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Drive problems in ADHD - neurophysiological correlates


Drive problems in ADHD - neurophysiological correlates

Drive is the ability and will to engage in goal-oriented activity. Drive disorders can manifest themselves in the form of inhibition (e.g. depression) or restless impulsiveness (e.g. ADHD).
Motivation, on the other hand, is a current process that is triggered by the stimulation of a motive. A motive is a persistent characteristic of a person. Motivation is therefore a state of a person at a certain point in time, i.e. in a certain situation.

Neurologically, drive problems are primarily associated with the striatum, the reinforcement center of the brain.

1. Anhedonia as a result of dopamine deficiency, among other things

Anhedonia is an impaired ability to experience positive emotions, the loss of the ability to feel joy in situations that used to bring joy.

Anhedonia correlates with:

  • reduced dopamine levels1
    • in the mesocorticolimbic system (mPFC, VTA, NAc)
    • in the nucleus accumbens
  • Deficits in the processing of reward information2
  • reduced activity in the nucleus accumbens34
  • Changes in neurotransmitter levels in the nucleus accumbens of DA, 5-HT and noradrenaline4
  • increased expression of Glu1 receptors in the nucleus accumbens5
  • reduced expression of Glu2 receptors in the nucleus accumbens5
  • reduced NMDA-2B receptor expression in the nucleus accumbens6
  • reduced functional connectivity
    • of the posterior vmPFC (seed region) and NAc, VTA/Substantia nigra, OFC (left) and insula (right)7
    • of the right NAc nucleus with the left middle anterior OFC and the right inferior parietal lobe in MDD8

In many psychological problems where the drive to obtain pleasurable things is reduced, the PFC is overexcited. In an overexcited state (characterized by increased dopamine and noradrenaline levels), it signals to the nucleus accumbens in the striatum that further effort is not worthwhile. The nucleus accumbens then reduces its dopaminergic activity - with the result that rewards no longer seem so appealing. If the overexcitation of the PFC is stopped, the nucleus accumbens is once again open to stimulation and can reactivate the motivation to strive for things that promise pleasure. In summary, a lot of dopamine in the (m)PFC reduces the dopamine level in the striatum.9101112

An article in Heise, written in a way that is wonderfully understandable even for laypeople, explains this interaction of an overexcited PFC and an underactivated nucleus accumbens (part of the striatum) in relation to anhedonia and motivation problems.13

Conversely, reduced activity of dopamine transporters (which is the result of downregulation due to increased dopamine levels, but can also occur for other reasons) causes increased motivation, as is known in bipolar disorders in manic phases.14
The results on the number of DAT in ADHD are inconsistent (see above).

2. Reward discounting due to dopamine deficiency and hypoactivity in the striatum

Adults with ADHD showed reduced activation in a number of brain regions (including the dorsolateral PFC, anterior frontal gyrus, ACC, caudate nucleus and cerebellum) during a delay discounting task under fMRI. At the same time, the extent to which those affected discounted (devalued) delayed rewards was associated with reduced activation of the cerebellum. As a result, the striatum was underactivated in relation to reward anticipation and the dorsolateral PFC and the orbitofrontal cortex were overactivated in relation to reward acceptance.15

The brain’s reinforcement center is located in the nucleus accumbens, a part of the striatum, which is part of the basal ganglia. A reduced number of dopamine D2 and D3 receptors in the reward center of the brain in ADHD sufferers means that fewer things are found rewarding, i.e. sufficiently exciting, than in non-affected people.16 Children with ADHD show a flattened dopaminergic mesolimbic reactivity to stimuli/expectation of reward in the ventral striatum.1718 The severity of ADHD symptoms correlated with hypoactivation of the right nucleus accumbens during reward anticipation.19

The level of motivational problems (as well as the level of inattention) in ADHD correlated with a reduced number of D2 and D3 dopamine receptors in the striatum. In contrast, other altered personality parameters in ADHD did not correlate with the number of D2 and D3 receptors.2016

3. GABA deficiency reduces drive for long-term goals

GABA deficiency in the PFC and hippocampus appears to correlate with drive problems related to long-term rewards, although GABA deficiency is not associated with anhedonia or behavioral depression. Mice with reduced GABA levels in the hippocampus and cortex (esp. mPFC) showed a range of effort-related behavioral deficits that could not be explained by anhedonia or behavioral despair. Dopamine in the anterior cingulate cortex (ACC) is involved in evaluating the effort cost of performing actions. Cortical GABA reduction, through a deficit in ACC dopamine release, appears to primarily affect effort-based behaviors that require a lot of effort with little benefit and are not triggered by reward-oriented behavior.21
GAD67 is an enzyme that converts glutamate to GABA and is controlled by the GAD1 and GAD2 genes. A cortical GAD67 reduction with a simultaneous decrease in GABA levels is frequently observed in schizophrenia and depression.

  1. Rodrigues, Leão, Carvalho, Almeida, Sousa (2010): Potential programming of dopaminergic circuits by early life stress. Psychopharmacology (Berl). 2011 Mar;214(1):107-20. doi: 10.1007/s00213-010-2085-3.

  2. Höflich A, Michenthaler P, Kasper S, Lanzenberger R (2019): Circuit Mechanisms of Reward, Anhedonia, and Depression. Int J Neuropsychopharmacol. 2019 Feb 1;22(2):105-118. doi: 10.1093/ijnp/pyy081. PMID: 30239748; PMCID: PMC6368373.

  3. Keller J, Young CB, Kelley E, Prater K, Levitin DJ, Menon V (2013): Trait anhedonia is associated with reduced reactivity and connectivity of mesolimbic and paralimbic reward pathways. J Psychiatr Res. 2013 Oct;47(10):1319-28. doi: 10.1016/j.jpsychires.2013.05.015. PMID: 23791396.

  4. Wang S, Leri F, Rizvi SJ (2021): Anhedonia as a central factor in depression: Neural mechanisms revealed from preclinical to clinical evidence. Prog Neuropsychopharmacol Biol Psychiatry. 2021 Aug 30;110:110289. doi: 10.1016/j.pnpbp.2021.110289. PMID: 33631251. REVIEW

  5. Todtenkopf MS, Parsegian A, Naydenov A, Neve RL, Konradi C, Carlezon WA Jr (2006): Brain reward regulated by AMPA receptor subunits in nucleus accumbens shell. J Neurosci. 2006 Nov 8;26(45):11665-9. doi: 10.1523/JNEUROSCI.3070-06.2006. PMID: 17093088; PMCID: PMC4205583.

  6. Jiang B, Wang W, Wang F, Hu ZL, Xiao JL, Yang S, Zhang J, Peng XZ, Wang JH, Chen JG (2013): The stability of NR2B in the nucleus accumbens controls behavioral and synaptic adaptations to chronic stress. Biol Psychiatry. 2013 Jul 15;74(2):145-55. doi: 10.1016/j.biopsych.2012.10.031. PMID: 23260228.

  7. Young CB, Chen T, Nusslock R, Keller J, Schatzberg AF, Menon V (2016): Anhedonia and general distress show dissociable ventromedial prefrontal cortex connectivity in major depressive disorder. Transl Psychiatry. 2016 May 17;6(5):e810. doi: 10.1038/tp.2016.80. PMID: 27187232; PMCID: PMC5070048.

  8. Liu R, Wang Y, Chen X, Zhang Z, Xiao L, Zhou Y (2021): Anhedonia correlates with functional connectivity of the nucleus accumbens subregions in patients with major depressive disorder. Neuroimage Clin. 2021;30:102599. doi: 10.1016/j.nicl.2021.102599. PMID: 33662708; PMCID: PMC7930634.

  9. Ferenczi, Zalocusky, Liston, Grosenick, Warden, Amatya, Katovich, Mehta, Patenaude, Ramakrishnan, Kalanithi, Etkin, Knutson, Glover, Deisseroth (2016): Prefrontal cortical regulation of brainwide circuit dynamics and reward-related behavior. Science. 2016 Jan 1;351(6268):aac9698. doi: 10.1126/science.aac9698

  10. Heinz (2000): Das dopaminerge Verstärkungssystem, Seite 10

  11. Kolachana, Saunders, Weinberger (1995): Augmentation of prefrontal cortical monoaminergic activity inhibits dopamine release in the caudate nucleus: an in vivo neurochemical assessment in the rhesus monkey. Neuroscience. 1995 Dec;69(3):859-68.

  12. Louilot, Le Moal, Simon (1989): Opposite influences of dopaminergic pathways to the prefrontal cortex or the septum on the dopaminergic transmission in the nucleus accumbens. An in vivo voltammetric study. Neuroscience. 1989;29(1):45-56.

  13. Lehmann (2016): Warum nicht einfach aufgeben?

  14. Milienne-Petiot, Kesby, Graves, van Enkhuizen, Semenova, Minassian, Markou, Geyer, Young (2016): The effects of reduced dopamine transporter function and chronic lithium on motivation, probabilistic learning, and neurochemistry in mice: Modeling bipolar mania; Neuropharmacology. 2016 Oct 11;113(Pt A):260-270. doi: 10.1016/j.neuropharm.2016.07.030

  15. Ortiz, Parsons, Whelan, Brennan, Agan, O’Connell, Bramham, Garavan (2015): Decreased frontal, striatal and cerebellar activation in adults with ADHD during an adaptive delay discounting task. Acta Neurobiol Exp (Wars). 2015;75(3):326-38. n = 21

  16. Friedmann (2014): A Natural Fix for A.D.H.D.; New York Times Online

  17. Scheres, Milham, Knutson, Castellanos (2007): Ventral striatal hyporesponsiveness during reward anticipation in attention-deficit/hyperactivity disorder. Biol Psychiatry. 2007 Mar 1;61(5):720-4. doi: 10.1016/j.biopsych.2006.04.042. PMID: 16950228.

  18. Durston, Tottenham, Thomas, Davidson, Eigsti, Yang, Ulug, Casey (2003): Differential patterns of striatal activation in young children with and without ADHD. Biol Psychiatry. 2003 May 15;53(10):871-8. doi: 10.1016/s0006-3223(02)01904-2. PMID: 12742674.

  19. Akkermans, van Rooij, Naaijen, Forde, Boecker-Schlier, Openneer, Dietrich, Hoekstra, Buitelaar (2019): Neural reward processing in paediatric Tourette syndrome and/or attention-deficit/hyperactivity disorder. Psychiatry Res Neuroimaging. 2019 Aug 14;292:13-22. doi: 10.1016/j.pscychresns.2019.08.004.

  20. Volkow, Wang, Newcorn, Kollins, Wigal, Telang, Fowler, Goldstein, Klein, Logan, Wong, Swanson (2011): Motivation deficit in ADHD is associated with dysfunction of the dopamine reward pathway; Mol Psychiatry. 2011 Nov;16(11):1147-54. doi: 10.1038/mp.2010.97.

  21. Kolata, Nakao, Jeevakumar, Farmer-Alroth, Fujita, Bartley, Jiang, Rompala, Sorge, Jimenez, Martinowich, Mateo, Hashimoto, Dobrunz, Nakazawa (2018): Neuropsychiatric Phenotypes Produced by GABA Reduction in Mouse Cortex and Hippocampus. Neuropsychopharmacology. 2018 May;43(6):1445-1456. doi: 10.1038/npp.2017.296.