Aggression in ADHD - Neurophysiological correlates

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

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

The determining neurotransmitters are testosterone, cortisol and serotonin. A high testosterone value with a simultaneously low cortisol value 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 brain regions a reduced dopamine level causes this, since dopamine levels are not the same throughout the brain.

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

1. The 2 types of aggression¶

There are two types of aggression:

1.1. Hot (reactive) aggression¶

• Defensive reaction when attacked by self or other member of the group
• Reactive, impulsive affect-driven aggression¹
• Signs of anger, activates sympathetic nervous system
• Involved brain region: dorsal part of the central cavernous gray (periaqueductal gray)
• Decreased serotonin level²
• Overreactivity of the amygdala³

1.2. Cold (proactive) aggression¶

• Reaction to attacks of a different kind
• Also called purposeful, proactive or instrumental aggression¹
• Prey behavior
• No anger/rage signs, efficient attack, no sympathetic activation
• Involved brain region: ventral part of the central cavernous gray
• Is associated with reduced emotionality (callous unemotional traits, reduced empathy)³
• No decreased serotonin level²
• Reduced reactivity of the amygdala³

Aggression must always be distinguished from dominance behavior.

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

That aggression and impulsivity are distinct constructs is also evident in mice with an Adgrl3 gene defect, which show increased impulsivity and decreased aggression.⁴

2. Aggression brain system¶

Aggression is significantly regulated in the brain by an 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 cavernous gray) in the midbrain. The gating is done by hypothalamus and amygdala, while the control is done by the PFC.⁶

Androgen receptors that bind the androgenic steroid hormones testosterone and dihydrotestosterone are commonly found in⁷

• Amygdala
• Hippocampus
• Cerebral cortex

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

A high cortisol response, on the other hand, dampens the amygdala because cortisol, which is secreted 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 secreted. Thus, an acute high exogenous cortisol level has the result of reducing aggression and anxiety.¹

Impulsive-aggressive sufferers exhibit reduced connectivity between the amygdala and PFC.¹¹¹²
Neurofeedback could be suitable to improve such connectivities.

Reactive aggression in ADHD correlated with high activity in:¹³

• right insula
• Hippocampus
• middle and upper frontal areas

3. Aggression inhibition by serotonin¶

Serotonin cannot cross the blood-brain barrier. The following illustration concerns only serotonin in the brain.

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

In male prisoners, aggression correlated with:¹⁹

• Tryptophan serum level decreased
• Kynurenine serum level decreased
• 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)
• Impulsivity increased
• ADHD symptoms increased
• IQ decreased
• Global function values reduced
• Mood disorders more common
• Substance abuse/dependence more common
• Borderline more often
• Conduct disorder more often (Conduct disorder)
• Antisocial behavior more often

Especially the 3 features

• 5-HT/(Trp∗1000) ratio increased
• Antisocial behavior increased
• 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).

Zuckermann’s theory that impulsivity is accompanied by increased dopamine levels, however, does not seem to be confirmed. Rather, Cloninger’s theory seems to be confirmed, according to which impulsivity is promoted by low serotonin and low dopamine levels.²⁰ According to the inverse-U theory, according to which excessive as well as reduced neurotransmitter levels cause almost identical deficits in the respective brain region, these two theories are not mutually exclusive.

Low serotonin levels also correlate with lower social skills.
Destruction of the raphe nuclei, where serotonin is produced in the brain, causes indirect triggering of aggression via serotonin deficiency in the PFC, which is now unable to inhibit aggression and impulsivity due to lack of serotonin.

Reduced numbers of (2A) serotonin transporters have been found in impulsive-aggressive men as well as women.²²²³²⁴ For more on this, see Montova et al.²⁵

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

A high ratio of testosterone to cortisol is thought to promote the emergence of hot aggression (reactive, impulsive, affect-driven aggression), whereas serotonin modulates between hot and cold aggression (cold: goal-directed aggression).¹²⁶

Testosterone is the hormone of the last stage of the hypothalamic-pituitary-gonodal (HPG) axis, while cortisol is the hormone of the last stage of the hypothalamic-pituitary-adrenocortical (HPA) axis. These two stress axes influence each other by inhibiting each other.²⁷

Cortisol inhibits all stages of the HPG axis. Testosterone inhibits the HPA axis only at the (first) stage of the hypothalamus.²⁸²⁹²⁷

This mutual interaction of the HPG and HPA axes easily swings toward a dominance of one of the two hormone systems (cortisol or testosterone). However, HPG dominance is much more common in men because the production of sex hormones (such as testosterone) is controlled solely by the HPG axis in men, whereas in women they are produced approximately in half by the HPG axis and the adrenal cortex (HPA axis),³⁰ so the significance of this issue in women is considerably less.

A prolonged ratio of high testosterone to low cortisol further causes expression of genes that promote social aggression while impairing cortical control.²

High cortisol causes CRH gene expression in the amygdala, which promotes anxiety/anxiety and social phobia.³¹³² In line with this, high cortisol responses are associated with internalizing stress phenotypes (e.g., ADHD-I, more frequent anxiety) and low cortisol responses are associated with externalizing stress phenotypes (e.g., ADHD-HI, less frequent anxiety).

D-amphetamine medications such as lisdexamfetamine medications (Elvanse) increase cortisol levels but not testosterone levels.³³

Increased were

• Glucocorticoids (as caused by methylphenidate)
  • Cortisol
  • Cortisone
  • Corticosterone
  • 11-dehydrocorticosterone,
  • 11-Deoxycortisol
• The androgens
  • Dehydroepiandrosterone
  • Dehydroepiandrosterone sulfate,
  • Δ4-androstene-3,17-dione (androstenedione)
• Progesterone (this only in men)

Unchanged

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

An increase in plasma glucocorticoid levels by guanfacine is likely.³⁴ Studies on the effect of guanfacine on testosterone levels are not yet known to us.

Stimulants (methylphenidate and amphetamine drugs) decrease the concentration of androgens.
There is a correlation between ADHD-HI and a polymorphism of the androgen receptor gene leading to its higher expression.³⁵

An increase in testosterone levels alleviates depression. This also affects patients with normal testosterone levels.³⁶

5. Aggression, adrenaline and noradrenaline¶

• Aggression and outward anger correlate with elevated norepinephrine³⁷
• Anxiety, on the other hand, correlates with increased adrenaline³⁷

6. Irritability and dopamine¶

Low dopaminergic activity in the PFC is thought to be a predictor of irritability.³⁸

7. Behavioral correlates of aggression¶

Aggression correlates with

• High urge for reward³⁹
• Low sensitivity to punishment (prototypical for psychopathy)³⁹⁴⁰
• Novelty seeking⁴¹
• One large study compared the correlation of various symptoms with aggressiveness.⁴²
  Externalizing symptoms showed here a significantly higher correlation to aggression than internalizing symptoms, which, however, may well be present alongside aggression.
  Correlation to aggressiveness (descending):
  • Emotional reactivity: 65 %
  • Rule breaks: 63 %
  • Social problems: 60 %
  • Emotional lability: 51 %
  • Hyperactivity with impulsivity: 51 %
  • ADHD: 45 %
    Here, ADHD-HI and ADHD-I do not seem to have been considered separately. If they were considered separately, we would 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 seems to be independent of externalizing or internalizing tendencies. Thus, it exists equally strongly in both ADHD-HI and ADHD-I.
  • Autism spectrum disorder: 38 %
  • Sleep problems: 38 %
  • Withdrawn-depressed: 38 %
  • Fear: 37 %⁴³
  • 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 / Coercion: 11 %
  • Social isolation: 11 %
  • Dependency: 4%
  • Prosocial behavior: -25% (minus = negative correlation)
• Another study confirmed the correlation of anger to externalizing problems.⁴⁴
• No correlation was found between⁴⁵
  • Aggression and depression
    The extent to which internalizing and externalizing subtypes of depression were considered separately in this study is not known to us.
  • Aggression and academic performance.
• Suicidality is more strongly associated with hot (reactive) aggression than with cold (proactive) aggression. The association between hot aggression and suicidality presupposed high hyperactivity/impulsivity.⁴⁶

8. Other correlations¶

Low cortisol levels and low anxiety correlate with

• High willingness to take risks / risky decisions⁴⁰
• While administration of cortisol increased risk taking.⁴⁷

High levels of testosterone correlated with

• High urge for rewards⁴⁸
• Low sensitivity to penalties⁴⁸
• Higher rejection of offers in the Ultimatum Game (explanation below) by men⁴⁹ as by women⁵⁰.

Low testosterone levels were correlated with

• Low urge for rewards⁴⁸
• High sensitivity to penalties⁴⁸

The effect of testosterone levels, meanwhile, appears to be sex-dependent.
In the Ultimatum Game, a partner is offered a portion of the game amount. If the partner accepts, both keep the divided sum; if the partner refuses, both receive nothing. Whereas testosterone administration in men resulted in more unfair offers,⁵¹ testosterone administration in women increased the rate of fairer (more generous) offers (but not rejection of unfair offers).⁵² The study authors of the study in women hypothesize that testosterone in women promotes the pursuit of higher social status, which is associated with avoidance of conflict. This could be related to “tend and befriend” behavior as a stress symptom, according to our unverified hypothesis.

Anxiety correlated with

• High sensitivity to punishment³⁹
• Low urge for reward³⁹

Low autonomic nervous system arousal has been associated with low behavioral inhibition (lack of inhibition).⁴¹

All these facts indicate that certain ADHD symptoms can be assigned to the individual subtypes, which can be distinguished on the basis of the ratio of testosterone and cortisol levels. Additionally, the serotonin level could (co-)explain the measure of impulsivity.

Testosterone appears to directly affect the activity of dopaminergic neurons,⁵³ as does cortisol.⁵⁴

Emotional dysregulation, irritability, anger, and agitation in ADHD correlate with ADHD-specific genes and not with genes specifically associated with affective disorders (depression).⁵⁵