.
  • Autism spectrum disorder: 38 %
  • Sleep problems: 38 %
  • Withdrawn-depressive: 38 %
  • Fear: 37 %⁴⁵
  • Somatic complaints: 30 %
  • Physical coordination problems (gross/fine motor skills): 30%
  • Depression 27.5 %
  • Emotional-anxious: 26 %
  • Peer problems (social problems in the group): 24 %
  • Social phobia 14 %
  • OCD / Compulsion: 11 %
  • Social isolation: 11 %
  • Dependency: 4 %
  • Prosocial behavior: -25 % (minus = negative correlation)
• Another study confirmed the correlation between anger and externalizing problems.⁴⁶
• No correlation was found between⁴⁷
  • Aggression and depression
    We do not know to what extent the internalizing and externalizing subtypes of depression were considered separately in this study.
  • Aggression and academic performance.
• Suicidality is more strongly associated with hot (reactive) aggression than with cold (proactive) aggression. The link between hot aggression and suicidality presupposed high hyperactivity/impulsivity.⁴⁸

8. Further correlations¶

Low cortisol levels and low anxiety correlate with

• High willingness to take risks / risky decisions⁴²
• While the administration of cortisol increased the willingness to take risks.⁴⁹

High testosterone levels correlated with

• High urge for rewards⁵⁰
• Low sensitivity to penalties⁵⁰
• Higher rejection of offers in the Ultimatum Game (see explanation below) by men⁵¹ than by women⁵².

A low testosterone level correlated with

• Low urge for rewards⁵⁰
• High sensitivity to penalties⁵⁰

However, the effect of testosterone levels appears to be gender-dependent.
In the ultimatum game, one partner is offered a share of a game sum. If the partner accepts, both keep the shared sum; if the partner refuses, both receive nothing. While testosterone administration in men resulted in more unfair offers,⁵³ testosterone administration in women increased the rate of fairer (more generous) offers (but not the rejection of unfair offers).⁵⁴ The authors of the study on women assume that testosterone promotes the pursuit of a higher social status in women, which is associated with the avoidance of conflict. According to our unverified hypothesis, this could have to do with “tend and befriend” behavior as a stress symptom.

Anxiety correlated with

• High sensitivity to punishment⁴¹
• Low urge for reward⁴¹

Low arousal of the autonomic nervous system was associated with low behavioral inhibition (lack of inhibition).⁴³

All these facts indicate that certain ADHD symptoms can be assigned to the individual subtypes, which can be differentiated based on the ratio of testosterone and cortisol levels. In addition, the serotonin level could (co-)explain the degree of impulsivity.

Testosterone appears to directly influence the activity of dopaminergic neurons,⁵⁵ as does cortisol.⁵⁶

Emotional dysregulation, irritability, anger and agitation in ADHD correlate with ADHD-specific genes and not with genes specifically associated with affective disorders (depression).⁵⁷