1. Hyperactivity primarily mediated by 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 regulatory circuit. Within the striatum, it is the nucleus accumbens in the ventral striatum that causes hyperactivity through disinhibition. The dorsal striatum is involved in the selection, initiation, and execution of voluntary motor responses.
Only the right hemisphere of the PFC is involved, which processes the negative emotions (such as stress), while the left hemisphere is responsible for positive emotions.
According to other sources, motor hyperactivity is modulated by a loop between prefrontal motor cortex → putamen (in lateral striatum) → thalamus → prefrontal motor cortex.
Dopamine degradation in the striatum occurs primarily via DAT. Polymorphisms of the DAT gene are therefore involved in hyperactivity and the other symptoms mediated via the striatum.
Whether DAT in the striatum are increased, normal, or decreased in ADHD is unclear.
This raises the question of how much DAT are really involved in symptom mediation in ADHD. While, on the one hand, smoking can be viewed as a self-medication for dopaminergic enhancement and DAT reduction, on the other hand, smoking does not eliminate ADHD symptom. It is possible that the key to resolving the apparent contradiction lies in the short-term nature of the dopaminergic effect produced by smoking.
Increased DAT count is associated with decreased dopamine levels in the striatum. Since the DAT number is even higher in ADHD-HI than in ADHD-I, the dopamine level is even lower in ADHD-HI than in ADHD-I.
It is discussed that the decreased dopamine level due to the increased DAT count in ADHD-HI triggers hyperactivity.
Rats that do not / hardly form functional DAT due to genetic manipulation have significantly increased dopamine levels in the striatum, as expected. Nevertheless, they also suffer from hyperactivity. This could still be explained by the fact that too high a neurotransmitter level triggers very similar symptoms as too low a neurotransmitter level, since the optimal neurotransmitter level required for optimal signal transmission does not exist. It would be conceivable that if the dopamine level were elevated only because the dopamine is not re-stored from the synaptic cleft into the vesicles for lack of DAT, it would be present in high proportion in the synaptic cleft, but just not in response to a stimulus (to create a common decision base together with many other nerves, by simultaneously transmitting nerve signals through dopamine release), but as an always present activation, which, like a disturbing background noise on the radio, is also a noise, but has nothing at all to do with the music to be transmitted.
Thus, even in the genetically engineered DAT-less rats, treatment with amphetamine, methylphenidate, D1 receptor agonists, or halperidol reduces hyperactivity. Similarly, in mice with DAT hypofunction, hyperactivity (in addition to attention and memory problems) was found to be reduced by amphetamine medication. Amphetamine medication thus also normalized the insufficient number of DAT in the striatum.
Adults have a much lower number of dopamine transporters in the striatum than children. For every 10 years of age, there is a decrease of 7%, with the decrease being significantly higher at ages up to about 40 years than thereafter. In 50-year-olds, the number is only about half as high as in 10-year-olds.
Certain “at-risk” polymorphisms of the DAT gene correlate more strongly with measures of symptoms of hyperactivity and impulsivity and less with symptoms mediated by the PFC (inattention, working memory problems) because the PFC regulates dopamine via COMT rather than DAT.
In the striatum, dopamine depletion also appears to occur through membrane-bound COMT. Mb-COMT knockout mice (mice lacking 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.
MPH has different neurological effects depending on the dosage. Because MPH binds to DAT at moderate to high doses, moderate- to high-dose MPH is well effective for hyperactivity and impulsivity. Therefore, most ADHD-HI or ADHD-C sufferers respond well to moderate- to high-dose MPH, whereas ADHD-I sufferers are reported to benefit less.
At low doses, methylphenidate preferentially enhances dopaminergic neurotransmission in the PFC, from which ADHD-I sufferers should benefit much better.
On this side, however, sufferers of the hyperactive-impulsive type (EEG: excessive high beta) are known to achieve good results with minimal doses of stimulants already in terms of inner restlessness and attention. Only drive and mood were improved only with higher doses.
Similarly, we know ADHD-I sufferers who cope very well with quite high doses of MPH. The mechanisms of action therefore seem to be more complex.
The principle of dose dependence in the effects of stimulants may correspond to the dose-dependent effects of dopamine and norepinephrine on the PFC-but with different results. Low increases in dopamine and norepinephrine (such as occur during manageable stress) improve PFC performance. Low-dose MPH increases dopamine and norepinephrine levels in the PFC. Thus, the effects of low-dose MPH and slightly elevated dopamine/norepinephrine in the PFC are concurrent.
High levels of dopamine and norepinephrine shut down the PFC.
Higher amounts of MPH continue to affect the striatum (via DAT) and no longer improve PFC performance (where the few DAT are already occupied by small amounts of MPH and therefore a higher amount of MPH no longer has a positive effect).
Hyperactivity and impulsivity are also caused by overexpression of the Atxn7 gene in the PFC and striatum. Atomoxetine was able to resolve the hyperactivity and impulsivity in this case.
Severe hyperactivity correlated in a study
at rest 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 of the ADHD-HI subtype, which is typical in children, changes in adulthood to a permanent inner restlessness, to being driven.
2.1. Dopa decarboxylase activity
While there is a reduction in striatal and prefrontal dopa decarboxylase activity in children with hyperactivity, this is not reproducible in adults with ADHD-HI.
2.2. HVA (homovanillic acid)
While several study in boys with hyperactivity found a clear correlation to increased HVA levels in cerebrospinal fluid, which correlated with good response to MPH and AMP, another study in adults with ADHD-HI could not find an increase of HVA in cerebrospinal fluid. This also suggests that persistent ADHD in adulthood has an altered pathophysiological basis.
The HVA is a degradation product of dopamine and is measured in the cerebrospinal fluid or in the urine, whereby the former is considerably more time-consuming, but allows significantly better statements about the dopamine metabolism in the brain. A measurement in urine involves the dopamine metabolism of the entire body and is therefore of little significance. HVA measurements of cerebrospinal fluid can also only reference the total dopamine breakdown of the brain without allowing statements about dopamine levels in individual brain regions.
The finding that MPH or AMP administration is accompanied by a decrease in HVA in the cerebrospinal fluid of children with decreased hyperactivity could possibly be explained by a decrease in dopamine production in the substantia nigra.
DAT decrease sharply in adulthood. As discussed in 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 symptomatology from hyperactivity in childhood to inner restlessness and being driven.
3. Excess or deficiency of dopamine causes hyperactivity
Two parallel prefrontal-striatal-thalamic-cortical circuits are involved in the control of motor responses by the striatum.
The “direct” way:
PFC → inner segment of 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 dopamine deficiency as well as dopamine excess:
- In the inner segment of the globus pallidus
- In the nucleus accumbens
- In the outer segment of the globus pallidus (due to insufficient inhibition)
4. Excessively elevated beta as a possible cause of hyperactivity
A small subgroup of the mixed type genetically exhibits hyperactive frontal lobes with excessively increased beta activity. This neurological abnormality is not seen in ADHD-I, but only in a subgroup of the mixed type, which differs from the rest of ADHD-C only in a greater tendency to tantrums, moody mood swings, and increased delinquency. ADHD sufferers with excessive beta are physically hyperactive (adults: internal agitation) but not neurologically hyperactive. Typically, compared to non-affected individuals
- Beta increased overall
- Delta is significantly reduced centrally posteriorly
- Alpha is reduced overall
- Significantly reduces the overall posterior power
- Reduces the theta / beta ratio overall.
- Skin conductance is significantly reduced (just as in sufferers with excessively elevated theta)
It follows that the theta / beta ratio is not associated with arousal.
This small group with excessively elevated beta is to be distinguished from the larger group with excessively elevated theta, which corresponds more to the ADHD-I type. In this group of ADHD sufferers, in comparison to non-affected persons
- 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, et al And ⇒ Neurofeedback as ADHD therapy.
5. Relatively low alpha
One study reported relatively lowered alpha causing problems with motor inhibition. Neurofeedback training that subsequently increased alpha at rest improved motor inhibition in ADHD.
6. Other striatal relevant genes as a possible cause of hyperactivity
The Gm6180 pseudogene 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.
Hyperactivity and impulsivity is also caused by overexpression of the Atxn7 gene in the PFC and striatum. Atomoxetine was able to resolve the hyperactivity and impulsivity in this case. Not surprisingly, the question of drug efficacy depends on the way in which the symptom in question is caused.
7. Zonulin elevated in hyperactivity
Zonulin is a protein that controls intestinal wall permeability. Elevated zonulin levels represent increased permeability of the intestinal wall.
A study of 40 ADHD sufferers and 41 nonaffected individuals found elevated zonulin levels in the ADHD sufferers, and the elevated zonulin levels correlated with hyperactivity at the same time, 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.
More about Zonulin and its effect:
⇒ Increased intestinal permeability in ADHD
8. Orexin increased in hyperactivity, decreased in hypoactivity
Orexin antagonists reduce stimulant-induced motor hyperactivity.
9. Latrophilin-3: gene knockout causes hyperactivity
In rats, the latrophilin-3 gene was knocked down. This caused
- Weight (females only)
Startle response to acoustic stimuli
- In the striatum:
Dopamine D1 receptor (DRD1)
- Aromatic L-amino acid decarboxylase (AADC)
- Of dopamine and cAMP-regulated neuronal phosphoprotein (DARPP-32)
- Activity after amphetamine administration
- Anxiousness (females only)
No change from
- 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)
- Survival rate
These results are consistent with studies in humans, mice, zebrafish, and Drosophila.
10. NURR1 knockout causes hyperactivity and impulsivity
NURR1 is a transcription factor that regulates the dopamine signaling pathway and decisively influences 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. Hyperactivity caused by NURR1 deactivation was reversed by methylphenidate.
11. Ether lipid deficiency causes hyperactivity and other ADHD symptoms
Deficiency of ether lipid (which has also been found in Alzheimer’s patients), as can be modeled by blockade of glycerone phosphate O-acyltransferase, leads to severe neurotransmitter imbalance. The symptoms observed in mice are
- Memory problems
- Social behavior
- Behavioral problems
- Altered anxiety reactions
- Depressive symptoms
Social curiosity and nesting behavior were unchanged.
Nigrostriatal dopamine levels were significantly decreased, as were vesicular monoamine transporter levels and norepinephrine release.
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). B12 deficiency can increase homocysteine levels in several ways. B12 deficiency (or the excess homocysteine levels it triggers) may explain up to 13% of the hyperactivity/impulsivity symptoms of ADHD.
13. Overexpression of the Atxn7 gene
Hyperactivity and impulsivity is further also caused by overexpression of the Atxn7 gene in the PFC and striatum.
14. Changes in pupil dilation
Pupil dilation is an indirect arousal index modulated noradrenergically 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.
15. Limbic system
Hyperactivity/impulsivity symptoms in ADHD correlated with limbic system activation…:
16. D2 receptor - dopamine transporter - communication disorder
D2 receptor and DAT communicate directly via certain proteins. If this communication is interrupted (by means of certain peptides), mice develop pronounced motor hyperactivity.
17. D4 receptor has no correlation with hyperactivity
In humans, the D4 receptor is found exclusively in the PFC, but not in the striatum.
Polymorphisms of the DRD4 gene therefore have more impact in ADHD on the (cognitive) symptoms mediated by the PFC, such as inattention or working memory problems, and less on the symptoms mediated by the striatum (such as hyperactivity or impulsivity):
- Single nucleotide polymorphisms (SNP) in the promoter region of DRD4
DRD4-7R does not correlate with hyperactivity or impulsivity.
18. Speculation: hyperactivity as a compensatory mechanism against stress and inflammation?
Possibly, hyperactivity could be a healthy (in approach) compensatory mechanism of the body to provoke inflammation and stress reduction.
Contrary to previous assumptions, exercise does not seem 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 daily, about as much as an American does per week, but use no more energy daily than sedentary office workers in the United States. The Hadza are active and fit into their 70s and 80s and are said to have no diabetes or heart disease.
However, high caloric expenditure from exercise shuts down stress systems and inflammatory responses, reducing the caloric expenditure that the stress responses would have caused. to use it for exercise. This could be the nutritional equivalent of the long-standing finding that exercise has a stress-regulating effect. It also sheds new light on decreased appetite the common side effect of stimulants. Thinking speculatively, this could be an adaptive response to the decreased energy expenditure of the body due to the decreased stress responses.
We therefore wonder to what extent hyperactivity as a symptom of the externalizing ADHD subtypes might be a (misdirected) compensatory response of the body, since inflammation is more frequent in the externalizing stress phenotype than in the internalizing ADHD-I subtype.