Impulsivity in ADHD - Neurophysiological correlates

• 1. What impulsivity correlates with
• 2. Neurophysiological correlates of impulsivity
  • 2.1. Neurophysiological correlates
    • 2.1.1. Neurophysiological correlates of action impulsivity
    • 2.1.2. Neurophysiological correlates of elective impulsivity
    • 2.1.3. Neurophysiological correlates of impulsivity
  • 2.2. Overexpression of the ATXN7 gene
  • 2.3. Amygdala
  • 2.4. Ventral striatum
  • 2.5. Increased connectivity between ventral tegmentum and middle cingulum
  • 2.6. Decreased myo-inositol levels in the vlPFC but not in the striatum
  • 2.7. Increased lateralization of the “posterior thalamic radiation”
  • 2.8. Nucleus accumbens
  • 2.9. No evidence of parietal involvement
• 3. Impulsivity and neurotransmitters / hormones
  • 3.1. Dopamine
  • 3.2. Serotonin
  • 3.3. Adenosine, cannabinoids
  • 3.4. Corticoids
• 4. Sleep deprivation impairs inhibition

1. What impulsivity correlates with¶

Impulsivity correlates with:

• Externalizing rather than internalizing mental problems¹
• Less sleep on weekends²
• A lower affinity for food according to the Mediterranean diet²
• Use of technical equipment for more than 3 hours/day²
• Birth via cesarean section²
• Birth weight of more than 2.5 kg²
• Not breastfed²
• Sports more than 3 days / week (low correlation)²
• Tendency to engage in risky behavior³
• Impulsivity and delay aversion seem to correlate with timing skills.⁴

Except for birth circumstances and breastfeeding, we believe the correlates are likely to be consequences rather than causes of impulsivity.

2. Neurophysiological correlates of impulsivity¶

Impulsivity is associated with activity in a network of orbitofrontal cortex (OFC) → striatum → thalamus.⁵

2.1. Neurophysiological correlates¶

2.1.1. Neurophysiological correlates of action impulsivity¶

Neurophysiologically, inhibition problems is modulated by a circuit consisting of:⁶

• pre-supplementary motor area (preSMA)
• right inferior frontal gyrus (rIFG)
• Striatum
• subthalamic nucleus (STN) comprises.

Action impulsivity and choice impulsivity are moderated by the genes for:⁶

• D4R
• DAT
• COMT
• α2AR

2.1.2. Neurophysiological correlates of elective impulsivity¶

Choice impulsivity (CI) is modulated by brain circuitry consisting of⁶

• ventromedial prefrontal cortex (vmPFC)
  • glutamatergic neurons
• posterior cingulate cortex (pCC)
  • glutamatergic neurons
• Nucleus accumbens (NAc)

Action impulsivity and choice impulsivity are moderated by the genes for:⁶

• D4R
• DAT
• COMT
  • A COMT inhibitor increased (in healthy subjects) the choice of more distant rewards. This leads to impairments of the striatum. Since COMT degrades dopamine in the PFC, this suggests a correlation of decreased dopamine levels in the PFC and devaluation of distant rewards ⁷
• α2AR

In SHR, in vivo electrophysiological recordings found neural encoding of discounting behavior in prefrontal and orbitofrontal cortex in the presence of rewards:⁸

• OFC neurons
  • were activated regardless of the value of the reward
  • exhibited significantly higher neuronal discharge rates
  • the reward-predicting OFC neurons
    • coded the value of rewards in control animals
    • were strongly activated at SHR after receiving a small immediate amplifier
• mPFC neurons
  • for large rewards: similarly active as for controls
  • for smaller rewards: higher discharge rates than controls
  • no reaction to the value of the rewards

2.1.3. Neurophysiological correlates of impulsivity¶

Impulsivity correlates with higher activity in the following brain regions:

• Ventral amygdala (bilateral)⁹¹⁰
• Parahippocampal gyrus⁹
• Left dorsal anterior cingulate (Brodmann area 32)⁹
• Caudate nucleus (bilateral)⁹

Impulsivity correlates with lower activity in the following brain regions:

• Dorsal amygdala⁹
• Ventral PFC (Brodmann area 47)⁹
• Anterior cingulum¹¹¹² and posterior cingulum¹²
• Right medial frontal gyrus¹¹
• Right precentral gyrus¹¹

Impulse inhibition (inhibition) correlates neurologically with increased activity in the

• Right (anterior lateral) obitofrontal cortex (OFC)¹³¹⁰ or dorsolateral PFC.¹⁴
• Orbitomedial PFC
  Decreased dopaminergic excitation of the omPFC decreases the ability to inhibit impulsivity.⁷

One study found no evidence of abnormalities in neurocognitive processes as represented by the diffusion decision model (DDM) or in go/no-go performance in ADHD. However, responses to failed inhibition in brain regions associated with error monitoring correlated closely with more efficient task performance, externalizing behavior, and ADHD symptoms. This study thus sows doubt as to whether go/no-go task activation truly reflects the neural basis of inhibition and found evidence that error-related contrasts provide better information.¹⁵

2.2. Overexpression of the ATXN7 gene¶

Hyperactivity and impulsivity is also caused by overexpression of the Atxn7 gene in the PFC and striatum.¹⁶ Atomoxetine was able to resolve the hyperactivity and impulsivity in this case.

2.3. Amygdala¶

Connectivity of brain networks is increased locally around the amygdala and decreased to the anterior cingulate and posterior cingulate in the cortex. The preponderance of connections around the amygdala relative to cortical connections results in an increased impulsive response to stimuli with decreased cortical inhibition.¹²

Delay aversion (impatience) correlates with a reduced amygdala.¹⁷

2.4. Ventral striatum¶

A study in monkeys concluded that low doses of MPH reduce impulsivity, whereas higher doses have a sedative effect. The impulsivity-inhibiting effect occurred particularly in the ventral striatum.¹⁸
This follows empirical experience that ADHD sufferers, especially children, can sometimes appear apathetic under MPH. In our opinion, this indicates an overdose following this study.

2.5. Increased connectivity between ventral tegmentum and middle cingulum¶

One study found a correlation between subjectively perceived impulsivity and significantly increased functional connectivity between ventral tegmentum and middle cingulate with L-dopa administration.¹⁹

2.6. Decreased myo-inositol levels in the vlPFC but not in the striatum¶

In rats with high impulsivity, significant reductions in myo-inositol levels were reported in the infralimbic PFC, but not in the striatum, compared with rats with low impulsivity. In the infralimbic PFC, significant reductions in transcript levels of key proteins involved in the synthesis and recycling of inositol (IMPase1) were conspicuous at the same time. Knockdown of IMPase1 in the infralimbic PFC increased impulsivity.²⁰
Myo-inositol (cyclohexane-cis-1,2,3,5-trans-4,6-hexol) is the most common isomer of inositol (inositol = cyclohexane hexol, a hexahydric cyclic alcohol). It is an intracellular “second messenger.” Oral administration improves insulin resistance and fat and glucose metabolism and lowers androgen levels.²¹

2.7. Increased lateralization of the “posterior thalamic radiation”¶

A significantly higher lateralization of posterior thalamic radiation (PTR) was found in children with ADHD. PTR lateralization correlated with inhibition in healthy controls but not in children with ADHD.²²

2.8. Nucleus accumbens¶

In rodents, lesions of the nucleus accumbens or basolateral amygdala lead to impulsive decision-making, but lesions of the ACC or mPFC do not. Lesions of the OFC reduce impulsivity. Impulsive decisions could thus represent the result of abnormal processing of the magnitude of rewards or a reduced effect of delayed reinforcement.
Rodents with a lesion of the nucleus accumbens perceive reward magnitude normally but show a selective deficit in learning instrumental responses with delayed reinforcement. This may suggest that the nucleus accumbens is a reinforcement learning system that mediates the effects of delayed rewards.²³

2.9. No evidence of parietal involvement¶

One study found no evidence of expected parietal modulation in the presence of increased inhibition. However, this lack of modulation was mediated by individual ADHD symptom severity. A correlation between intraparietal sulcus (IPS) activity and events to be inhibited was evident in less severe ADHD symptoms. However, this correlation disappeared in more severe ADHD symptoms. Similarly, functional connectivity between the IPS and the right inferior frontal gyrus correlated with conditions of high inhibitory demand, whereas this correlation decreased with increasing symptom severity.²⁴

3. Impulsivity and neurotransmitters / hormones¶

3.1. Dopamine¶

Impulsivity (like distractibility and depression) is characterized by:¹

• A reduced tonic (long-lasting) dopamine level
  and
• A reduced phasic (short-term) dopamine response to stimuli in the mesolimbic system.

The ADHD symptom of lack of inhibition of executive functions is caused dopaminergically by the basal ganglia (striatum, putamen), whereas the lack of inhibition of emotion regulation is caused noradenergically by the hippocampus.²⁵ Therefore, the former is more amenable to dopaminergic treatment. Emotion regulation and affect control, on the other hand, are better treated noradrenergically.

3.2. Serotonin¶

Other sources describe that impulsivity is induced by a deficiency of serotonin.²⁶²⁷ Low affinity of the serotonin transporter in platelets correlated with high impulsivity, whereas increased SERT affinity correlated moderately with increased aggressiveness and externalizing behavior. SERT expression had no effect. Serotonin availability in the synaptic cleft seems to depend more on affinity than on the number of SERTs. ²⁸

Serotonin inhibits aggression, so a deficiency of serotonin (in conjunction with high testosterone and low cortisol levels) promotes aggression. More ⇒ Aggression as a consequence of high testosterone with a concomitant attenuated cortisol response.

High serotonin levels in the PFC reduce aggression and impulsivity.^2930313233
Zuckermann’s theory that impulsivity is accompanied by increased dopamine levels 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.³⁴ Against the background of the inversed-U theory, according to which too low as well as too high neurotransmitter levels in one brain area cause almost identical problems, these two possibilities would not have to exclude each other,

One study found identical serotonin concentrations in platelets in ADHD-affected and non-affected children, and no relation to attention problems or hyperactivity, but a positive correlation to impulsive behavior.³⁵

We have observed that in ADHD-HI, low doses (2 to 5 mg/day) of SSRIs (e.g., escitalopram) produce very rapid improvement in impulsivity. There seems to be an immediate effect of serotonin in this case, as the effect does not occur after several weeks, as it does as a result of downregulation of the 5-HT receptors with higher-dose SSRI administration as an antidepressant (escitalopram: 10 to 20 mg / day). Downregulation of the receptors should be avoided as far as possible in this case, which is why the lowest dosage that is still helpful should be used.

3.3. Adenosine, cannabinoids¶

SHR rats, representing a model of ADHD-HI, responded to a cannabinoid CB1 receptor agonist with increased impulsivity (enhanced preference for short-term reward). This response was prevented by a single administration of caffeine (a nonspecific adenosine receptor antagonist) but was enhanced by chronic caffeine administration.³⁶
In contrast, a cannabinoid antagonist reduced impulsivity and increased preference for later, but larger, rewards.³⁶

3.4. Corticoids¶

Response inhibition (inhibition) enhanced by mild stress in healthy subjects in a stop-signal task is worsened by a mineralocorticoid antagonist.³⁷
This suggests involvement of mineralocorticoid receptors or the balance between mineralocorticoid receptors and glucocorticoid receptors upon inhibition.

4. Sleep deprivation impairs inhibition¶

ADHD correlates with sleep deprivation. Increasing sleep duration significantly improved inhibition in children with ADHD.³⁸