Paula and I think that, in first episode bipolar illness, physically * injurious events [such as hypercapnia in COPD or chronic ventilatory failure] crucially occur in the setting of exacerbations and infections [57,58], which lead to acute decompensations for limited periods of time , after which patients typically fail to recover the baseline status they had before the acute event. * AMP-Activated Protein Kinase (AMPK) at the Crossroads Between CO2Retention and Skeletal Muscle Dysfunction in Chronic Obstructive Pulmonary Disease (COPD) Int J Mol Sci. 2020 Feb; 21(3): 955. Published online 2020 Jan 31. doi: 10.3390/ijms21030955 A Jaitovitch et al
This is what happened we think happened to Paula and this is what I believe also happened to * Dr Emile Kraepelin’s manic depressive patients . * Manic depressive insanity Emile Kraepelin 1926
We think that these patients require additional supportive medical, nutritive and rehabilitative care to potentially recover to their baseline physical and mental status.
The abnormal respiratory rates that Kraepelin described and that we found in Paula suggests that these patients have a problem controlling the endogenous carbon dioxide continually produced by cell metabolism . Endogenous C02 cannot be allowed to build up to toxic near toxic levels and must be exhaled. If it isn’t exhaled in sufficient amounts for one reason or another, then accumulation beyond what is needed can develop into a dose related ” hypercapnic encephalopathy “, in the setting of exacerbations and infections [57,58], which lead to acute decompensations for limited periods of time after which patients typically fail to recover the baseline status they had before the acute event“.
The skeletal muscle system is a key player in moving air in and out of the lungs. The respiratory muscles are part of the skeletal muscle system and in states of poor physical health, these muscles can break down and make inhaling and exhaling harder. The sensation of difficult breathing is called dyspnea. If dyspnea involves is due to the weakness of the respiratory muscles, it can be very distressing, yet near impossible to describe. Paula is especially at risk of added problems with the complex ,motor act of ventilation because of her abnormal respiratory rate, and because of her limitations in handling further breathing challenges when ill and physically weakened by the effects of a virus or when in a period of developmental hormonal changes which affect skeletal muscle and/or when intermittently or chronically exposed to high levels of indoor/outdoor chemical substances, including higher CO2 in the air.
The average respiratory rate is 12-15 breaths per minute. Paula seems to be breathing at a normal rate she is not. Further examination shows that her baseline breathing rate is depressed at 3 breaths per minute with active exhaling and inhaling [this is very abnormal, she has a high level of “work of breathing” at rest with every breath] . Dr Kraepelin also mentions abnormal respiratory rates and specifically, depressed rates of breathing in bipolar stages of depression.
We think that this is important. We think that this indicates a problem with control of breathing which is somehow stable enough in health, but can lead to hypercapnic encephalopathy after physical illness that weakens skeletal muscle, including respiratory muscle. Ventilatory failure means difficulty moving air in and out of the lungs in the correct ratio’s.
* ” CO2 retention or hypercapnia activates multiple signaling pathways in diverse species and tissues. In skeletal muscle, we have found that hypercapnia regulates muscle anabolism and catabolism via AMPKα2 “ We think that this has implications for respiratory skeletal muscle use for ventilation . We think that this also has implications for the strength and integrity of non respiratory skeletal muscle affecting locomotor activity and speed during illness. The motor subtypes of hypo motor quiet delirium and hyper motor [including mania] wild delirium as well as the appearance of psychomotor retardation and psychomotor excitement could be be effects of metabolic disturbances on the spinal motor neurones. Disturbances due to changes affecting the regulation of muscle anabolism and catabolism by dose response chronic patterns of hypercapnia, after initial physical or chemical insult.. * International J. of the Molecular Sciences 2020 Jan 31;21(3):955. doi: 10.3390/ijms21030955. A. Jaitovitch et al , Review :AMP-Activated Protein Kinase (AMPK) at the Crossroads Between CO2 Retention and Skeletal Muscle Dysfunction in Chronic Obstructive Pulmonary Disease (COPD)
Paula and I think that the effects of acute episodes of hypercapnia [and possibly intermittent hypoxia] due to weakened skeletal muscle can be very serious in people with already compromised respiratory rates in health and can precipitate respiratory failure and encephalopathy. We think that medical supportive techniques to help clear infection and inflammation, medical and respiratory rehabilitative and nutritional techniques [as in cystic fibrosis or COPD] supportive techniques to help move air in and out of the lungs while the muscles are weakened, can help the patient with a hypercapnic encephalopathy to recover and again their baseline muscle strength and return to their baseline ventilatory and mental function. We think that, in view of the effects of exacerbations of hypercapnia on skeletal and respiratory muscle and on the brain, that the two are intimately related. We think that even if the depressed breathing rate and * lack of normal flexibility of the respiratory rate affecting possible retention of CO2, , is a permanent injury, , skeletal and brain function can return to previous conditions of baseline health and normal consciousness and function of the mind can be rescued.
- Paula’s respiratory rate rises only sluggishly during exercise, leaving the brain to work out tidal volumes relevant to maintaining adequate [whether normal or not] tidal volumes. There is a limit to how wide a tidal volume can be increased, so it must become tricky to maintain adequate minute ventilation during respiratory challenges due to illness to due to exercise, but somehow, during health Paula is able to accomplish this and avoid major levels of hypercapnic ventilatory failure. It seems obvious to us that chronically abnormal respiratory rates and minute ventilation and its relationship to mental status needs more study . The first step to studying levels of hyper and hypo capnia is to count breathing rate a few times at baseline in health, especially if spirometry and the lungs are normal, since chronically abnormal rates at rest suggests a problem with the motor ventilatory system and would explain brain, mood and skeletal motor changes seen in chronic forms of delirium or dementia, and also the brain, mood and skeletal motor changes [amount of activity and speed of activity] seen in the different stages of manic depressive insanity.
- It is especially interesting to note that the pattern of respiratory rate and locomotor activity and speed seem to go together during bipolar attacks in Kraepelin’s studies: Depressed rates of breathing with psychomotor retardation in bipolar depressed states and Cheynes Stokes type breathing with psychomotor excitement in manic ones. If I had to guess, I would suggest that exacerbations of hypercapnia for whatever reason affects the skeletal muscles and muscle anabolism and catabolism in dose related ways , accounting for the changing responses driving the mood, cognitive impairment and locomotor activity levels and the speed of movements [maybe due to intracellular changes affecting whole muscle contraction?] as the organism tries to recover in the absence of supportive medical interventions. In delirium and in manic depressive insanity, spontaneous recovery might take a long time, during which the patient might be mentally and physically incapacitated, losing precious time of normal productive living.
- . And what is the worst, without looking at gross signs of motor function, including respiratory rate and feedback responses to higher internal CO2, no one will know what is wrong. Because they will not have collected the data, as Kraepelin and I have done.
- What is even worse, is that hypercapnia causes huge unspoken distress and dose response periods of fear and or intoxication-like euphoria, that others will mistake for an emotional/psychological issue rather than a metabolic one. The treatments are very different, as you can imagine. The obvious success of psychological treatments involving breathing and relaxation techniques, will help, because of the link between the respiratory rate and depth and improving the movement of air into and out of the body in a conscious manner. Since long term baseline breathing rates are directed involuntarily and unconsciously, this is not likely to be a permanent solution to exacerbations of hidden”control of breathing” issues, hidden only because respiratory rate and the motor ventilatory system are neglected in medicine and in research and even in molecular and biochemical science.
The brain monitors our internal state of carbon dioxide production and tries to maintain the correct ratio’s of this endogenous product through proper function of the skeletal motor system, mostly our respiratory muscles, but the other skeletal muscles can be engaged in times of need. Skeletal muscles such as the accessory respiratory muscles and even the bigger thigh muscles or the arms or even the fingers [in fidgeting, for example]. All skeletal muscles can help in the interests of keeping PCO2 stable throughout its continual production from cell metabolism. It is fascinating really.
Taken together, our data suggest that hypercapnia leads to changes in the metabolic activity of skeletal muscle cells, which results in impaired muscle regeneration and recovery after injury [affecting ventilatory and non-ventilatory skeletal muscles.].…….Human skeletal muscle is about 40% of the body mass and is formed by a bundle of contractile multinucleated muscle fibers, resulting from the fusion of myoblasts (Laumonier and Menetrey, 2016). Healthy skeletal muscle undergoes continuous and repeating cycles of damage and repair to maintain muscle mass (Tidball, 2011; Laumonier and Menetrey, 2016). As such, skeletal muscle repair is essential for recovery from physical or chemical insult (Laumonier and Menetrey, 2016). Skeletal muscles rely on satellite cells for repair, which are stem cells that lie dormant beneath the basal lamina. Once satellite cells become activated, they proliferate, differentiate, and fuse with mature muscle fibers to overcome the damaged state (Snijders et al., 2015; Laumonier and Menetrey, 2016). Elevated CO2 Levels Delay Skeletal Muscle Repair by Increasing Fatty Acid Oxidation Front. Physiol., 21 January 2021 | https://doi.org/10.3389/fphys.2020.630910 Jacob L Snajzder et al.
AMPK is recognized as the cellular energy sensor and metabolic regulator. It has been linked to the pathogenesis of muscle atrophy, (Snijders et al., 2015; Laumonier and Menetrey, 2016). Elevated CO2 Levels Delay Skeletal Muscle Repair by Increasing Fatty Acid Oxidation Front. Physiol., 21 January 2021 | https://doi.org/10.3389/fphys.2020.630910 Jacob L Snajzder et al.
What is AMPK? As a cellular energy sensor, AMP-activated protein kinase (AMPK) is activated in response to a variety of conditions that deplete cellular energy levels, such as nutrient starvation (especially glucose), hypoxia and exposure to toxins that inhibit the mitochondrial respiratory chain complex. Exp Mol Med. 2016 Apr; 48(4): e224. Published online 2016 Apr 1. doi: 10.1038/emm.2016.16 AMPK activators: mechanisms of action and physiological activities J Ha et al
As CO2 retention occurs almost exclusively in the context of pulmonary diseases [and we would add syndromes of ventilatory failure], this review is focused on the description of AMPK as a sensor of CO2 and its implications for pulmonary physiology and physiopathology; and on the mechanisms regulating locomotor muscle turnover . Conclusions :CO2 retention or hypercapnia activates multiple signaling pathways in diverse species and tissues. In skeletal muscle, we have found that hypercapnia regulates muscle anabolism and catabolism via AMPKα2 International J. of the Molecular Sciences 2020 Jan 31;21(3):955. doi: 10.3390/ijms21030955. A. Jaitovitch et al , Review : AMP-Activated Protein Kinase (AMPK) at the Crossroads Between CO2 Retention and Skeletal Muscle Dysfunction in Chronic Obstructive Pulmonary Disease (COPD)
The research on skeletal muscle would explain the skeletal locomotor muscle atrophy which occurred during Paula’s depressive episode and the resulting changes to muscle strength and endurance would explain both her difficulty breathing and her psychomotor retardation. We would hypothesize that both locomotor muscle turnover and brain tissue turnover are impaired during syndrome resulting in abnormal PCO2 and that abnormal PCO2 in the different tissues are linked in cases of ventilatory failure affecting the function of both in detrimental ways.
Myogenic stem (satellite) cells contribute to muscle homeostasis in the context of organ development and injury-repair cycles . Injurious events crucially occur in COPD in the setting of exacerbations and infections [57,58], which lead to acute decompensations for limited periods of time after which patients typically fail to recover the baseline status they had before the acute event . Indeed, frequency and severity of COPD exacerbations and infections powerfully associate with loss of muscle and lung integrity, and with higher mortality over time [59,60,61]. In stable conditions, adult muscle satellite cells remain in a quiescent state, which means that they are maintained in a G0 phase that can be re-engaged in cell proliferation upon activation (that potential capacity differentiates quiescent from terminally differentiated and from senescent G0 states). Satellite cells activation leads to two distinct consecutive stages: A symmetrical cell division phase that expands the satellite cells pool in order to produce myogenic cells and also repopulate the pool of cells needed to return to quiescence; and asymmetrical division, which commits cells to the myogenic differentiation . There is not research done in the field myogenesis in the context of CO2 retention. However, we have observed that chronically hypercapnic mice demonstrate evidence of nuclear centralization , a histological hallmark of muscle repair after injurious events which typically require satellite cells involvement. Moreover, our previous analysis of muscle proteome from animals exposed to chronic hypercapnia reveals “ATP binding” (GO:0005524) as the most downregulated ontology term . As this term is highly enriched in bioenergetics-related genes, that proteome suggests possible bioenergetic effects induced by high CO2.. Because CO2 is a highly diffusible species (~20 times higher diffusibility across biological membranes than O2) [9,62], it is likely that hypercapnia’s effects appreciated on the muscle fiber are also impactful on the satellite cells’ microenvironment. AMP-Activated Protein Kinase (AMPK) at the Crossroads Between CO2Retention and Skeletal Muscle Dysfunction in Chronic Obstructive Pulmonary Disease (COPD) Int J Mol Sci. 2020 Feb; 21(3): 955. Published online 2020 Jan 31. doi: 10.3390/ijms21030955 A Jaitovitch et al
What about the molecular system of consciousness and function of the brain, the nervous system and the mind? What of brain tissue turnover and the effects of dose related hyper or hypocapnia?
Well, it seems that recent research has found satellite cells in the brain and in the spinal cord as well.
Satellite glial cells (SGCs) closely envelop cell bodies of neurons in sensory, sympathetic and parasympathetic ganglia. This unique organization is not found elsewhere in the nervous system. SGCs in sensory ganglia are activated by numerous types of nerve injury and inflammation. The activation includes upregulation of glial fibrillary acidic protein, stronger gap junction-mediated SGC–SGC and neuron–SGC coupling, increased sensitivity to ATP, downregulation of Kir4.1 potassium channels and increased cytokine synthesis and release. There is evidence that these changes in SGCs contribute to chronic pain by augmenting neuronal activity and that these changes are consistent in various rodent pain models and likely also in human pain. Therefore, understanding these changes and the resulting abnormal interactions of SGCs with sensory neurons could provide a mechanistic approach that might be exploited therapeutically in alleviation and prevention of pain. We describe how SGCs are altered in rodent models of four common types of pain: systemic inflammation (sickness behaviour), post-surgical pain, diabetic neuropathic pain and post-herpetic pain. Emerging importance of satellite glia in nervous system function and dysfunction Nature Reviews Neuroscience Review Article Published: Menachem Hanani & David C. Spray
Research is ongoing, but I would not be surprised to hear that hypercapnia interferes with the activation of these nervous system satellite cells, keeping them dormant instead of activating them to repair parts of the nervous system, affecting brain function and the function of the mind [cognition and memory].
All of us interested in the topic of the molecular systems affecting the nervous system, consciousness and mind could tell the field of psychiatry that there are an awful lot of new discoveries being made and they may be important to understanding issues like mind and loss of mind, which is what Paula and I are discussing in this blog. Because I do not think that they are following these scientific advances.
And we are not discussing this from a philosophical viewpoint. We are using abnormal physiological patterns of vital signs, especially respiratory rate and minute ventilation as our roadmap to guide our thinking about the impaired cognition, memory [partial amnesia-see other posts] and locomotor changes seen in bipolar depressive episodes, in particular