The autonomic nervous system: sympathetic / parasympathetic nervous system

The autonomic nervous system (VNS) consists of two parts, the (more activating) sympathetic and the (more inhibiting) parasympathetic nervous system. These two systems form a dynamic balance. The autonomic nervous system is partially autonomous, i.e. many reactions are controlled directly in the spinal cord without the involvement of the brain, while others are regulated by higher-level entities (hypothalamus, brainstem, limbic system).
Sympathetic and parasympathetic nervous systems are not rigidly connected like a seesaw, but can be active or passive independently of each other.
Most organs of fulfillment are connected to sympathetic and parasympathetic nervous systems via direct nerves. Depending on the organ, both neurotransmitters have an inhibitory or stimulating effect.

A meta-study of 55 studies on the VNS in ADHD found no influence of the VNS on ADHD in nearly half of the studies. Nevertheless, stimulants and rewards do influence the CNS.¹

• 1. Sympathetic nervous system (activating)
• 2. Parasympathetic nervous system, vagus (inhibitory)
• 3. Control of sympathetic, parasympathetic and HPA axis
  • 3.1. Activation of the sympathetic nervous system
  • 3.2. Activation of the parasympathetic nervous system
• 4. Stress reaction of the autonomic nervous system
  • 4.1. Trigger
  • 4.2. Reaction
  • 4.3. Effect
• 5. Alpha-amylase as a biomarker of the autonomic nervous system
• 6. Measurement of the autonomic nervous system by means of heart rate variability (HRV)
• 7. Vegetative nervous system and ADHD
  • 7.1. Adrenaline levels reduced in ADHD
  • 7.2. Parasympathetic nervous system excessive and inflexible
  • 7.3. Findings on sympathetic nervous system in ADHD inconsistent
• 8. Changes in the autonomic nervous system caused by ADHD medications

1. Sympathetic nervous system (activating)¶

The sympathetic nervous system promotes the willingness to perform, activates and alarms.
Its nerves lead from the brainstem to the thoracic and lumbar parts of the spinal cord.

The sympathetic nervous system is a network of the brain regions²

• PVN, paraventricular nucleus / nucleus paraventricularis
  • A nucleus of the hypothalamus
  • Produces
    • Oxytocin
    • Antidiuretic hormone (low)
    • CRH
• Locus coeruleus
  • Produces noradrenaline
• Ventrolateral medulla
  • Produces noradrenaline
  • Regulates
    • Arterial blood pressure
    • Breathing

Transmitter control of the sympathetic nervous system occurs preganglionically (to the ganglion) via acetylcholine.
Binding to cholinoceptors:

• N receptors (nicotinergic)

Transmitter control postganglionically (from the ganglion) is via norepinephrine.
Binding to adrenoreceptors:

• Alpha receptors
• Beta receptors

2. Parasympathetic nervous system, vagus (inhibitory)¶

The parasympathetic nervous system inhibits the willingness to perform, calms and has a digestive effect.
Its nerves pass from the brainstem through the cranial nerves/cranial nerves and the sacral region of the spinal cord through the spinal cord nerves.

The parasympathetic nervous system is a network of the brain regions²

• NTS, nucleus tractus solitarius
  • Controls
    • Taste perception (“taste kernel”)
    • Breathing reflex
    • Gag reflex
    • Emetic reflex
• DMX, nucleus dorsalis nervi vagi, dorsal motor nucleus of the vagus
  • Part of the medulla oblongata
• NA, nucleus ambiguus
  • Part of the medulla oblongata

Transmitter control of the parasympathetic nervous system occurs preganglionically (up to the ganglion) as well as postganglionically (from the ganglion) by acetylcholine.

Binding to cholinoceptors

• N receptors (nicotinergic)
• M receptors (muscarinic)

3. Control of sympathetic, parasympathetic and HPA axis¶

The hypothalamus and brainstem moderate the actions of the sympathetic and parasympathetic nervous systems to maintain the body’s ever-changing conditions in what is known as homeostatic balance.

While the HPA axis is controlled by means of neurotransmitters and hormones (endocrine), the autonomic nervous system is controlled neuronally (electrically). Therefore, the reaction of the autonomic nervous system is much faster.

3.1. Activation of the sympathetic nervous system¶

• Amygdala → amygdala
  and
• Intralimbic cortex →
  • → nucleus of the solitary tract →
    • → Locus coeruleus →
      • → Sympathetic nervous system
    • → ventrolateral medulla →
      • → Sympathetic nervous system
    • → hypothalamus (there: paraventricular nucleus) → hypothalamus (there: paraventricular nucleus)
      • → Sympathetic nervous system
• Dorsomedial hypothalamus →
  • → hypothalamus (there: paraventricular nucleus) → hypothalamus (there: paraventricular nucleus)
    • → Sympathetic nervous system

Source³

3.2. Activation of the parasympathetic nervous system¶

• Stria terminalis (there: anterior bed nucleus) →
  • → hypothalamus (there: paraventricular nucleus) → hypothalamus (there: paraventricular nucleus)
    • → dorsal motor nucleus of the vagus nerve → dorsal motor nucleus of the vagus nerve
      • → Parasympathetic nervous system
  • → nucleus of the solitary tract →
    • → dorsal motor nucleus of the vagus nerve → dorsal motor nucleus of the vagus nerve
      • → Parasympathetic nervous system
    • → Nucleus ambiguus →
      • → Parasympathetic nervous system
• Prelimbic cortex →
  • → Nucleus ambiguus →
    • → Parasympathetic nervous system

Source³

4. Stress reaction of the autonomic nervous system¶

4.1. Trigger¶

• Great effort
• Emotional stress
• Severe pain
• Great dehydration

4.2. Reaction¶

Norepinephrine activates other organs of the body via the sympathetic nervous system.
Adrenaline is released by the adrenal medulla.

• Increased heart rate
  (norepinephrine and epinephrine via β1-receptors)
• Accelerated breathing
  (norepinephrine and epinephrine via β2-receptors)
• Increase blood pressure
  (norepinephrine and epinephrine via alpha1 and β receptors)
• Pupil dilation
• Increased supply of oxygen-rich blood to skeletal muscles in preparation for the fight-or-flight response
• Norepinephrine and epinephrine throttle blood supply to organs that are unimportant at the moment via β3-receptors
  • Intestine
  • Skin (reduce risk of bleeding in case of injury / fight, increase body heat)
• Stimulation of the liver to release high-energy glucose
• Sweat glands activated (cold sweat)
• Stimulation of the adrenal gland
  Reinforcement of the alert through
  • Increased release of adrenaline
  • Increased release of norepinephrine

4.3. Effect¶

• Heightened alert
• Increased escape behavior
• Increased energy consumption

A similar effect appears to occur in the central nervous system (brain and spinal cord), where the PFC is the “digestive” organ that is strengthened by moderate levels of norepinephrine and shut down by high levels of norepinephrine, while the sensorimotor and affective regions of the brain are strengthened by higher levels of norepinephrine.⁴

5. Alpha-amylase as a biomarker of the autonomic nervous system¶

Just as cortisol, as the last hormone of the HPA axis, is a very well measurable biomarker of the HPA axis (e.g. in saliva), the alpha-amylase level maps the reactivity of the sympathetic nervous system.⁵⁶

Both biomarkers can be easily measured in saliva.

For more on alpha-amylase in ADHD and its interaction with cortisol, see ⇒ α-amylase in ADHD As well as ⇒ Correlation between alpha-amylase and cortisol.

6. Measurement of the autonomic nervous system by means of heart rate variability (HRV)¶

The activity of the autonomic nervous system, especially that of the parasympathetic nervous system, can be measured noninvasively by measuring heart rate variability. This results in interesting approaches for diagnostics and therapy.
⇒ Heart rate variability (HRV) in ADHD

7. Vegetative nervous system and ADHD¶

7.1. Adrenaline levels reduced in ADHD¶

Adrenaline is usually measured in urine.
Among the basic functions of epinephrine: ⇒ Neurotransmitters - messenger substances.

• High adrenaline levels correlate with faster decisions, fewer errors in cognitive tests, and reduced adrenaline levels correlate with slower decisions and higher error rates in unstressed individuals.⁷
• In a boring, understimulating task, (unstressed) subjects with higher adrenaline levels performed better than those with lower adrenaline levels. In a demanding, overstimulating task, on the other hand, subjects with lower adrenaline levels performed better.⁷
• Young men (average age 24) who showed higher norepinephrine and epinephrine in response to stress were more efficient in tests. This effect was even stronger for adrenaline than for noradrenaline.⁸
• Subjects whose adrenaline levels increased during an attention test compared with the waiting time achieved better results.⁹
• Children whose adrenaline levels increased during an arithmetic test compared to a passive situation performed better on the test than children who did not respond with an adrenaline increase.¹⁰
• Subjective perception of stress correlates linearly with the level of adrenaline in healthy subjects.¹¹
• Adrenaline levels (but not norepinephrine) in stressful situations tend to decrease along with the individual’s sense of control and ability to direct.¹²
• Adrenaline release from the sympathetic adrenal gland is significantly reduced in children with aggressiveness, motor restlessness, and concentration difficulties under stressful as well as non-stressful conditions. Hyperactive boys show significantly lower adrenaline secretion under stress as well as outside stressful conditions than do nonstressful boys. Low sympathetic-adrenal reactivity is discussed as a risk factor and susceptibility indicator for social and / or profound behavioral disorders.¹³
• Individuals with depressive tendencies show a lower adrenal stress response to acute stress than do nondepressed individuals.¹⁴

7.2. Parasympathetic nervous system excessive and inflexible¶

One small study found in unmedicated children with ADHD:¹⁵

• An increased arousal of the parasympathetic nervous system
• Methylphenidate shifted the autonomic balance of children with ADHD toward normal levels, but did not reach the comparative levels of unaffected individuals
• MPH inhibits the normal response of the autonomic nervous system to a cognitive challenge.
• Methylphenidate appears to alter/suppress the normal stress response

Another study found differences in parasympathetic activity (PRS) in children with ADHD.¹⁶
Children with ADHD showed an inflexible increase in PRS, each of equal magnitude, at

• Negative emotions
• Positive emotions
• Suppression of an activity
• Activity induction

Children without ADHD, on the other hand, showed

• Negative emotions: PRS more elevated
• Positive emotions: PRS weaker increased
• Suppression of an activity: PRS more elevated
• Induction of an activity: PRS weaker increased

A replication study confirmed the rigid pattern of increased PRS in children with ADHD, and also found an increased sympathetic nervous system response. The changes in the sympathetic nervous system in ADHD correlated with disturbances in emotion reactivity, and the deviations in the parasympathetic nervous system correlated with disturbances in emotion regulation.¹⁷

A study of children with and without ADHD found no resounding differences in resting respiratory sinus arrhythmia (RSA) activity or reactivity. However, independent of ADHD status, each correlated with the other:¹⁸

• Reduced prosocial behavior with
  • Lower RSA value at rest
  • Lower reactive RSA decline
• Emotion regulation problems with
  • Increased reactive RSA decline to incentives.

Respiratory sinus arrhythmia (RSA) consists of oscillatory increases and decreases in heart rate during the respiratory cycle. It represents parasympathetic/vagal effects on the heart. The RSA is thought to represent neural traffic through the vagus nerve¹⁹. The vagus nerve is thought to represent a physiological mechanism for rapid acceleration and deceleration of cardiac output in response to environmental (including social) demands.²⁰

7.3. Findings on sympathetic nervous system in ADHD inconsistent¶

The cardiac pre-ejection period (PEP) is a systolic time interval mediated by the sympathetic nervous system (SNS) that encompasses the depolarization of the left ventricle until the onset of blood ejection into the aorta (the time from the onset of electrical stimulation of the left ventricle (onset of the Q wave on the ECG) to the opening of the aortic valve). PEP represents mesolimbic dopamine reactivity, particularly during the reward response.²¹ A longer PEP is a marker of reduced sympathetic nervous system activity, although this may be co-determined by other factors.²²

A study of 2,209 participants found a correlation between inattention and a prolonged pre-ejection period (PEP), suggesting an attenuated sympathetic nervous system in relation to inattention.²³ A small study also found underarousal of the sympathetic nervous system in unmedicated children with ADHD.¹⁵ Another study found no abnormalities of the sympathetic nervous system in ADHD.¹⁶ In contrast, another study found an increased sympathetic nervous system response in children with ADHD. Sympathetic nervous system abnormalities in ADHD correlated with disturbances in emotion reactivity, and parasympathetic nervous system abnormalities correlated with disturbances in emotion regulation.¹⁷
One study found significant reductions in electrodermal activity in adolescents with ADHD with and without comorbid conduct disorder, consistent with lower anxiety levels in impulsivity. An attenuated PEP response to reward was found only in adolescents with ADHD and comorbid conduct disorder, not in ADHSD alone.²⁴ Further study also suggests that decreased reward reactivity of the mesolimbic dopaminergic system is reflected in attenuated PEP signals to reward and is particularly correlated with aggressive externalizing behavior.²⁵²⁶²⁷ In ADHD without comorbid externalizing disorders, there was no evidence of mesolimbic dopaminergic. Two studies that found decreased heart rate variability to reward in ADHD did not differentiate between ASD(H)S and comorbid externalizing disorders.²⁸²⁹

A study of children with and without ADHD found no resounding differences in resting cardiac pre-ejection period (PEP) activity or reactivity. However, independent of ADHD status, each correlated with each other:¹⁸

• Behavioral problems and aggression with
  • Prolonged PEP at rest
  • Reduced PEP reactivity to incentives

8. Changes in the autonomic nervous system caused by ADHD medications¶

A study of adolescents with ADHD found decreased sympathetic and parasympathetic nervous system activity compared to unaffected individuals. This difference was almost equalized by a sustained-release MPH preparation.³⁰