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Hyperactivity in ADHD - Neurophysiological correlates

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Hyperactivity in ADHD - Neurophysiological correlates

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1. Hyperactivity primarily mediated by the striatum

Hyperactivity, as exhibited by ADHD-HI and ADHD-C, is mediated by the striatum, which is connected to the PFC via the striatofrontal dopamine circuit.1 2345678 Within the striatum, it is the nucleus accumbens in the ventral striatum that causes hyperactivity through disinhibition.910 The dorsal striatum is involved in the selection, initiation and execution of voluntary motor responses.8 Only the right hemisphere of the PFC is involved,11 which processes negative emotions (such as stress), while the left hemisphere is responsible for positive emotions.

A slight increase in dopamine (in healthy animals, i.e. exceeding the normal level) in the ventral striatum increases hyperactivity. An extreme increase in the dorsal striatum causes stereotypical behavior, as can occur in ASD10
Since the dopamine effect follows the inverted-U pattern, the reduced dopamine as a deviation from the optimal level is also responsible for hyperactivity in ADHD.

According to other sources, motor hyperactivity is modulated by a loop between prefrontal motor cortex → putamen (in the lateral striatum) → thalamus → prefrontal motor cortex.12

Dopamine degradation in the striatum occurs primarily via DAT. Polymorphisms of the DAT gene are therefore involved in hyperactivity and other symptoms mediated via the striatum.11314151617184519202122

Whether DAT in the striatum is increased, normal or decreased in ADHD is unclear.
This raises the question of how much the DAT are really involved in symptom mediation in ADHD. While on the one hand smoking can be seen as a self-medication for dopamine increase and DAT reduction, on the other hand smoking does not eliminate the ADHD symptom. Perhaps the key to resolving the apparent contradiction lies in the short-term nature of the dopaminergic effect of smoking.
An increased DAT count is associated with a reduced dopamine level in the striatum. As the DAT count is even higher in ADHD-HI than in ADHD-I, the dopamine level in ADHD-HI is even lower than in ADHD-I.
It is discussed that the reduced dopamine level due to the increased DAT count in ADHD-HI triggers hyperactivity.

As expected, rats that do not form / barely form functional DAT due to genetic manipulation have a significantly increased dopamine level in the striatum. Nevertheless, they also suffer from hyperactivity. This could still be explained by the fact that too high a neurotransmitter level triggers very similar symptoms to too low a neurotransmitter level, as the optimal neurotransmitter level required for optimal signal transmission does not exist. It is conceivable that if the dopamine level is only elevated because the dopamine is not stored again from the synaptic cleft into the vesicles due to a lack of DAT, it is present in high proportion in the synaptic cleft, but not in response to a stimulus (in order to create a common basis for decision-making together with many other nerves, by simultaneously transmitting nerve signals through the release of dopamine), but as an ever-present activation, which, like an annoying background noise on the radio, is also a noise but has nothing to do with the music being transmitted.
Treatment with amphetamine, methylphenidate, D1 receptor agonists or halperidol also reduced hyperactivity in genetically manipulated DAT-less rats.23 Hyperactivity (in addition to attention and memory problems) was also observed in mice with DAT deficiency, which was reduced by amphetamine medication. Amphetamine medication therefore also normalized the low number of DAT in the striatum.24

Adults have a significantly lower number of dopamine transporters in the striatum than children. For every 10 years of age, there is a decrease of 7 %, whereby the decrease is significantly higher up to around 40 years of age than thereafter. In 50-year-olds, the number is only about half as high as in 10-year-olds.2526

Certain “risk” polymorphisms of the DAT gene correlate more strongly with the degree of symptoms of hyperactivity and impulsivity and less with the symptoms mediated by the PFC (inattention, working memory problems), since the PFC does not regulate dopamine via DAT (but via COMT).272128
In the striatum, dopamine degradation also appears to occur through membrane-bound COMT. Mb-COMT knockout mice (mice without membrane-bound COMT) show increased dopamine levels in the striatum, but not in the PFC. This suggests that mb-COMT is involved in dopamine degradation in the striatum, whereas only soluble COMT may be involved in the PFC.29

MPH has different neurological effects depending on the dosage. Since moderate to high doses of MPH bind to DAT, moderate to high doses of MPH are effective for hyperactivity and impulsivity. This is why most people with ADHD-HI or ADHD-C respond well to moderate to high doses of MPH, while people with ADHD-I are said to benefit less from it.2730313233

At low doses, methylphenidate preferentially enhances dopaminergic neurotransmission in the PFC, from which people with ADHD-I are said to benefit significantly better.2734

However, people with ADHD of the hyperactive-impulsive type (EEG: excessively high beta) are known to achieve good results in terms of restlessness and attention with minimal doses of stimulants. Only drive and mood were only improved with higher doses.
Similarly, we know people with ADHD-I who cope very well with quite high doses of MPH. The mechanisms of action therefore appear to be more complex.

The principle of dose dependence in the effect of stimulants could correspond to the dose-dependent effect of dopamine and noradrenaline on the PFC - albeit with different results. Low elevations of dopamine and noradrenaline (as occur during manageable stress) improve PFC performance. Low-dose MPH increases dopamine and noradrenaline levels in the PFC. The effect of low-dose MPH and slightly increased dopamine / noradrenaline in the PFC is therefore concurrent.
High levels of dopamine and noradrenaline switch off the PFC.
Higher amounts of MPH continue to act on the striatum (via DAT) and no longer improve the performance of the PFC (where the few DAT are already occupied by small amounts of MPH and a higher amount of MPH therefore no longer has any positive effects).3536

Hyperactivity and impulsivity are also caused by overexpression of the Atxn7 gene in the PFC and striatum.37 In this case, atomoxetine was able to eliminate the hyperactivity and impulsivity.

Severe hyperactivity correlated in one study with38
in idle mode with increased functional connectivity:

  • In the left putamen
  • In the right caudate nucleus
  • In the right central operculum
  • In a part of the right postcentral gyrus within the auditory and sensorimotor network

2. Age-related differences in hyperactivity

The hyperactivity typical of the ADHD-HI subtype in children turns into a permanent inner restlessness in adulthood, a feeling of being driven.

2.1. Dopa decarboxylase activity

While there is a reduction in striatal and prefrontal dopa decarboxylase activity in children with hyperactivity,39 this is not reproducible in adults with ADHD-HI.40

2.2. HVA (homovanillic acid)

While several studies in boys with hyperactivity found a clear correlation to increased HVA levels in the cerebrospinal fluid, which correlated with good response to MPH and AMP,4142 43 another study in adults with ADHD-HI could not find an increase in HVA in the cerebrospinal fluid. This also suggests that persistent ADHD in adulthood has an altered pathophysiological basis.44

HVA is a degradation product of dopamine and is measured in the cerebrospinal fluid or in urine, whereby the former is considerably more complex, but allows much better conclusions to be drawn about the dopamine metabolism in the brain. A measurement in urine involves the dopamine metabolism of the entire body and is therefore not very meaningful. HVA measurements of the cerebrospinal fluid can also only reference the overall dopamine metabolism of the brain, without allowing statements to be made about the dopamine level in individual brain regions.

The finding that MPH or AMP administration is associated with a decrease in HVA in the cerebrospinal fluid of children with reduced hyperactivity could possibly be explained by a decrease in dopamine production in the substantia nigra.43

2.3. DAT

The DAT decline sharply in adulthood. As explained in section 1, the striatum plays a significant role in the neurological mediation of hyperactivity. DAT are primarily located in the striatum.
This could explain the significant change in symptoms from hyperactivity in childhood to inner restlessness and being driven.

3. Dopamine excess or dopamine deficiency cause hyperactivity

Two parallel prefrontal-striatal-thalamic-cortical circuits are involved in the control of motor reactions by the striatum.438

The “direct” way:

PFC → inner segment of the globus pallidus → thalamus → PFC

The purpose is a net amplification (by means of a disinhibition of excitatory cells of the thalamus) of the original cortical output. Dopamine deficiency in this circuit causes difficulties in movement initiation as known from Parkinson’s disease.

The “indirect” way:

The outer segment of the globus pallidus and its synapses → inhibit projections of the subthalamic nucleus to the → inner globus pallidus, causing a net inhibition of cortical dopamine production. Dopamine deficiency in this circuit causes excessive motor activity.

ADHD-HI hyperactivity can result from both dopamine deficiency and dopamine excess:45

  • Excess dopamine4647
    • In the inner segment of the globus pallidus8

or

  • Dopamine deficiency48
    • In the nucleus accumbens49
    • In the outer segment of the globus pallidus (due to insufficient inhibition)8

4. Excessively elevated beta as a possible cause of hyperactivity

A small subgroup of the mixed type exhibits genetically determined hyperactive frontal lobes with excessively increased beta activity. This neurological abnormality is not found in ADHD-I, but only in a subgroup of the mixed type, which differs from the rest of ADHD-C only by a greater tendency to tantrums, mood swings and increased delinquency.5051 People with ADHD with excessive beta are physically hyperactive (adults: inner restlessness), but not neurologically hyperactive. Typically, compared to non-affected persons52

  • Beta increased overall
  • Delta is significantly reduced centrally posteriorly
  • Alpha is reduced overall
  • Significantly reduces the overall posterior performance
  • The theta / beta ratio is reduced overall.
  • The skin conductance is significantly reduced (just like in a person with ADHD with excessively elevated theta)

Consequences are that the theta / beta ratio is not associated with arousal.52

This small group with excessively elevated beta must be distinguished from the larger group with excessively elevated theta, which corresponds more to the ADHD-I type. In this group of people with ADHD, compared to people without ADHD52

  • Total frontal power significantly increased
  • Theta significantly increased
  • Significantly increases the theta / beta ratio
  • Alpha reduced across the entire skullcap
  • Beta reduced across the entire skullcap

More on subtypes of ADHD according to EEG and QEEG at ⇒ The subtypes of ADHD: ADHD-HI, ADHD-I, SCT and others And ⇒ Neurofeedback as ADHD therapy.

5. Relatively low alpha

One study reports relatively low alpha, which causes problems with motor inhibition. Neurofeedback training, which subsequently increased alpha in the resting state, improved motor inhibition in ADHD.53

6. Other striatal-relevant genes as a possible cause of hyperactivity

The pseudogene Gm6180 for n-cofilin (Cfl1) is expressed 20-fold higher in hyperactive mice (bred for hyperactivity). Latrophilin 3 (Lphn3) and its ligand fibronectin-leucine-rich transmembrane protein 3 (Flrt3) are downregulated in hyperactive mice.54

Hyperactivity and impulsivity are also caused by overexpression of the Atxn7 gene in the PFC and striatum.37 In this case, atomoxetine was able to eliminate the hyperactivity and impulsivity. It is not surprising that the effectiveness of medication depends on the way in which the symptom in question is caused.

7. Zonulin increased in hyperactivity

Zonulin is a protein that controls the permeability of the intestinal wall. Elevated zonulin levels represent increased permeability of the intestinal wall.

A study of 40 people with ADHD and 41 people without ADHD found elevated zonulin levels in the people with ADHD, with the elevated zonulin levels also correlating with hyperactivity,55 so there may be a higher association with ADHD-HI than with ADHD-I.
Another study found elevated serum zonulin and occludin levels in children with ADHD.56

More about Zonulin and its effects:
⇒ Increased intestinal permeability in ADHD

8. Orexin increased with hyperactivity, decreased with hypoactivity

Orexin antagonists reduce motor hyperactivity induced by stimulants.57

9. Latrophilin-3: Gene knockout causes hyperactivity

The latrophilin-3 gene was switched off in rats. This resulted in58

  • Increase from

    • Hyperactivity
    • Weight (only for females)
    • Shock sensitivity to acoustic stimuli
    • In the striatum:
      • Dopamine transporter
      • Dopamine D1 receptor (DRD1)
      • Tyrosine hydroxylase
      • Aromatic L-amino acid decarboxylase (AADC)

  • Reduction of

    • Growth
    • Of the dopamine- and cAMP-regulated neuronal phosphoprotein (DARPP-32)
    • Activity after amphetamine administration
    • Anxiety (only in females)

  • No change from

    • DRD2
    • DRD4
    • Vesicular monoamine transporter-2
    • N-methyl-d-aspartate (NMDA)-NR1, -NR2A or -NR2B
    • Lphn1, Lphn2 and Flrt3 by qPCR and their protein products (no upregulation)
    • Reproduction
    • Survival rate

These results are consistent with studies on humans, mice, zebrafish and Drosophila.

10. NURR1 knockout causes hyperactivity and impulsivity

NURR1 is a transcription factor that regulates the dopamine signaling pathway and has a decisive influence on the development of dopaminergic neurons in the midbrain. Mice in which NURR1 was deactivated developed hyperactivity and impulsivity, but not the other ADHD symptoms such as anxiety, physical coordination problems, altered social behavior or memory problems. Neither tyrosine hydroxylase (which limits catecholamine synthesis) nor dopamine levels were altered by NURR1 blockade. The hyperactivity caused by NURR1 deactivation could be remedied by methylphenidate.59

11. Ether lipid deficiency causes hyperactivity and other ADHD symptoms

A deficiency of ether lipid (which has also been found in Alzheimer’s patients), as modeled by blocking glycerone phosphate O-acyltransferase, leads to a severe disorder of neurotransmitter balance. The symptoms observed in mice are60

  • Hyperactivity
  • Memory problems
  • Social behavior
  • Behavioral problems
  • Changed anxiety reactions
  • Depressive symptoms

Social curiosity and nesting behavior were unchanged.

The nigrostriatal dopamine level was significantly reduced, as was the number of vesicular monoamine transporters and the release of noradrenaline.61

12. Elevated homocysteine levels (e.g. due to B12 deficiency) can trigger hyperactivity

Low B12 levels correlate with increased hyperactivity/impulsivity in ADHD and Oppositional Defiant Disorder (ODD).6263 B12 deficiency can increase homocysteine levels in several ways.64 B12 deficiency (or the excessive homocysteine levels it triggers) can explain up to 13% of the hyperactivity/impulsivity symptoms of ADHD.62

13. Overexpression of the Atxn7 gene

Hyperactivity and impulsivity are also caused by overexpression of the Atxn7 gene in the PFC and striatum.37

14. Changes in pupil dilation

Pupil dilation is an indirect index of arousal that is noradrenergically modulated by the autonomic nervous system and activity in the locus coeruleus. Hyperactivity / impulsivity correlates with pupil dilation to happy faces, not to unhappy or neutral faces.65

15. Limbic system

Hyperactivity/impulsivity symptoms in ADHD correlated with an activation of the limbic system:66

16. D2 receptor - dopamine transporter - communication disorder

The D2 receptor and DAT communicate directly via certain proteins. If this communication (via certain peptides) is interrupted, mice develop pronounced motor hyperactivity.67

17. Excess dopamine synthesis

Overexpression of dUBE3A (the Drosophila homolog of UBE3A) in Drosophila

  • reduces dendritic branching68
    • dUBE3A appears to be essential for proper neuronal development
  • increases tetrahydrobiopterin [THB] (a rate-limiting cofactor for monoamine synthesis)69
  • this increases the dopamine level
    • Increase in dopamine levels causes hyperactivity (Ferdousy et al., 2011),
      The loss of dUBE3A causes69
  • Reduction of THB
  • significant reduction in the dopamine pools
    • Hypoactivity

18. D4 receptor - correlation to hyperactivity

Reports that the D4 receptor is found exclusively in the PFC in humans, but not in the striatum3570 or only in small quantities71, have been refuted by more recent studies.72

Genro reported that in the 6-OHDA-lesioned rat, which shows transient hyperactivity as well as learning and memory deficits73, locomotor hyperactivity correlates with increased D4R density in the striatum.747572 D4 receptor binding in the PFC or nucleus accumbens was not affected. The hyperactivity could be enhanced in the animals with a D4 agonist and attenuated with a D4 antagonist.76

D4-KO mice showed no hyperactivity.77

19. 5HT1B-KO

Mice without a serotonin 1B receptor show hyperactivity during the day and at night, as well as reduced anxiety behavior.78

20. Speculation: Hyperactivity as a compensatory mechanism against stress and inflammation?

It is possible that hyperactivity could be a (somewhat) healthy compensatory mechanism of the body to provoke inflammation and stress reduction.

Contrary to previous assumptions, sports do not appear to increase calorie consumption. Among the Hadza people, active hunter-gatherers in Africa, women walk an average of 8 km and men an average of 14 km a day, i.e. about as much as an American per week, but do not consume more energy per day than sedentary office workers in the USA.79808182 The Hadza are active and fit well into their 70s and 80s and are said to have neither diabetes nor heart disease.
However, high calorie expenditure through exercise shuts down stress systems and inflammatory responses, reducing the calorie expenditure that the stress responses would have caused. to use this for exercise.8183 This could be the nutritional equivalent of the long-standing finding that sports have a stress-regulating effect.84 It also sheds new light on reduced appetite the common side effect of stimulants. Speculatively, this could be an adaptive response to the body’s reduced energy expenditure due to the reduced stress response.

We therefore wonder to what extent hyperactivity as a symptom of the externalizing ADHD subtypes could possibly be a (misguided) compensatory reaction of the body, since inflammation is more common in the externalizing stress phenotype than in the internalizing ADHD-I subtype.

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