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Neurophysiological correlates of attention problems in ADHD.


Neurophysiological correlates of attention problems in ADHD.

There are several types of attention. Focusing on single, specific stimuli is a different form of attention than the rambling awareness of new stimuli. The former is associated with concentration, the latter with distractibility.

1. Attention problems in ADHD are located in the PFC

Inattention is primarily caused by the dlPFC.1 In ADHD, functions in the PFC and in closely related cortical and subcortical regions are weaker, especially in the right hemisphere.2

Whereas the dlPFC accommodates working memory (sustained attention and executive problems = problem-solving behavior) (for review, see Neurophysiological correlates of working memory problems in ADHD) Selective attention is thought to be modulated by a cortico-striato-thalamo-cortical loop originating in the dorsal anterior cingulate cortex (dACC) and projecting to the striatum, then to the thalamus, and back to the dACC. Inefficient activation of the dACC can lead to ADHD-type symptoms,3 such as.

  • Too little attention to detail
  • Negligence error
  • Not listening
  • Lose things
  • Get distracted
  • Things forgotten

A significant increase in BOLD activation between interference and noninterference conditions in the dorsal anterior cingulate cortex (dACC, Brodmann area 32) correlated with scores on the inattention and hyperactivity subscales of the ADHD self-report scales in ADHD sufferers as well as nonaffected individuals.4

Selective attention is said to be particularly well studied with the Stroop test.3
For more on the Stroop test, see Stroop Test In the subsection Attention and reaction tests in the section Tests in the section ADHD - Diagnostic methods in the section Diagnostics.

The right cerebral hemisphere regulates the inhibition of inappropriate behavioral and emotional responses. The (right) dlPFC regulates behavior in addition to sustained attention. Injuries in the right dlPFC cause attentional problems (along with attention direction and task switching problems), filtering problems, and impulse control problems.2567

Emotion regulation, on the other hand, occurs through the ventrolateral PFC.28

1.1. ACTH impairs concentration, increases distractibility

ACTH is a hormone secreted by the pituitary gland, the 2nd stage of the HPA axis, as part of its stress response. ACTH impairs selective and focused attention and causes an altered working mode in the PFC, where inhibition of the processing of “irrelevant” stimuli is reduced.
See more at *⇒ ACTH was probably conducive to survival in the millions of years of nomadic hominids. We therefore regard the effects of ACTH not as harm but as benefit - even if this stress benefit has become less useful since the enemies are no longer saber-toothed tigers and hostile tribes but deadline stress and overflowing mail accounts.

Cortisol, on the other hand, influences memory more than attention.

2. D4 receptor abnormalities correlate with inattention

In humans, the DRD4 receptor is found exclusively in the PFC, but not in the striatum.910

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):

  • DRD4 7-repeat allele1112
  • Single nucleotide polymorphisms (SNP) in the promoter region of DRD413

DRD4-7R consequently does not correlate with hyperactivity or impulsivity.141516

3. D2/D3 receptor deficiency in the striatum and inattention

The brain’s reinforcement center (the term reward center is inappropriate, because it not only rewards pleasant experiences but influences every form of action) is located in the nucleus accumbens, a part of the striatum, which in turn is part of the basal ganglia. A reduced number of dopamine D2 and D3 receptors in the striatum in ADHD sufferers means that less dopamine can be taken up there from the synaptic cleft, which is why fewer things are found (rewarding), as sufficiently exciting, than in non-affected individuals. The level of motivational problems as well as the level of inattention in ADHD correlate with the reduced number of D2 and D3 dopamine receptors in the brain’s reinforcement center. In contrast, other altered personality parameters in ADHD did not correlate with the number of D2 and D3 receptors.1718
This view leads first to the finding that attentional problems are not exclusively mediated by the PFC, but also by the striatum.
According to another account, blockade of dopamine D1, D2, and D4 receptors by corresponding antagonists does not improve attention or response inhibition.19

Agonists such as antagonists of the D3 receptor improve slowing after errors and compulsive nose-poke behavior, but impair performance on other tasks.19

4. Blockages in thinking / inability to make decisions due to PFC deactivation

While slightly elevated levels of dopamine and norepinephrine, such as occur during mild and manageable stress, increase the performance of the PFC, norepinephrine and dopamine levels, which continue to rise at even higher levels of stress (especially unmanageable threatening stress), cause the PFC to shut down and shift behavioral control to other brain regions.
In the case of on norepinephrine, this occurs via the noradrenergic α-1 receptors, which have a lower affinity for norepinephrine than α-1 and β receptors and are therefore activated only by very high levels of norepinephrine. α1-Receptor agonists such as phenylephrine or (at high concentrations) SKF81297 can mimic these effects of high NA and DA levels, respectively.20 Agonists stimulate the receptors.
α1-Receptor agonists drive down the PFC in this manner.2021

Cortisol also addresses noradrenergic α-1 receptors, enhancing the PFC-deactivating effect of high noradrenaline levels.

A similar model is found for cortisol, which controls the “normal” mode at high-affinity mineralocorticoid receptors and shuts down the HPA axis only at high levels at low-affinity glucocorticoid receptors.

5. Distractibility from PFC, inattention from boredom from striatum?

This may be due to the different character of attention problems in the different subtypes. Whereas in hyperactivity inattention is mainly provoked by high distractibility, ADHD-I sufferers (without hyperactivity) tend to be quickly bored and therefore turn their attention quickly to new stimuli. This pattern may well be understood as a motivational problem located in the striatum.

We therefore form the following working hypothesis:

  1. Attention problems in ADHD-HI and ADHD-C (with hyperactivity) result from the ADHD-HI-typical overactivation of the PFC and are therefore more characterized by distractibility
  2. Attention problems in ADHD-I (with no or little hyperactivity) result from the ADHD-I-typical underactivation of the PFC, are therefore more motivationally characterized, characterized by boredom, and are neurophysiologically more strongly located in the striatum.

We suggest that ADHD-HI and ADHD-C are characterized by sustained mild (in the sense of: below the levels that would cause PFC shutdown) stimulation of the PFC by dopamine and norepinephrine, whereas ADHD-I and SCT are characterized by very strong stimulation by norepinephrine and dopamine during stress, which causes frequent PFC shutdown via alpha-1 adrenoceptors.
⇒ section Neurophysiological and endocrine differences between ADHD-HI/ADHD-C and ADHD-I in post The subtypes of ADHD: ADHD-HI, ADHD-I, SCT, and others
Neurophysiological correlates of thinking blocks and decision problems

Volkow’s discussion can be easily reconciled with this.22

Differences exist in regions of the dopaminergic reinforcement system on the left side of the brain, all of which correlate with attention problems (r = 0.3 to 0.35).23

5.1. Overexpression of the THRSP gene and inattention

According to a study, overexpression of the thyroid hormone responsive gene (THRSP) in the striatum leads to the development of a pure inattentive phenotype in mice.24 THRSP overexpression correlated with overexpression of dopaminergic genes (DAT, tyrosine hydroxylase, dopamine D1 and D2 receptors) in the striatum. Methylphenidate improved attention and normalized the expression levels of dopaminergic genes in the THRSP OE mice.

6. Attention and brain networks

6.1. Connectivity of the cerebellum with the noradrenergic attentional center and the default mode network

Functional connectivity of the cerebellum to the anterior and posterior DAN (dorsal noradrenergic attention center) and DMN (default mode network) correlates with attention. Decreased connectivity decreases attention.25

The noradrenergic attention center controls selective attention.
The dopaminergic and noradrenergic attentional centers

For more on the aberrant function of the DMN in ADHD and its normalization by stimulants, including further references, see DMN (Default Mode Network) In the article Neurophysiological correlates of hyperactivity.

Another study reports a Default Mode Network (DMN) and Task Positive Network (TPN) network showing significant deviations in inattention. In inattention, there was a negative correlation between delta in the anterior cingulate and precuneus and delta and theta in the mPFC and alpha and gamma in medial frontal regions.26

One study found hierarchical functional integration of the DMN decreased and segregation (= separation, splitting) of the DMN increased in AD(HHD). According to this, the abnormalities in the DMN in ADHD are thought to be caused by changes in functional segregation and integration into its higher-level subnetworks. The adaptive reorganization capacity of brain network states was reduced in ADHD sufferers, and therefore reduced adaptive regulation between DMN subnetworks in ADHD was hypothesized to support correspondingly normal cognitive functions.27

6.2. Decreased connectivity in the dorsal frontoparietal executive network

One study reports decreased connectivity in the dorsal frontoparietal executive network, consisting of

  • Right dlPFC
  • Posterior parietal cortex

which correlated with the severity of attention problems in ADHD. This correlation was independent of age or gender.
Increased connectivity was also associated with increased attention and better accuracy on NoGo tasks.28

In addition, deviations in the connectivity of the Salience network, consisting of

  • Right anterior insula
  • Right dorsal anterior cingulate cortex (rdACC)
  • Right ventrolateral PFC (rvlPFC)

6.3. Low fractional anisotropy

A reduction in “fractional anisotropy” was associated with decreased attention in a study of brain white matter.29

Another study found that in children with as well as without ADHD, mean fractional anisotropy in inattention correlated with significantly increased lateralization of the external capsule (“external capsule”).30

7. EEG and attention

7.1. Alpha modulation in response to human eye gaze correlates with severity of inattention

In children with ADHD, the measure of inverse alpha activity in the left parieto-occipital brain region compared with unaffected individuals is thought to predict the severity of inattention.31

7.2. Decreased 12-HZ spindles in sleep phase 2 in frontal EEG

12-HZ spindles in stable non-REM sleep relative to 14-HZ spindles in frontal EEG correlated negatively with inattention and positively with reaction time variability.32

7.3. Current density of delta, theta, and alpha in the parietal lobe

One study reported significant differences in current density of the delta, theta, and alpha frequency bands in the parietal lobe between children with ADHD and those not affected. This correlates with problems in shifting attention.33

7.4. Smaller amplitudes and longer P-300 latency for event-related potentials

Attention deficits are reported to be associated with smaller amplitudes and P300 waves with longer latency in event-related potentials.34

8. Proactive - not reactive - cognitive control impaired

One study found evidence of problems with proactive cognitive control in ADHD, but less so with reactive cognitive control.35 Proactive control is understood as a form of active, goal-relevant information activation and maintenance in preparation for cognitively challenging events. Reactive control, on the other hand, involves the reactivation of temporary goal-relevant information following the detection of interference and its resolution.

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  25. Rohr, Dimond, Schuetze, Cho, Lichtenstein-Vidne, Okon-Singer, Dewey, Bray (2019): Girls’ attentive traits associate with cerebellar to dorsal attention and default mode network connectivity. Neuropsychologia. 2019 Feb 20;127:84-92. doi: 10.1016/j.neuropsychologia.2019.02.011. n = 52

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