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Learning problems in ADHD - neurophysiological correlates

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Learning problems in ADHD - neurophysiological correlates

Learning problems are very common with ADHD. Learning here does not just mean learning vocabulary or formulas during school, but much more generally the acquisition of helpful behaviors to avoid or solve problems. Many people with ADHD reported that even as adults they are unable to learn from mistakes. They make a mistake over and over again, even though they realize at the same time that they are repeating the mistake.
In ADHD, the level of growth hormones is often reduced. Growth hormones and neurotrophic substances such as BDNF and dopamine are essential for the neuroplasticity of the brain. Stimulants increase the levels of growth hormones and thus improve neuroplasticity. According to a study, atomoxetine can restore long-term potentiation.1 Since dopamine is essential for neuronal plasticity (the production of new synaptic connections) and stimulants, like atomoxetine, increase the dopamine levels that are reduced in ADHD, stimulants also have the effect of promoting learning behavior.

This explains why stimulants for ADHD can improve the conditions for subsequent successful psychotherapy. If the ability to learn is impaired due to a lack of neuroplasticity in the brain, the normal ability to learn from experience is reduced. This means that people with ADHD are unable to learn from bad experiences in order to avoid them in the future.

Consequently, the same people with ADHD who suffered from making the same mistakes over and over again before their medication told us that they could now avoid mistakes and not keep repeating them.

Memory is divided into different functions:2

  • Short-term memory
    • Processes and remembers recorded information from the last few minutes
  • Long-term memory
    • Processes and remembers hours, days, months or the whole life
  • Implicit memory
    • Includes simple classical conditioning, non-associative learning, perceptual skills and motor skills, such as riding a bike or playing the piano
  • Declarative memory
    • Stores information about specific events and the associated temporal and personal associations. Is needed to recognize people, faces and places or to remember events from one’s own past. Includes sensory perception, feelings and motivations.

Learning and motivation are complementary functions of a cycle. Motivation is future-oriented. Motivation uses predictions about future rewards (values) to guide motivation and drive for current behavior. Learning is past-oriented. Learning uses the evaluation of states and actions of the recent past and updates their values. The values updated through learning can be used in subsequent motivational decision making. If the initiated (non-)behavior now initiates other results, this leads to an update of the (learning) evaluation.3

Memory processes in the PFC are primarily processed in Brodman area 10 (BA 10, anterior PFC).4 Motor functions are controlled by BA 8, emotions by BA 9 and emotion-related sensory functions by BA 11.

1. Learning: Synaptic plasticity through long-term potentiation (LTP) or long-term depression (LTD)

1.1. Long-term potentiation (LTP)

Long-term potentiation (LTP), particularly in the hippocampus and PFC, is considered to be the main mechanism for long-term memory. LTP is triggered by activation of NMDA receptors (a special glutamate receptor). Glutamate is the excitatory (activating) counterpart of the inhibitory (inhibiting) GABA. GABA and glutamate form a system that is in balance in a healthy state. In many mental disorders there is an imbalance between GABA and glutamate.5 GABA inhibits the LTP.6 In addition, a medium dopamine level is required for the induction of long-term potentiation (see below).

LTP is typically induced by series of high-frequency stimuli to presynaptic fibers. For LTP to occur, the postsynaptic cell at a synapse must be depolarized at the exact moment when transmitter is released from the presynaptic cell.7

In the hippocampus, stimuli at 50 Hz (γ-band) excite LTP.8

Dopamine modulates synaptic plasticity in the striatum. The combination of the 3 factors

  • Glutamate stimulation of a striatal dendritic spine process
  • postsynaptic depolarization
  • Dopamine release

causes the dendritic spine to grow, provided that the dopamine release occurs a maximum of 0.3 to 2 seconds after gluatergic stimulation.9

1.2. Long-term depression (LTD)

Long-term depression has nothing to do with the mental disorder depression, but describes a permanent weakening of signal transmission at the synapses of nerve cells. It is just as important for learning processes as LTP and is not merely a reversal process.

In the laboratory, rat PFC tissue showed either no LTP (rows repeated 4 times) or induced LTD (rows repeated 6 times) in response to stimuli at 50 Hz on presynaptic filters of layer I-II of rats. This is attributed to low extracellular dopamine levels. In contrast, live rats with intermediate extracellular dopamine levels show normal LTP in the PFC on 50 Hz stimuli.8

2. Neurotrophins for learning and memory processes

The most important substances in the brain for learning and memory processes are neurotrophins. The most important neurotrophin is BDNF.
BDNF is reduced by stress. BDNF is also reduced in ADHD.
Find out more at BDNF.

Stress reduces the BDNF level in the hippocampus.10 Various antidepressants, on the other hand, increase it. Conversely, direct administration of BDNF to the hippocampus reduces depressive symptoms in rats.

BDNF is said to be reduced in ADHD.11 Some other studies found no evidence of reduced BDNF in ADHD.

3. Neurotransmitters for learning and memory processes

The most important neurotransmitters for learning and memory processes are

  • Glutamate (especially the NMDA receptor)
  • GABA
  • Serotonin
  • Dopamine
  • Acetylcholine

3.1. Dopamine

Dopamine is relevant for synaptic plasticity in the PFC and striatum, among others.12131415163

Among other things, the PFC forms the long-term memory for abstract rules or strategies by means of long-term potentiation (LTP) as a form of synaptic plasticity.

Moderate tonic dopamine levels facilitate the induction of LTP, dopamine levels that are too high or too low worsen it (inverted U function).81718

The induction of LTD (“forgetting”) by low-frequency stimuli occurs independently of tonic dopamine through endogenous, phasically released dopamine during the stimuli. LTP (“learning”) is inhibited by

  • Blockade of the dopamine receptors during the stimuli
  • Inhibition of dopamine transporter activity.

In response to a reward, dopaminergic cells in the nucleus accumbens fire for as long as associative learning takes place. This enables the individual to automate behavioral control in relation to the reward stimulus (= learning). This process appears to be deficient in ADHD, in that dopamine deficiency in the nucleus accumbens causes difficulty in associating behavioral contingencies with reward, reducing the amount of time a child with ADHD can associate behavioral contingencies with a reward.19

In ADHD, a delayed reward for a behavior means that the association between the behavior and the potential reward cannot be learned - unlike in non-affected people, who can make this association over longer periods of time. This explains the devaluation of delayed rewards in ADHD as well as the typical learning problems.20

Drugs that, like stimulants, increase dopamine levels in the nucleus accumbens thereby extend the reinforcement gradient, providing more time for the associations between behavior and reward necessary for learning to develop. Drugs can therefore normalize the reinforcement gradient so that more normal learning is possible.21

3.1.1. Phasic dopamine = learning, tonic dopamine = motivation?

The previous view that phasic dopamine controls reward anticipation and thus learning, while tonic dopamine represents motivation, is being called into question:3

  • variation in tonic dopamine cell firing over longer time scales has not yet been demonstrated

  • the firing rates of dopaminergic cells do not change with changing motivation2223

  • a change in the proportion of active dopamine cells (i.e. a change from an active to an inactive state of dopaminergic neurons, which could control the amount of tonic dopamine) has so far only been demonstrated as a result of medication or drug administration, but not in the case of changes in motivation24

  • Dopamine level changes correspond to the approach to a goal (dopamine ramps) and are highest at the moment of goal achievement, not motivation2526

3.1.2. Dopamine as a neurotrophic factor

As explained above, dopamine has a neurotrophic effect, i.e. it increases neuroplasticity. Neuroplasticity is the prerequisite for learning adaptations in the brain.

Acute or short-term stress increases dopamine or dopaminergic activity in the midbrain. This appears to promote reward-related neuronal connectivity by enhancing the learning of associations between cue and reward 2728

Conversely, dopamine deficiency, such as that caused by chronic stress or ADHD, correlates with learning problems.

3.2. Glutamate

If the NMDA receptors and long-term potentiation in the CA1 region of the hippocampus are impaired, this leads to inadequate storage and memory of spatial information.
If glutamate receptors are overstimulated, this leads to injury or death of the corresponding nerve cell, probably due to excessive CA2+ influx.5

3.3. GABA

GABA is formed in the adrenal gland and is controlled in the same way as cortisol.

Blocking the GABA-A alpha5 receptors improves learning and memory.5 GABA-A alpha5 receptors are mainly located in the hippocampus.

3.3.1. GABA-A agonists impair learning and memory

Long-term exposure to GABA-A receptor agonists, for example allopregnanolone, benzodiazepines, barbiturates or alcohol

  • Reduced the activity of the hippocampus
  • Reduced the long-term potentiation (LTP) in the hippocampus (especially through propofol and THDOC (tetrahydrodeoxycorticosterone))
  • Impaired cholinergic processes in the hippocampus in relation to memory

and resulted in persistent learning and memory difficulties.5

Cortisol degradation products further increased the effect of allopregnanolone on the GABA-A receptors.
An allopregnanolone antagonist prevented the impairing effect of allopregnanolone on learning and memory processes.
Chronically elevated cortisol and GABA levels caused irreparable cognitive damage. Stress increased cortisol and GABA levels.5

The sex steroid medroxyprogesterone, a metabolite (breakdown product) of allopregnanolone, is often prescribed as hormone therapy after the menopause and doubles the risk of dementia and Alzheimer’s within five years.5 Medroxyprogesterone acts on the GABA-A receptor. The effect of medroxyprogesterone is similar to the effect of stress hormones in chronic stress.

In severe Alzheimer’s, the cortisol and GABA response is identical to that of chronic stress. In mild Alzheimer’s there are high and suppressible cortisol and GABA levels. In Alzheimer’s, there is often a picture of chronic stress and burnout syndrome. At the same time, the cholinergic neurotransmitter system is not in balance.5

3.3.2. GABA antagonists improve learning processes

Just as GABA-A agonists impair learning processes, GABA-A antagonists improve learning and memory processes.5

  • Pregnenolone sulphate
  • DHEAS
  • 3Beta-Hydroxypregnan Steroid (UC01011)

If - as described for dopamine - not only too high but also too low levels of GABA impair learning processes (inverted-U), agonists or antagonists should be helpful depending on the condition.

3.4. Serotonin (5HT)

Mice with blocked 5HT1A and 5HT2C transporters have impaired spatial learning, unlike mice with blocked 5HT1B transporters.
Reduced cholinergic and serotonergic functions cause severe memory difficulties.
The serotonin reuptake inhibitor fluoxetine increased neurogenesis in the dentate gyrus (= part of the hippocampus) after 3 weeks.10

Glucocorticoid-mediated chronic stress downregulated 5-HT1A receptors in the hippocampus in animal models.29 Serotonin significantly influences neuroplasticity, predominantly via long-term potentiation (LTP).30 LTP is the central neurophysiological mechanism of learning and memory.

Postsynaptic LTP requires synaptic activation of AMPA receptors. Serotonergic signaling modulates intracellular pathways involved in synaptic AMPA receptor delivery. Activation of 5-HT2A-dependent ERK1/2 pathways improves the efficiency of signaling between synapses by introducing AMPA receptors into postsynapses.30 AMPA receptors are a subtype of glutamate receptors.

3.5. Acetylcholine

Acetylcholine improves memory processes. The current standard treatment for Alzheimer’s disease is the administration of acetycholine degradation inhibitors.5

Allopregnanol prevents the release of acetylcholine in the hippocampus. This could be one way in which allopregnanol hinders learning processes.5

3.6. Cortisol

Psychological tests such as the TSST address social stress (public speaking / loud mental arithmetic in front of a judgmental group), which addresses the motive of belonging. Cortisol responds preferentially to this social stressor.
However, the cortisol response is habit-dependent. On the first test run, 80% of the test subjects have an increased cortisol level. Repeated tests reduce the cortisol stress response by reducing novelty and unpredictability, so that by the 3rd to 5th round only a third of the test subjects still have an elevated cortisol level - but with identical subjective stress perception and identical other parameters (adrenaline, noradrenaline, pulse).31

If vocabulary has to be learned in this state, cortisol is shown to have a significant influence on learning ability. Those test subjects who no longer showed a rise in cortisol due to familiarization with the stress test had a perfect memory performance, while the third of the test subjects with a rise in cortisol (and of these again mainly the female members) also showed considerable memory losses.
This effect could be reproduced in other test subjects by administering cortisol.31 Contrary to the assumption that this was due to an inhibition of retrieval processes32, there was barely any impairment of retrieval when the cortisol was given after the vocabulary had been learned or shortly before it was retrieved. It can therefore be assumed that cortisol impairs the learning/storage process, but not the retrieval process.

4. Hormones that influence learning

4.1. Oestrogen

Oestrogen improves verbal memory and motor skills.

Agonists of the gonadotropin releasing hormone, which restrict the function of the ovaries in fertile women, also cause limitations in verbal memory, which can be remedied by administering oestrogen.5

Two-day estrogen exposure leads to an increase in NMDA (glutamate) receptors in the hippocampus (dorsal CA1). At the same time, oestrogen appears to reduce GABA neurotransmission.

4.2. Progesterone

Progesterone appears to contribute to the development of dementia. In women who had had their ovaries removed (hysterectomy), oestrogen alone had no effect on the incidence of dementia. This indicates that the dementia-reducing effect is caused by progesterone.5

Progesterone impairs spatial memory. Allopregnalon, which only impairs learning at much higher concentrations, is a progesterone metabolite.

5. Brain regions associated with learning

5.1. Hippocampus

The hippocampus is largely responsible for learning and memory processes, especially for degenerative long-term memory. The CA1 region of the hippocampus is responsible for storing and remembering spatial images, while the CA3 region of the hippocampus is responsible for associative memory processes.5

A smaller hippocampus volume correlates with learning difficulties.10

5.2. Cortex

In SHR rats, which are a model animal for ADHD-HI (with hyperactivity), neurons in the cortex showed:33

  • Less branching of the neurites
  • A shorter maximum neurite length
  • Reduced axonal growth

These changes in the nerve cells in the cortex of the ADHD-HI model animals could be normalized in various ways:33

  • Caffeine caused a normalization of neuronal branching and expansion of via PKA and PI3K signals
  • The adenosine 2A receptor agonist CGS 21680 normalized neuronal branching via PKA signaling
  • The selective adenosine 2A receptor antagonist SCH 58261 normalized axonal growth via PI3K, not PKA

5.3. ACC

Gatzke-Kopp and Beauchaine34 describe the ACC as an interface between emotion and cognition,35 using information from afferent projections from the limbic system about reward prediction errors to guide behavioral response,36 which combines the following functions:

  • Target detection37
  • Performing tasks where you have to choose between competing answers (e.g. such as Go-No/Go and Stroop)
  • Conflict resolution during the decision-making process38
  • Motivational functions performed by the mesolimbic system and the limbic cortex
    • This is also supported by the characteristic profound apathy in the event of damage to the ACC

The functions of the ACC are divided:

  • Dorsal ACC
    • Cognitive functions
  • Ventral ACC
    • Affective processing
  • Interconnective exchange
    • Between cognitive and affective functions of the ACC39

It is possible that the ACC does not monitor actual error rates, but uses the dopaminergic limbic input as a “training signal” to recognize situations with a higher probability of error and thereby improve cognitive control over behavior.40 Consequences could be that dopamine deficiency in the mesolimbic system causes a temporal deficit in the learning of reward associations by first interfering with the input to the ACC and subsequently with the acquisition of cognitive control over vigilance during task performance.

6. Eye motor skills for learning problems (ADHD, dyslexia, dyspraxia)

In a group of disorders that affect learning ability (ADHD, dyslexia, dyspraxia), a review study found evidence of common eye motor disorders.41

7. Genetic changes that cause learning problems

Mutations in the genes of

  • Ephrin receptor A
  • Ephrin receptor B
  • Tyrosine kinase receptor B (TrkB)

reveal deficits in learning behavior in various tests,42

8. Men more frequently affected by learning problems

Learning problems affect more men than women because there are a number of genes on the X chromosome whose mutations lead to learning difficulties
mental retardation.43

9. Learning problems with ADHD the result of sleep problems?

One study compared students with and without ADHD who were given a learning task whose long-term consolidation is particularly sleep-dependent.44
The learning success was compared in a waking test (learning in the morning, examination after 12 hours in the evening) and a sleep-integrated test (learning in the evening, examination in the morning after sleep).
On the waking test, the learning outcomes of students with and without ADHD were comparable.
In the sleep-integrated test, the students without ADHD benefited from nighttime sleep, while the children with ADHD did not.


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