Learning problems in ADHD - Neurophysiological correlates

Learning problems occur very frequently with ADHD. Learning here does not only mean learning vocabulary or formulas during school time, but much more generally the acquisition of helpful behaviors to avoid or solve problems. Several affected persons reported that even as adults they cannot 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 levels of growth hormones, thereby improving neuroplasticity. Atomoxetine can restore long-term potentiation, according to one study.¹ Since dopamine is essential for neuronal plasticity (the creation of new synaptic connections) and stimulants, like atomoxetine, raise dopamine levels that are reduced in ADHD, stimulants also have the effect of enhancing learning behavior.

This explains why stimulants in ADHD can improve the prerequisite for subsequent successful psychotherapy. If the ability to learn is impaired due to a lack of neuroplasticity of the brain, the normally existing ability to learn from experiences is reduced. Thus, ADHD sufferers are unable to learn from bad experiences in order to avoid them in the future.

Consequently, the same sufferers who suffered from making the same mistakes over and over again prior to their medication reported to us that after a suitable medication adjustment, they could now avoid making mistakes and not keep repeating them.

Memory is divided into different functions:²

• Short-term memory
  • Processes and remembers recorded information of the last 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 associated temporal and personal associations. Needed to recognize people, faces, and places or to recall events of one’s past. Includes sensory perception, feelings and motivations.

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

• 1. Learning: synaptic plasticity through long-term potentiation (LTP) or long-term depression (LTD)
  • 1.1. Long-term potentiation (LTP)
  • 1.2. Long-term depression (LTD)
• 2. Neurotrophins for learning and memory processes
• 3. Neurotransmitter for learning and memory processes
  • 3.1. Dopamine
    • 3.1.1. Phasic dopamine = learning, tonic dopamine = motivation?
    • 3.1.2. Dopamine as a neurotrophic factor
  • 3.2. Glutamate
  • 3.3. GABA
    • 3.3.1. GABA-A agonists impair learning and memory
    • 3.3.2. GABA antagonists improve learning processes
  • 3.4. Serotonin (5HT)
  • 3.5. Acetylcholine
  • 3.6. Cortisol
• 4. Hormones that influence learning
  • 4.1. Estrogen
  • 4.2. Progesterone
• 5. Brain regions associated with learning
  • 5.1. Hippocampus
  • 5.2. Cortex
  • 5.3. ACC
• 6. Ocular motor skills in learning problems (ADHD, dyslexia, dyspraxia)
• 7. Gene changes that cause learning problems
• 8. Men more often affected by learning problems
• 9. Learning problems in ADHD a result of sleep problems?

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

1.1. Long-term potentiation (LTP)¶

Long-term potentiation (LTP) especially 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 specific glutamate receptor). Glutamate is the excitatory (activating) counterpart of the inhibitory (inhibitory) 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.⁴ GABA inhibits LTP.⁵ In addition, a medium level of dopamine 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 at a synapse, the postsynaptic cell must be depolarized at the exact time that transmitter is released from the presynaptic cell.⁶

In the hippocampus, stimuli at 50 Hz (γ-band) excite LTP.⁷

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

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

causes growth of the dendritic spinous process, provided that dopamine release occurs no more than 0.3 to 2 seconds after glumatergic stimulation.⁸

1.2. Long-term depression (LTD)¶

Long-term depression here 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 does not merely represent its reversal process.

In the laboratory, rat PFC tissue showed either no LTP (rows repeated 4 times) or induced LTD (rows repeated 6 times) to stimuli at 50 Hz on rat layer I-II presynaptic filters. This is attributed to low extracellular dopamine levels. In contrast, live rats with intermediate extracellular dopamine levels show normal LTP in the PFC to 50-Hz stimuli.⁷

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.
See more at ⇒ BDNF.

Stress reduces the BDNF level in the hippocampus.⁹ In contrast, various antidepressants increase it. Conversely, direct BDNF administration to the hippocampus reduces depressive symptoms in rats.

BDNF is reported to be decreased in ADHD.¹⁰ Some other studies found no evidence of decreased BDNF in ADHD.

3. Neurotransmitter 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 PFC and striatum, among others.^11121314153

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

Medium tonic dopamine levels facilitate the induction of LTP, too high or too low dopamine levels worsen it (inverted U function).⁷¹⁶¹⁷

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

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

In response to a reward, dopaminergic cells in the nucleus accumbens fire as long as associative learning occurs. This allows 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, such that the amount of time a child with ADHD can associate behavioral contingencies with a reward is reduced.¹⁸

In ADHD, delayed reward for a behavior causes the association between the behavior and the possible reward to be unlearned-unlike in unaffected individuals, who can make this association over longer periods of time. This explains the devaluation of delayed reward in ADHD as well as the typical learning problems.¹⁹

Drugs that, like stimulants, increase dopamine levels in the nucleus accumbens thereby prolong the reinforcement gradient, providing more time in which the associations between behavior and reward necessary for learning can develop. Medications can therefore normalize the reinforcement gradient such that more normal learning becomes possible.²⁰

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

The previous view that phasic dopamine controls reward expectancy and thus learning, whereas tonic dopamine represents motivation, is challenged:³

• variation in tonic dopamine cell firing over longer time scales has not yet been demonstrated
• firing rates of dopaminergic cells do not change with changing motivation²¹²²
• a change in the proportion of active dopamine cells (i.e., an alternation of active and inactive states of dopaminergic neurons, which could control the amount of tonic dopamine) has so far been demonstrated only as a consequence of medication or drug administration, but not with changes in motivation²³²⁴
• Dopamine level changes correspond to approaching 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 of the brain.

Acute or brief 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, as occurs due to chronic stress or in ADHD, correlates with learning problems.

3.2. Glutamate¶

If NMDA receptors and long-term potentiation in the CA1 region of the hippocampus are impaired, this leads to poor storage and memory of spatial information.
If glutamate receptors are overstimulated, this leads to injury or death of the corresponding neuron, probably due to excessive CA2+ influx.⁴

3.3. GABA¶

GABA is produced in the adrenal gland and controlled like cortisol.

Blockade of GABA-A alpha5 receptors improves learning and memory.⁴ GABA-A alpha5 receptors are predominantly located in the hippocampus.

3.3.1. GABA-A agonists impair learning and memory¶

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

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

and resulted in persistent learning and memory difficulties.⁴

Degradation products of cortisol further increased the effect of allopregnanolone on GABA-A receptors.
An allopregnanolone antagonist prevented the impairing effect of allopregnanolone on learning and memory processes.
Chronically excessive cortisol and GABA levels caused irreparable cognitive damage. Stress increased cortisol and GABA levels.⁴

The sex steroid medroxyprogesterone, a metabolite (breakdown product) of allopregnanolone, is often prescribed as hormone therapy after menopause and doubles the risk of dementia and Alzheimer’s disease within five years.⁴ Medroxyprogesterone acts at the GABA-A receptor. The effect of medroxyprogesterone is similar to the effect of stress hormones during chronic stress.

In full-blown AD, the cortisol and GABA response is identical to that in chronic stress. In mild AD there are high and suppressible levels of cortisol and GABA. In AD, there is often a picture of chronic stress and burnout syndrome. At the same time, the cholinergic neurotransmitter system is not in balance.⁴

3.3.2. GABA antagonists improve learning processes¶

Just as GABA-A agonists impair learning processes, GABA-A antagonists cause an improvement in learning and memory processes.⁴

• Pregnenolone sulfate
• 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.
Decreased 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.⁹

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

3.5. Acetylcholine¶

Acetylcholine improves memory processes. The current standard treatment for Alzheimer’s disease is the administration of acetycholine degradation inhibitors.⁴

Allopregnanol prevents acetylcholine release in the hippocampus. This could be one way in which allopregnanol impedes learning processes.⁴

3.6. Cortisol¶

Psychological tests like the TSST address social stress (public speaking/loud mental arithmetic in front of a group judging this), which addresses the motive of belonging. Cortisol responds preferentially to this social stressor.
The cortisol response, however, is habit-dependent. On the first test run, 80% of subjects have elevated cortisol levels. Repeated tests reduce the cortisol stress response by reducing novelty and unpredictability, so that in the third to fifth test only one third of the subjects have an elevated cortisol level - but the subjective stress perception and other parameters (adrenaline, noradrenaline, pulse) remain identical.³¹

If vocabulary has to be learned in this state, it is shown that cortisol exerts a significant influence on learning ability. Those subjects who no longer showed a rise in cortisol due to habituation to the stress test had perfect memory performance, while that third of the subjects with a rise in cortisol (and of these again mainly the female members) also showed significant memory losses at the same time.
This effect could be reproduced in other subjects by cortisol administration.³¹ Contrary to the assumption that this was due to an inhibition of retrieval processes³², hardly any retrieval impairments were shown when the cortisol was given only after learning the vocabulary or shortly before its retrieval. Therefore, it can be assumed that cortisol impairs the learning process/storage process, but not the retrieval process.

4. Hormones that influence learning¶

4.1. Estrogen¶

Estrogen improves verbal memory and motor skills.

Agonists of gonadotropin releasing hormone, which limit the function of the ovaries in fertile women, also cause limitations in verbal memory, which are remedied by estrogen administration.⁴

A two-day exposure to estrogen leads to an increase of NMDA (glutamate) receptors in the hippocampus (dorsal CA1). Estrogen seems to decrease GABA neurotransmission at the same time.

4.2. Progesterone¶

Progesterone appears to contribute against the development of dementia. In women who had their ovaries removed (hysterectomy), estrogen alone showed no effect on the incidence of dementia. This suggests that the dementia-reducing effect is caused by progesterone.⁴

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

5. Brain regions associated with learning¶

5.1. Hippocampus¶

The hippocampus is significantly responsible for learning and memory processes, especially for degenerative long-term memory. The CA1 region of the hippocampus is responsible for the storage and memory of spatial imagination, the CA3 region of the hippocampus for associative memory processes.⁴

Smaller hippocampal volume correlates with learning difficulties.⁹

5.2. Cortex¶

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

• A lower branching of the neurites
• A shorter maximum neurite length
• A reduced axonal growth

These changes in neurons in the cortex of ADHD-HI model animals could be normalized in several ways:³³

• Caffeine caused normalization of neuronal branching and extension from via PKA and PI3K signaling
• The adenosine 2A receptor agonist CGS 21680 normalized neuron 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 by using information from afferent projections from the limbic system about reward prediction errors to guide behavioral response,³⁶ which links the following functions:

• Target acquisition³⁷
• Performing tasks that require choosing between competing responses (e.g., such as Go-No/Go and Stroop)
• Conflict resolution during decision making³⁸
• Motivational functions performed by the mesolimbic system and the limbic cortex
  • This is also supported by the characteristic profound apathy in the case of ACC damage

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 dopaminergic limbic input as a “training signal” to recognize situations with a higher probability of error, thereby improving cognitive control over behavior.⁴⁰ It could follow that dopamine deficiency in the mesolimbic system causes a temporal deficit in the learning of reward associations by first interfering with input to the ACC and subsequently with the acquisition of cognitive control via vigilance during task performance.

6. Ocular motor skills in learning problems (ADHD, dyslexia, dyspraxia)¶

In a group of disorders affecting learning ability (ADHD, dyslexia, dyspraxia), a review investigation found evidence of common oculomotor disorders.⁴¹

7. Gene changes that cause learning problems¶

Mutations of the genes of

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

show deficits in learning behavior in various tests,⁴²

8. Men more often affected by learning problems¶

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

9. Learning problems in ADHD a result of sleep problems?¶

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