Neurophysiological correlates of hyperactivity in ADHD.
- 1. Hyperactivity primarily mediated by striatum
- 2. Age-related differences in hyperactivity
- 3. Excess or deficiency of dopamine causes hyperactivity
- 4. Excessively elevated beta as a possible cause of hyperactivity
- 5. Relatively low alpha
- 6. Other striatal relevant genes as a possible cause of hyperactivity
- 7. Zonulin elevated in hyperactivity
- 8. Orexin increased in hyperactivity, decreased in hypoactivity
- 9. Latrophilin-3: gene knockout causes hyperactivity
- 10. NURR1 knockout causes hyperactivity and impulsivity
- 11. Ether lipid deficiency causes hyperactivity and other ADHD symptoms
- 12. Elevated homocysteine levels (e.g. due to B12 deficiency) can trigger hyperactivity
- 13. Overexpression of the Atxn7 gene
- 14. Changes in pupil dilation
- 15. Limbic system
- 16. D2 receptor - dopamine transporter - communication disorder
- 17. D4 receptor has no correlation with hyperactivity
- 18. Speculation: hyperactivity as a compensatory mechanism against stress and inflammation?
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.1 2345678 Within the striatum, it is the nucleus accumbens in the ventral striatum that causes hyperactivity through disinhibition.9 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,10 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.11
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.11213141516174518192021
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 dopamine elevation and DAT reduction, on the other hand, smoking does not eliminate ADHD symptom. Possibly, 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 to 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 manipulated DAT-less rats, treatment with amphetamine, methylphenidate, D1 receptor agonists, or halperidol reduces hyperactivity.22 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.23
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.2425
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.262027
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.28
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.2629303132
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 act on 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).3435
Hyperactivity and impulsivity are also caused by overexpression of the Atxn7 gene in the PFC and striatum.36 Atomoxetine was able to resolve the hyperactivity and impulsivity in this case.
Severe hyperactivity correlated in a study37
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
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,4041 42 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.43
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.42
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
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:44
- Dopamine Deficiency47
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 by a greater tendency to tantrums, moody mood swings, and increased delinquency.4950 ADHD sufferers with excessive beta are physically hyperactive (adults: internal agitation) but not neurologically hyperactive. Typically, compared to non-affected individuals51
- 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.51
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 individuals51
- 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 reported relatively lowered alpha causing problems with motor inhibition. Neurofeedback training that subsequently increased alpha at rest improved motor inhibition in ADHD.52
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.53
Hyperactivity and impulsivity is also caused by overexpression of the Atxn7 gene in the PFC and striatum.36 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 non-affected individuals found elevated zonulin levels in the ADHD sufferers, with the elevated zonulin levels correlating with hyperactivity at the same time,54 so there may be a higher association with ADHD-HI than ADHD-I.
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.55
9. Latrophilin-3: gene knockout causes hyperactivity
In rats, the latrophilin-3 gene was knocked down. This caused56
- Weight (females only)
- Startle response to acoustic stimuli
- In the striatum
- Dopamine transporter
- Dopamine D1 receptor (DRD1)
- Tyrosine hydroxylase
- 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.57
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 are58
- 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.59
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).6061 B12 deficiency can increase homocysteine levels in several ways.62 B12 deficiency (or the excess homocysteine levels it triggers) may explain up to 13% of the hyperactivity/impulsivity symptoms of ADHD.60
13. Overexpression of the Atxn7 gene
Hyperactivity and impulsivity is further also caused by overexpression of the Atxn7 gene in the PFC and striatum.36
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 on happy faces, not on unhappy or neutral faces.63
15. Limbic system
Hyperactivity/impulsivity symptoms in ADHD correlated with limbic system activation…:64
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.65
17. D4 receptor has no correlation with hyperactivity
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):
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 they expend no more energy daily than sedentary office workers in the United States.73747576 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 through exercise shuts down stress systems and inflammatory responses, thus reducing the caloric expenditure that the stress responses would have caused. to use for exercise.7577 This may be the nutritional equivalent of the long-standing finding that exercise has a stress-regulating effect.78 It also sheds new light on decreased appetite the common side effect of stimulants. Thinking speculatively, this could be an adaptive response to the body’s decreased energy expenditure due to reduced 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.
Diamond (2014): Biologische und soziale Einflüsse auf kognitive Kontrollprozesse, die vom präfrontalen Kortex abhängen; In: Kubesch (Herausgeberin): Exekutive Funktionen und Selbstregulation – Neurowissenschaftliche Grundlagen und Transfer in die pädagogische Praxis; Huber, Seite 21 ↥ ↥
Filipek Semrud-Clikeman, Steingard, Renshaw, Kennedy, Biederman (1997): Volumetric MRI analysis comparing subjects having attention-deficit hyperactivity disorder with normal controls. J.Neurology. 1997 Mar;48(3):589-601. ↥
Schrimsher, Billingsley, Jackson, Moore (2002): Caudate nucleus volume asymmetry predicts attention-deficit hyperactivity disorder (ADHD) symptomatology in children. Journal of Child Neurology, 17( 12), 877-884. ↥ ↥
Soliva, Fauquet, Bidsa, Rovir, Cannona, Rilmos-Quiroga, et al (2010). Quantitative MR analysis of caudate abnormalities in pediatric ADHD: Proposal for a diagnostic test. Psychiatry Research, 182(3), 238-243. ↥ ↥
Vaidya, Austin, Kirkorian, Ridlehuber, Desmond, Glover et al. (1998): Selective effects of methylphenidate in attention deficit hyperactivity disorder: A functional magnetic resonance study. Proceedings of the National Academy of Science of the United States of America, 95, 14494-14499. ↥
Yael, Tahary, Gurovich, Belelovsky, Bar-Gad (2019): Disinhibition of the Nucleus Accumbens Leads to Macro-Scale Hyperactivity Consisting of Micro-Scale Behavioral Segments Encoded by Striatal Activity. J Neurosci. 2019 Jul 24;39(30):5897-5909. doi: 10.1523/JNEUROSCI.3120-18.2019. ↥
Casey, Castellanos, Giedd, Marsh, Hamburger, Schubert, Vauss, Vaituzis, Dickstein, Stacey, Sarfatti Rapoport (1997): Implication of right frontostriatal circuitry in response inhibition and attention-deficit/hyperactivity disorder. Journal of tile American Academy of Child andAdolescent Psychiatry}; 36, 3 74-383. ↥
Stahl (2013): Stahl’s Essential Psychopharmacology, 4. Auflage, Chapter 12: Attention deficit hyperactivity disorder and its treatment, Seite 475 ↥
Barr, Feng, Wigg, Schachar, Tannock, Roberts, Malone, Kennedy (2001): 5′-Untranslated region of the dopamine D4 receptor gene and attention-deficit hyperactivity disorder. Am. J. Med. Genet., 105: 84–90. doi:10.1002/1096-8628(20010108)105:1<84::AID-AJMG1068>3.0.CO;2-Q ↥
Daly, Hawi, Fitzgerald, Gill (1999): Mapping susceptibility loci in attention deficit hyperactivity disorder: preferential transmission of parental alleles at DAT1, DBH and DRD5 to affected children. Molecular Psychiatry. 1999, Vol. 4 Issue 2, p192. 5p. ↥
Gill, Daly, Heron, Hawi, Fitzgerald (1997): Confirmation of association between attention deficit hyperactivity disorder and a dopamine transporter polymorphism. Mol Psychiatry. 1997 Jul;2(4):311-3. ↥
Shook, Brady, Lee, Kenealy, Murphy, Gaillard, VanMeter, Cook, Stein, Vaidya (2011): Effect of dopamine transporter genotype on caudate volume in childhood ADHD and controls. Am. J. Med. Genet., 156: 28–35. doi:10.1002/ajmg.b.31132 ↥
Waldman, Rowe, Abramowitz, Kozel, Mohr, Sherman, Cleveland, Sanders, Gard, Stever (1998): Association and linkage of the dopamine transporter gene and attention-deficit hyperactivity disorder in children: Heterogeneity owing to diagnostic subtype and severity. Am J Hum Genet. 1998 Dec; 63(6): 1767–1776. doi: 10.1086/302132 ↥ ↥
Yang, Chan, Jing, Li, Sham, Chen (2007): A meta-analysis of association studies between the 10-repeat allele of a VNTR polymorphism in the 3′-UTR of dopamine transporter gene and attention deficit hyperactivity disorder. Am. J. Med. Genet., 144B: 541–550. doi:10.1002/ajmg.b.30453 ↥
Leo, Sukhanov, Zoratto, Illiano, Caffino, Sanna, Messa, Emanuele, Esposito, Dorofeikova, Budygin, Mus, Efimova, Niello, Espinoza, Sotnikova, Hoener, Laviola, Fumagalli, Adriani, Gainetdinov (2018): Pronounced Hyperactivity, Cognitive Dysfunctions, and BDNF Dysregulation in Dopamine Transporter Knock-out Rats; J Neurosci. 2018 Feb 21;38(8):1959-1972. doi: 10.1523/JNEUROSCI.1931-17.2018. ↥
Mereu, Contarini, Buonaguro, Latte, Managò, Iasevoli, de Bartolomeis, Papaleo (2017): Dopamine transporter (DAT) genetic hypofunction in mice produces alterations consistent with ADHD but not schizophrenia or bipolar disorder. Neuropharmacology. 2017 Jul 15;121:179-194. doi: 10.1016/j.neuropharm.2017.04.037. ↥
Krause, Krause (2014): ADHS im Erwachsenenalter, Schattauer, Seite 232, mit etlichen Nachweisen ↥
Dougherty, Bonab, Spencer, Rauch, Madras, Fischman (1999): Dopamine transporter density in patients with attention deficit hyperactivity disorder. Lancet 354: 2132-2133; Article (PDF Available) in The Lancet 354(9196):2132-3 · December 1999 with 294 Reads (Stand 10/2016); DOI: 10.1016/S0140-6736(99)04030-1 ↥
Diamond (2014): Biologische und soziale Einflüsse auf kognitive Kontrollprozesse, die vom präfrontalen Kortex abhängen; In: Kubesch (Herausgeberin): Exekutive Funktionen und Selbstregulation – Neurowissenschaftliche Grundlagen und Transfer in die pädagogische Praxis; Huber, Seite 22 ↥ ↥ ↥
Jucaite, Fernell, Halldin, Forssberg, Farde (2005): Reduced midbrain dopamine transporter binding in male adolescents with attention-deficit/hyperactivity disorder: Association between striatal dopamine markers and motor hyperactivity; Biological Psychiatry, Volume 57, Issue 3, 1 February 2005, Pages 229-238; https://doi.org/10.1016/j.biopsych.2004.11.009 ↥
Tammimaki, Aonurm-Helm, Zhang, Poutanen, Duran-Torres, Garcia-Horsman, Mannisto (2016): Generation of membrane-bound catechol-O-methyl transferase deficient mice with disctinct sex dependent behavioral phenotype. J Physiol Pharmacol. 2016 Dec;67(6):827-842. ↥
Milich, Balentine, Lynam (2001): ADHD Combined Type and ADHD Predominantly Inattentive Type Are Distinct and Unrelated Disorders. Clinical Psychology: Science and Practice, 8: 463–488. doi:10.1093/clipsy.8.4.463 ↥
Berridge, Devilbiss, Andrzejewski, Arnsten, Kelley, Schmeichel, Hamilton, Spencer (2006): Methylphenidate preferentially increases catecholamine neurotransmission within the prefrontal cortex at low doses that enhance cognitive function. Biol Psychiatry. 2006 Nov 15;60(10):1111-20. ↥
Diamond (2014): Biologische und soziale Einflüsse auf kognitive Kontrollprozesse, die vom präfrontalen Kortex abhängen; In: Kubesch (Herausgeberin): Exekutive Funktionen und Selbstregulation – Neurowissenschaftliche Grundlagen und Transfer in die pädagogische Praxis; Huber, Seite 23 ↥ ↥
Dela Peña, Botanas, de la Peña, Custodio, Dela Peña, Ryoo, Kim, Ryu, Kim, Cheong (2018): The Atxn7-overexpressing mice showed hyperactivity and impulsivity which were ameliorated by atomoxetine treatment: A possible animal model of the hyperactive-impulsive phenotype of ADHD. Prog Neuropsychopharmacol Biol Psychiatry. 2018 Aug 17;88:311-319. doi: 10.1016/j.pnpbp.2018.08.012. ↥ ↥ ↥
Sörös, Hoxhaj, Borel, Sadohara, Feige, Matthies, Müller, Bachmann, Schulze, Philipsen (2019): Hyperactivity/restlessness is associated with increased functional connectivity in adults with ADHD: a dimensional analysis of resting state fMRI. BMC Psychiatry. 2019 Jan 25;19(1):43. doi: 10.1186/s12888-019-2031-9. ↥
Ernst, Zametkin, Matochik, Jons, Cohen (1998): DOPA decarboxylase activity in attention deficit hyperactivity disorder adults. A (fluorine-18) fluorodopa positron emission tomographic study; J. Neurosci. 18, 5901-5907, 1998 zitiert nach Franck (2003): Hyperaktivität und Schizophrenie – eine explorative Studie; Dissertation, Seite 68 ↥
Castellanos, Elia, Kruesi, Marsh, Gulotta, Potter, Ritchie, Hamburger, Rapoport (1996): Cerebrospinal fluid homovanillic acid predicts behavioral response to stimulants in 45 boys with attention deficit/hyperactivity disorder. Neuropsychopharmacology. 1996 Feb;14(2):125-37. ↥
Castellanos, Elia, Kruesi, Gulotta, Mefford, Potter, Ritchie, Rapoport (1994): Cerebrospinal fluid monoamine metabolites in boys with attention-deficit hyperactivity disorder. Psychiatry Res. 1994 Jun;52(3):305-16. ↥
Ernst, Liebenauer, Tebeka, Jons, Eisenhofer, Murphy, Zametkin (1997): Selegiline in ADHD adults: Plasma monoamine and monoamine metabolites. Neuropsychopharmacology 16, 276-284, 1997, zitiert nach Franck (2003): Hyperaktivität und Schizophrenie – eine explorative Studie; Dissertation, Seite 68 ↥
Giros, Jaber, Jones, Wightman, Caron (1996): Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter. Nature. 1996 Feb 15;379(6566):606-12. doi: 10.1038/379606a0. PMID: 8628395. ↥
Viggiano, Grammatikopoulos, Sadile (2002): A morphometric evidence for a hyperfunctioning mesolimbic system in an animal model of ADHD. Behav Brain Res. 2002 Mar 10;130(1-2):181-9. doi: 10.1016/s0166-4328(01)00423-5. PMID: 11864733. ↥
Shaywitz, Yager, Klopper (1976): Selective brain dopamine depletion in developing rats: an experimental model of minimal brain dysfunction. Science. 1976 Jan 23;191(4224):305-8. doi: 10.1126/science.942800. PMID: 942800. ↥
Cardinal, Pennicott, Sugathapala, Robbins, Everitt (2001): Impulsive choice induced in rats by lesions of the nucleus accumbens core. Science. 2001 Jun 29;292(5526):2499-501. doi: 10.1126/science.1060818. PMID: 11375482. ↥
Clarke, Barry, Dupuy, Heckel, McCarthy, Selikowitz, Johnstone (2011): Behavioural differences between EEG-defined subgroups of children with attention-deficit/hyperactivity disorder. Clinical Neurophysiology, 122, 1333-1341. ↥
Clarke, Barry, Dupuy, McCarthy, Selikowitz, Johnstone (2013). Excess beta activity in the EEG of children with attention-deficit/hyperactivity disorder: a disorder of arousal? International Journal of Psychophysiology, 89, 314-319 ↥ ↥ ↥
Deiber, Hasler, Colin, Dayer, Aubry, Baggio, Perroud, Ros (2019): Linking alpha oscillations, attention and inhibitory control in adult ADHD with EEG neurofeedback. Neuroimage Clin. 2019 Dec 24;25:102145. doi: 10.1016/j.nicl.2019.102145. ↥
Sorokina, Saul, Goncalves, Gogola, Majdak, Rodriguez-Zas, Rhodes (2018): Striatal transcriptome of a mouse model of ADHD reveals a pattern of synaptic remodeling. PLoS One. 2018 Aug 15;13(8):e0201553. doi: 10.1371/journal.pone.0201553. eCollection 2018. ↥
Özyurt, Öztürk, Appak, Arslan, Baran, Karakoyun, Tufan, Pekcanlar (2018): Increased zonulin is associated with hyperactivity and social dysfunctions in children with attention deficit hyperactivity disorder. Compr Psychiatry. 2018 Nov;87:138-142. doi: 10.1016/j.comppsych.2018.10.006. n = 81 ↥
Gentile, Simmons, Watson, Connelly, Brailoiu, Zhang, Muschamp (2018): Effects of Suvorexant, a Dual Orexin/Hypocretin Receptor Antagonist, on Impulsive Behavior Associated with Cocaine. Neuropsychopharmacology. 2018 Apr;43(5):1001-1009. doi: 10.1038/npp.2017.158. ↥
Regan, Hufgard, Pitzer, Sugimoto, Hu, Williams, Vorhees (2019): Knockout of latrophilin-3 in Sprague-Dawley rats causes hyperactivity, hyper-reactivity, under-response to amphetamine, and disrupted dopamine markers. Neurobiol Dis. 2019 Jun 6:104494. doi: 10.1016/j.nbd.2019.104494. ↥
Montarolo, Martire, Perga, Spadaro, Brescia, Allegra, De Francia, Bertolotto (2019): NURR1 deficiency is associated to ADHD-like phenotypes in mice. Transl Psychiatry. 2019 Aug 27;9(1):207. doi: 10.1038/s41398-019-0544-0. ↥
Dorninger, Gundacker, Zeitler, Pollak, Berger (2019): Ether Lipid Deficiency in Mice Produces a Complex Behavioral Phenotype Mimicking Aspects of Human Psychiatric Disorders. Int J Mol Sci. 2019 Aug 13;20(16). pii: E3929. doi: 10.3390/ijms20163929. ↥
Dorninger, König, Scholze, Berger, Zeitler, Wiesinger, Gundacker, Pollak, Huck, Just, Forss-Petter, Pifl, Berger (2019): Disturbed neurotransmitter homeostasis in ether lipid deficiency. Hum Mol Genet. 2019 Jun 15;28(12):2046-2061. doi: 10.1093/hmg/ddz040. ↥
Yektaş, Alpay, Tufan (2019): Comparison of serum B12, folate and homocysteine concentrations in children with autism spectrum disorder or attention deficit hyperactivity disorder and healthy controls. Neuropsychiatr Dis Treat. 2019 Aug 6;15:2213-2219. doi: 10.2147/NDT.S212361. eCollection 2019. ↥ ↥
Saha, Chatterjee, Verma, Ray, Sinha, Rajamma, Mukhopadhyay (2018): Genetic variants of the folate metabolic system and mild hyperhomocysteinemia may affect ADHD associated behavioral problems. Prog Neuropsychopharmacol Biol Psychiatry. 2018 Jun 8;84(Pt A):1-10. doi: 10.1016/j.pnpbp.2018.01.016. ↥
Pusceddu, Herrmann, Kleber, Scharnagl, März, Herrmann (2019): Telomere length, vitamin B12 and mortality in persons undergoing coronary angiography: the Ludwigshafen risk and cardiovascular health study. Aging (Albany NY). 2019 Sep 6;11(17):7083-7097. doi: 10.18632/aging.102238. ↥
Kleberg, Frick, Brocki (2020): Increased pupil dilation to happy faces in children with hyperactive/impulsive symptoms of ADHD. Dev Psychopathol. 2020 Feb 27:1-11. doi: 10.1017/S0954579420000036. PMID: 32102703. n = 71 ↥
Jakobi, Arias-Vasquez, Hermans, Vlaming, Buitelaar, Franke, Hoogman, van Rooij (2022): Neural Correlates of Reactive Aggression in Adult Attention-Deficit/Hyperactivity Disorder. Front Psychiatry. 2022 May 19;13:840095. doi: 10.3389/fpsyt.2022.840095. PMID: 35664483; PMCID: PMC9160326. ↥
Lee, Pei, Moszczynska, Vukusic, Fletcher, Liu (2007): Dopamine transporter cell surface localization facilitated by a direct interaction with the dopamine D2 receptor. EMBO J. 2007;26(8):2127–2136. doi:10.1038/sj.emboj.7601656 ↥
Lasky-Su, Lange, Biederman, Tsuang, Doyle, Smoller, Laird, Faraone (2008): Family-based association analysis of a statistically derived quantitative traits for ADHD reveal an association in DRD4 With inattentive symptoms in ADHD individuals. Am. J. Med. Genet., 147B: 100–106. doi:10.1002/ajmg.b.30567 ↥
Auerbach, Benjamin, Faroy, Geller, Ebstein (2001): DRD4 related to infant attention and information processing: a developmental link to ADHD? Psychiatric Genetics: March 2001 – Volume 11 – Issue 1 – p 31-3 ↥
Rowe, Stever, Giedinghagen, Gard, Cleveland, Terris, Mohr, Sherman, Abramowitz, Waldman (1998): Dopamine DRD4 receptor polymorphism and attention deficit hyperactivity disorder. ID.Mol Psychiatry. 1998 Sep;3(5):419-26. ↥
Bellgrove, Hawi, Lowe, Kirley, Robertson, Gill (2005): DRD4 gene variants and sustained attention in attention deficit hyperactivity disorder (ADHD): Effects of associated alleles at the VNTR and −521 SNP†; American journal of medical genetics, Volume 136B, Issue 1, 5 July 2005, Pages 81–86; DOI: 10.1002/ajmg.b.30193 ↥
Johnson, Kelly, Robertson, Barry, Mulligan, Daly, Lambert, McDonnell, Connor, Hawi, Gill, Bellgrove (2008): Absence of the 7-repeat variant of the DRD4 VNTR is associated with drifting sustained attention in children with ADHD but not in controls; American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 147B, 6, 927-937; doi = 10.1002/ajmg.b.30718 ↥
Krämer, Rojo, Schüle, Cunillera, Schöls, Marco-Pallarés, Cucurell, Camara, Rodriguez-Fornells Münte (2009): ADHD candidate gene (DRD4 exon III) affects inhibitory control in a healthy sample; BMC Neuroscience200910:150; https://doi.org/10.1186/1471-2202-10-150 ↥
Pontzer, Wood (2021): Effects of Evolution, Ecology, and Economy on Human Diet: Insights from Hunter-Gatherers and Other Small-Scale Societies. Annu Rev Nutr. 2021 Oct 11;41:363-385. doi: 10.1146/annurev-nutr-111120-105520. PMID: 34138633. ↥
Dugas, Harders, Merrill, Ebersole, Shoham, Rush, Assah, Forrester, Durazo-Arvizu, Luke (2011): Energy expenditure in adults living in developing compared with industrialized countries: a meta-analysis of doubly labeled water studies. Am J Clin Nutr. 2011 Feb;93(2):427-41. doi: 10.3945/ajcn.110.007278. PMID: 21159791; PMCID: PMC3021434. METASTUDIE ↥