Meditation and Locus ceruleus

The locus ceruleus is Latin for “the blue place” that is blue owing to an enzyme called dopamine beta hydroxylase. Harvard Univeristy has a piece on fear learning. This Harvard post seems to favor the use of selective noradrenaline reuptake inhibitors just as we have selective serotonin reuptake inhibitors. The Melnychuk publication that my post reviews favors deep breathing to achieve synchronicity.

A neurotransmitter is a compound released by the pre-synaptic neuron (blue) into the synaptic cleft. Receptors on the surface of the post-synaptic neuron (orange) bind the neurotransmitter causing an action potential to travel though the second neuron to a third neuron…

Note the pre-synaptic blue neuron has a reuptake pump to prevent accumulation of the neurotransmitter.

Wikipedia has a page that expands on these reuptake inhibitors of serotonin and noradrenaline. If fear learning is part of what has enabled our species to survive up until now, perhaps proper mindfulness and nutrition can alleviate the need for Big Pharma drugs. Dopamine beta hydroxylase is a copper cofactor enzyme that converts dopamine to noradrenaline (aka norepinephrine). This post will review work on the locus ceruleus response to carbon dioxide, CO2. The point of this chemical reaction scheme is that oxygen O=O is just as much as its function. Think of this when you take your deep breaths.

This paper came out of the Center for Brain Health in Dublin Ireland. The official PubMed reference is

Melnychuk MC, Dockree PM, O’Connell RG, Murphy PR, Balsters JH, Robertson IH. Coupling of respiration and attention via the locus coeruleus: Effects of meditation and pranayama. Psychophysiology. 2018 Sep;55(9):e13091. PubMed

Yogapedia defines pranayama as a preliminary step towards meditation. Prana is the Sanskrit word for “vital life force.” Yama is the Sanskrit word for “control.”

The review introduces us to to the Dutch explorer Jan Huygens, who lived in the 1500s. Jan laid sick in bed after a long sea journey. He observed two pendulum clocks hanging on a common beam. He noticed very small vibrations passing through the two clocks. The clocks were either perfectly synchronized or off by 180o. Very small vibrations were passing between clocks, through the beam upon which they were fixed, causing the pendula to drift into, and then remain, permanently fixed, in one of two states – either perfect synchronization, or anti-synchronization (a stable phase relationship of 180°). Melnychuk argues that biological systems are the same way.

A Modern day bedroom with two hanging pendulum clocks placed on a common beam.

In this modern day recreation we might also imagine a ceiling fan with its on synchronicity. How do we use pranayama to bring balance and control in our functions? This post is divided into the same sections as the Melnychuk review. More images have been added for better clarity.

If we are to go back in time we need to go back to the days of Pierre-Simon LaPlace whose theorem states that anything that happens in the time domain can be described as a sum of functions happening in the frequency domain.

The image on left is from NI Knowledge.

In physical systems we only see the sum of the individual “sine waves.” Calculus developed by LaPlace allows us to see the individual frequencies that that may appear to be a lot of noise over a course of a time interval. An Internet search on “Time is an illusion” reveals work of Albert Einstein, modern physics, and modern psychology. The interesting thing about the Melnychuk publication is that it describes how one frequency component, breathing, can interact with other frequency components of this process we call life.

The neurotransmitter noradrenaline plays a critical role in regulating brain function. Some of the functions from peer reviewed publications cited by Melnychuk and coauthors include:

  • regulating sleep-waking states
  • cortical arousal
  • signal detection threshold
  • decision processes

The LC exhibits rapid firing during moments of distraction and almost no firing during GABA induced REM sleep. The concept of exploratory and exploitative behaviors was also mentioned. This image explains the difference between tonic and phasic responses to a square wave stimulus.

Wikipedia lists these locus ceruleus inputs

  • The medial prefrontal cortex
  • the integrator of environmental and autonomic signals, the Nucleus paragigantocellularis
  • involved in gaze, the the nucleus prepositus.
  • the lateral hypothalamus
  • → Amygdala and Hippocampus
  • → Brain stem and Spinal cord
  • → Cerebellum
  • → Cerebral cortex
  • → Hypothalamus
  • → Tectum
  • → Thalamus
  • → Ventral tegmental area

The LC senses both low pH and increased concentrations of carbon dioxide, CO2. When these conditions are met, there is increased firing of the LC

The chemical equilibrium between CO2 and bicarbonate and H+ has been added. CO2 is gassed off when we breath.

We are up to three cycles breathing, CO2, and blood pH.

A passing comment was made that cortical noradrenaline is decreased during meditation. The LC receives input from the anterior cingulate corex (ACC) which is thought to drive LC-noradrenergic (LC-NA) system into one of two stable states of activity, a high tonic (sustained) mode or a phasic (bursting) mode accompanied by moderate tonic activity. Meditation is thought to help an individual revamp their brains to a changing environment. Wikipedia authors have compiled an interesting overview of the ACC: social awareness, perception of pain, reward based learning, consciousness, anxiety, and depression.

An interesting claim is made by Melnychuk and coauthors that each hemisphere of our brains contain 25,000 LC neurons each with their copper cofactor dopamine beta hydroxylase.

DMN default mode network is associated with mind wandering.

Meditation reduces DMN. Meditation and pranayama also produce changes in respiration and autonomic nervous system activity. A comment was made that theta activity is inversely correlated with the default mode network. Frontal theta activity is correlated with respiration.

Much of section 3 involved building the case that respiration, pupil dilation and blood oxygen level dependency (BOLD) activation are correlated. This was measured in 14 individuals during an 8-minute resting scan and a 20-minute auditory oddball task.

Some of this is ironic because it takes us back to the 1500s and Huygens and his pendulum clocks all entangled in some sort of synchronicity.

Equation 1. Method used to calculate phase coherence (R), where N is the sample size of the angular distribution, i = -1 (imaginary operator), e is the natural logarithm, and 𝜃3𝑎𝑛𝑑 𝜃8
are instantaneous phase angles (in radians) from two different signals at time 𝑡.. R returns an average vector of length 0 ≤ 𝑅 ≤ 1.0. Instantaneous phase values are calculated using the Hilbert Transform.

Equation 2. Description of the coupled dynamical system of autonomous oscillators of
respiration, LC tonic activity, and task-focused/DMN oscillation (“attentional refresh
cycle”), where 𝜙 is a first order derivative describing a variable’s phase evolution with
respect to time, w is the natural frequency of the oscillator, e is the coupling strength, F
is the coupling function (a 2π-modular function), f is the instantaneous phase, and x are
stochastic, linear, or nonlinear (potentially 2π-periodic) noise terms.

The authors are proposing coupling strengths (ε) and noise terms (ζ)

Reaction time variability (RTV) groups are a form of binning tasks requiring attention to perform. The authors were interested in how respiration rates affect these differences. Alzheimer’s Disease, ADHD, depression, and so on can affect RTV. High RTV is present more so in TBI patients with focal frontal lesions as opposed to non-frontal lesions. RTV also co-varies with LC tonic firing rate and pre-stimulus pupil diameter in simple target detection tasks.

Figure 4. Analysis of participants binned into high and low RTV. A. Stimulus-locked instantaneous respiratory
phase angle x RTV (Low v High groups). Participant mean stimulus locked respiratory phases were used for
clarity of presentation. RTV on radial axis. B. Stimulus-locked respiratory waveform averaged across all trials for Low and High RTV groups. The authors never defined “Arb units.” This could be arbitrary units.

Panel A is clearly a graph in polar coordinates. At 3 o’clock we have 0o. Going counter clockwise to 12o’clock we have 90o

A pictorial description of how Panel A may have been generated.

Wikipedia authors have compiled a particularly interesting sub section on the insular cortex that might play int some of the higher goals of meditation:

Melnychuk and coauthors discuss attention to respiratory activity and other visceral ignals targeting tonic LC phase angle and amplitudes. They think it is possible that insular changes could alter More specifically, it is possible that insular changes could alter coupling between respiration and attention by improving signal transmission of respiratory activity back to the cortex, allowing more effective synchronization of respiration to task. They claim that most forms of meditation and pranayama involve paying strict attention to respiration and other visceral sensations to prevent mind wandering.

Two interesting statements were made in this section.

  1. The LC tends to increase sympathetic activity and decreases parasympathetic activity.
  2. Parasympathetic influence is reduced via inhibitory projections to the vagal nuclei, while the LC’s excitatory effect on sympathetic activity is more complex, involving combinations of excitatory and inhibitory projections.

LC neurons are sensitive to fluctuating CO2 levels, and should detect fluxuations in respiratory activity. References were cited claiming vagal nerve stimulation increasing LC activity. Vagal nerve stimulation ws claimed to reduce seizures and drug resistant depression. possibly involving the nucleus of the solitary tract (NTS),Stretch receptors in the lungs inhibit vagal input to the LC, possibly via the NTS. More sine waves.

Obtained by an image search. Vicente MC, Dias MB, Fonseca EM, Bícego KC, Gargaglioni LH. Orexinergic system in the locus coeruleus modulates the CO2 ventilatory response. Pflugers Arch. 2016 May;468(5):763-74. PubMed appears to be the source publication.

What are other sources of sine waves in the locus ceruleus? This image was obtained from an Internet. Som investigators are interested in Orexin receptors in the LC. The above PubMed abstract suggests that the sleep hormone orexin may contribute to the hypercaptic response in the dark phase. Another sine wave.

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