What is wrong with Paula?

In order to deal with the subtly changing composition of the air we breathe, as well as dealing with the changing nature of the air carried by the blood to our cells, we have a flexible system to deal with gas exchange in our lungs and in our veins, arteries, kidney and other organs.

Paula’s system is broken.

Paula does not feel its brokenness .

Paula is not aware of her broken system.

It is not visible [unless you test the system].

Paula does not tend to feel shortness of breath even when in great ventilatory distress.

Breathing is a complex process that relies heavily on the coordinated action of the muscles of respiration and the control center in the brain.…….Respiratory centers located within the medulla and the pons are responsible for generating the baseline respiratory rhythm. However, an aggregated sensory input from the peripheral sensory system monitoring oxygen levels and the central sensory system monitoring pH modifies the rate and depth of respiration. These signals, along with several other sensory inputs coming from peripheral mechanoreceptors, modulate the respiratory rhythm to create a unified neural signal, sent to the primary muscles of respiration. The total input culminates in a respiratory rate of approximately 12 breaths per minute for an average adult while at rest. StatPearls, Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Physiology, Respiratory Drive Joshua E. Brinkman; Fadi Toro; Sandeep Sharma.

Let us repeat this once more, studies show that an average adult while at rest, will have a respiratory rate of 12 breaths per minute.

Yet Paula, an average adult, has a respiratory rate of 3-4 breaths per minute at rest. And Paula has bipolar illness. Do other people who have bipolar illness also have abnormal respiratory drive and hidden abnormal breathing, they may be unaware of ?

No one knows. Dr Emile Kraepelin thought so but he died in 1926 and no one has listened to him or looked at his studies since his death. Manic Depressive Insanity, Chapter 3 Bodily Signs, 1926.

....Pathophysiology: As mentioned previously, the respiratory control center responds to altered levels of CO2 and O2 by changing the respiratory rate and pattern. …. StatPearls, Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Physiology, Respiratory Drive Joshua E. Brinkman; Fadi Toro; Sandeep Sharma.

……again, the respiratory control center responds to altered levels of CO2 and O2 by changing the respiratory rate and pattern, unless it doesn’t. Can Paula respond to altered levels of C02 and 02 adequately when her baseline breathing at rest is so incredibly slow?

We don’t know.

Her breathing is not only slow, it is laboured, although this is not visible and Paula is not really aware of it, because she thinks this to be normal. Paula uses extra or accessory muscles to help her exhale. Exhaling is normally a passive process [like letting air out of a balloon]. But not for Paula. Why? No one knows.

Expiration

In healthy people quiet expiration or exhalation is passive and relies on elastic recoil of the stretched lungs as the inspiratory muscles relax, rather than on muscle contraction.  Nursing Times 13 JUNE, 2006 VOL: 102, ISSUE: 24, PAGE NO: 26 The respiratory system – Part 4: breathing Marion Richardson

Does Paula’s active exhaling mean that she is not healthy? We do not know.

What it really means is that doctors and nurses notice active exhaling and perhaps even bradypnea [slower than normal breathing rate] only in very sick patients and are not aware that some people have these features in health and that this will limit their ability to manage their C02/02 ratios adequately when challenged by other physical stressors such as illness [infection] or injury or blood loss or deficiency states.

A number of factors influence the rate and depth of respiration:

– We have a limited amount of voluntary control over respiration. For example, we can control expiration while talking or singing; Nursing Times 13 JUNE, 2006 VOL: 102, ISSUE: 24, PAGE NO: 26 The respiratory system – Part 4: breathing Marion Richardson

– If the lungs begin to overinflate, stretch receptors in the bronchioles and alveoli are triggered and switch off the respiratory centre so that air is expelled and the lungs return to normal; Nursing Times 13 JUNE, 2006 VOL: 102, ISSUE: 24, PAGE NO: 26 The respiratory system – Part 4: breathing Marion Richardson

Paula does not have overinflation.

 Chemical factors play a very important role. Blood pH and levels of oxygen and carbon dioxide are constantly monitored by specialised chemoreceptors. A rise in CO2 and a resultant fall in pH will increase the rate and depth of breathing, [unless it doesn’t], so that CO2 is blown off and the levels return to normal. Nursing Times 13 JUNE, 2006 VOL: 102, ISSUE: 24, PAGE NO: 26 The respiratory system – Part 4: breathing Marion Richardson

We are not sure if a rise in metabolic C02 changes Paula’s slow breathing rate at all. Only motor activity seems to change her respiratory rate and even then, her respiratory rate never approaches the normal rate of 12 breaths per minute. It is very strange. When sick with a cold and stuffy nose, Paula’s breathing rate at rest remains at 3 breaths per minute or even slightly slower at 2.5 breaths per minute.

These changes seem to act directly on the medullary centres. A fall in blood oxygen levels also sends impulses to the medulla to increase the rate and depth of breathing but usually only when they are very low. Nursing Times 13 JUNE, 2006 VOL: 102, ISSUE: 24, PAGE NO: 26 The respiratory system – Part 4: breathing Marion Richardson

The switch to mania seems to involve a switch to faster breathing with apneas [periodic breathing? or cheyenne stokes breathing?]; this suggests that the switch may be due to a fall in blood oxygen levels. This remains to be studied.

Pathophysiology

As mentioned previously, the respiratory control center should respond to altered levels of CO2 and O2 by changing the respiratory rate and pattern; but not in Paula. Interestingly, the response to hypoxia differs from the response to hypercapnia. Hypoxia induces a breathing pattern of rapid and shallow breaths with a relatively higher increase in respiratory rate than tidal volume. [this describes the pattern of breathing Kraepelin saw in mania- perhaps it is time to study this using modern technology] The aim is to decrease the cost of breathing by avoiding the need to overcome the lungs’ higher elastance at high volumes. In simple terms, breathing with high tidal volumes requires more negative pressure generation in the intra-pleural space, and thus, more oxygen utilization by respiratory muscles, especially in an already hypoxic patient. Hypercapnia, on the other hand, triggers a breathing pattern of deep and slow breaths with a relatively more significant increase in tidal volume than respiratory rate. This pattern aims to limit dead space ventilation and optimize carbon dioxide elimination. This is the pattern that Paula displays at rest. StatPearls, Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Physiology, Respiratory Drive Joshua E. Brinkman; Fadi Toro; Sandeep Sharma.

Does Paula have chronic hypercapnia? Chronic hypercapnia can have no symptoms. Paula does have a pattern of deep and slow breaths. This pattern does seem to limit dead space ventilation and optimize carbon dioxide elimination. No one knows. She has no brain lesion that would explain her pattern of breathing. Her MRI is normal. As long as Paula is well, her doctors do not want to know. And when she has an attack of bipolar depression with partial autobiographic amnesia, they do not think to check her blood gases. And while she is incapacitated in this way, she forgets to tell them.

It seems that no one is interested in the relationship between Paula’s broken breathing and her episodes of loss of mind.

Perhaps because air is invisible? And difficult to measure? Metabolic gases for sure are hard to measure. And they are subject to the body being able to create enough of a gradient to allow air to flow into the lungs. And we create this gradient with work, using our respiratory muscles throughout our lives. It is not unlikely to suggest that parts of this mechanical system might weaken or change invisibly throughout life.

Still, this hardly seems like a good reason to explore the mechanisms of broken breathing , difficulty adjusting to differing environmental conditions inside and outside a person, and the risk of chronic respiratory failure [type 2] during bipolar attacks and possible treatments to rescue sufficient gas exchange in order to be able to restore the function of the mind.

How many patients , in the throes of a manic depressive attack, have hidden mechanical problems making proper gas exchange difficult under challenging physical condition?

How many patients like Paula are there in the bipolar population? Do abnormal and hidden [until carefully measured] respiratory rates at rest occur in other [ambulatory] dementia’s How many ambulatory people are having difficulty exchanging sufficient levels of air with each breath?

And why the dementia accompanying severe depression and severe mania reversible ?

Is it possible that excess metabolic carbon dioxide in the blood is something that the body and brain know well how to deal with because it has protective qualities [limits inflammation] and because it is a normal metabolite within limits?

Ideas regarding carbon dioxide as a normal metabolite [within normal limits] rather than only as a waste product are slowly gaining attention. Maybe there is a link between thinking and PC02. Maybe PC02, with other gaseous metabolites, is part of what creates thought, and an imbalance of these metabolite gases contributes to loss of rational thought. Thought is invisible, metabolite gases are invisible. Who knows?

And breathing, using the muscles of respiration and muscles in the throat and muscles/bones of the torso and muscles such as the diaphragm and postural muscles of the back and even locomotor muscles which affect the diaphragm, will create air exchange and create life and possibly mind.

Carbon dioxide (CO2) is a fundamental physiological gas known to profoundly influence the behaviour and health of millions of species within the plant and animal kingdoms in particular. A recent Royal Society meeting on the topic of ‘Carbon dioxide detection in biological systems’ was extremely revealing in terms of the multitude of roles that different levels of CO2 play in influencing plants and animals alike. While outstanding research has been performed by leading researchers in the area of plant biology, neuronal sensing, cell signalling, gas transport, inflammation, lung function and clinical medicine, there is still much to be learned about CO2-dependent sensing and signalling. 
The Royal Society Publishing  12 February 2021 https://doi.org/10.1098/rsfs.2020.0033  Carbon dioxide-dependent signal transduction in mammalian systems D. E. PhelanC. MotaC. LaiS. J. Kierans and E. P. Cummins

And guess what? There are even more links between breathing and bipolar illness.

It turns out that Glutamate is key to both depression and to respiratory rate, volume and rhythm.

Glutamate is the predominant excitatory neurotransmitter in the ventral respiratory column

Highlights:

  1. Glutamatergic drive to the preBötzinger Complex is essential for respiratory rhythm
  2. Glutamatergic drive to the Bötzinger Complex contributes to respiratory phase timing
  3. Inspiratory premotor neurons receive continuous tonic excitatory inputs.
  4. Bötzinger Complex neurons inhibit inspiratory premotor neurons during expiration Respir Physiol Neurobiol. 2019 Feb; 260: 37–52.  The contribution of endogenous glutamatergic input in the ventral respiratory column to respiratory rhythm Denise R. Cook-Snyder,a Justin R. Miller,b Angela A. Navarrete-Opazo,c Jennifer J. Callison,c Robin C. Peterson,aFrancis A. Hopp,d Eckehard A. E. Stuth,c,e Edward J. Zuperku,c,d and  Astrid G. Stuckec,e


Glutamatergic neurons in the retrotrapezoid nucleus (RTN) function as respiratory chemoreceptors by regulating breathing in response to tissue CO2/H+.  Elife 2021 May 20;10:e60317. doi: 10.7554/eLife.60317. Somatostatin-expressing parafacial neurons are CO 2/H + sensitive and regulate baseline breathing. Colin M Cleary 1Brenda M Milla 1Fu-Shan Kuo 1Shaun James 1William F Flynn 2Paul Robson 2 3Daniel K Mulkey

Overview

Glutamatergic neurons produce the neurotransmitter glutamate, which is the main excitatory neurotransmitter in the mammalian central nervous system. It is involved in most of the brain’s fundamental processes such as cognition, learning, memory, and sensory perception. Dysregulation of glutamatergic neurotransmission is associated with many neurological disorders including epilepsy, schizophrenia, Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis, and stroke. https://www.rndsystems.com/resources/cell-markers/neural-cells/neurons/glutamatergic-neuronal-markers

And …… There is also emerging evidence (Table ​(Table2)2) linking the pathogenesis of depression to alterations in glutamate and glutamate signalling, as we can read below:

……. The versatility of glutamate as the brain’s foremost excitatory neurotransmitter and modulator of neurotransmission and function is considered common knowledge. Years of research have continued to uncover glutamate’s effects and roles in several neurological and neuropsychiatric disorders, including depression..……….Several studies have linked dysregulation of glutamate neurotransmission with the development and progression of neurodevelopmental, neurodegenerative and psychiatric disorders such as autism, epilepsy and schizophrenia[52,53]. There is also emerging evidence (Table ​(Table2)2) linking the pathogenesis of depression to alterations in glutamate and glutamate signalling[12,52]. Levine et al[54], using a proton magnetic resonance spectroscopy (MRS) technique examined the relationship between cerebrospinal fluid (CSF) metabolites, such as glutamate and glutamine on depressive symptoms in hospitalized persons with severe unmedicated depression, and reported that compared to control subjects, glutamine level in the CSF of depressed patients was elevated. Also, using high performance liquid chromatography with fluorometric detection, Mitani et al[55] examined the relationship between plasma levels of glutamate on severity of depression and concluded that plasma levels of glutamate as well as alanine and L-serine were reflective of the severity of depression. The impact of brain glutamate levels on depression and depression phenotypes have been studied extensively[5660]. Auer et al[56] and Hasler et al[57] using MRS reported region-specific changes in the levels of brain glutamate in patients with depression. The result of a recent meta-analysis of MRS studies also supported the hypothesis that glutamatergic neurotransmission was involved in the pathophysiology of depression[60]. In another meta-analysis, Luykx et al[58] also reported region and state specific alterations in glutamate and glutamine concentrations in depression. The importance of glutamatergic neurotransmission in depression has been further supported by studies that showed altered glutamine concentrations despite normal glutamate levels[59,61]. World J Psychiatry. 2021 Jul 19; 11(7): 297–315. Glutamate and depression: Reflecting a deepening knowledge of the gut and brain effects of a ubiquitous molecule Adejoke Yetunde Onaolapo and  Olakunle James Onaolapo

Remember….. Glutamate is the predominant excitatory neurotransmitter in the ventral respiratory column.

Could there be links between Paula’s abnormal respiratory rate at rest and findings of abnormal glutamate neurotransmission in depression? Is resting respiratory rate and minute ventilation [respiratory rate times tidal volume] the link? Does Paula’s broken breathing put her at risk for worsening hypercapnia and partial loss of declarative or explicit memory, altered mood, cardiovascular signs and insomnia during attacks? Could this be the case in other people with bipolar illness?

Are the alterations in glutamate and glutamate signalling seen in depression due to worsening hypercapnia?

Has anyone carefully worked up bipolar patients in depressive and manic stages for possible abnormalities in carbon dioxide levels in the blood? Kraepelin was interested in the development of blood gas analysis for this very reason but he died before this technology would become clinically available.

What if depression and changes to glutamate neurotransmission are due to exacerbations of hypercapnia and periods of reversible [initially] severe hypercapnia?

Severe Hypercapnia

The symptoms of severe hypercapnia require immediate medical attention, as they can cause long-term complications. Some cases may be fatal. [ symptoms can also disappear if they do not progress beyond confusion and if attacks are infrequent].

Severe hypercapnia symptoms include:

  • confusion [as reported by Kraepelin in depression and in mania]
  • coma
  • depression or paranoia
  • hyperventilation or excessive breathing [ as in mania]
  • irregular heartbeat or arrhythmia [as Kraepelin reported in depression ]
  • loss of consciousness
  • muscle twitching [also reported in depression by Kraepelin]
  • panic attacks
  • seizures

What to know about hypercapnia https://www.medicalnewstoday.com/articles/320501

Hypercapnia respiratory failure would explain what is wrong with Paula.

No doctor we know is exploring this possibility.

We have spent decades looking for one to explore her abnormal breathing, never mind finding a doctor to ponder the link between her respiratory depression and her attacks of bipolar depression and mania.

It can take a long long time to introduce new concepts to basic scientists and clinical scientists.

And no one, it seems, wants to look more closely into unseen mechanical problems dealing with metabolic carbon dioxide.

No one, it seems knows enough to look at the importance of air to mind and loss of mind.

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