Paula’s breathing is chronically altered.

Neuroplasticity within the cardiorespiratory control network

When environmental and/or physiologic conditions are chronically altered, as during chronic hypoxia or hypercapnia, neurophysiological systems are challenged to maintain homeostasis, requiring adjustments in integrated physiological control systems. The physiological adaptation process to chronically altered states is known as acclimatization, which has been well characterized for high altitude exposure/chronic hypoxia. Despite the high clinical relevance of hypercapnia in disease states and environmental conditions of hypercapnia, the physiological adaptations to chronic hypercapnia are not well‐characterized. We have previously shown that the physiological acclimatization process to chronic environmental hypercapnia is time‐dependent and requires an integrated physiological response across multiple systems including ventilatory, circulatory, renal, gastric, and thermal control systems (Burgraff et al. 2018). For example, a major initial response to elevated CO₂ is an acidosis‐induced increased ventilation likely driven by peripherally and centrally mediated chemoreflex systems (Forster and Smith 2010; Smith et al. 2010). We think that this does not happen to Paula, particularly when she retains C02 due to upper respiratory illness. Her respiratory rate remains low and gets even lower if such a thing can be imagined. However, when the increased CO₂ is sustained, the kidney slowly increases HCO₃ ⁻ and blood and CSF pH are restored toward normal. We think that this occurs when Paula is otherwise healthy despite her depressed breathing. This change attenuates the H⁺ stimulus for ventilation which is likely a major reason ventilation decreases between 1 and 24 h of increased CO₂. However, we also showed that steady‐state ventilation during chronic hypercapnia exceeds that which is predicted from the acute ventilatory chemoreflex, pointing to additional adaptive mechanisms that underlie this new “set‐point” of ventilation (Burgraff et al. 2018). We suspect that Paula’s depressed breathing is her new “set point” of ventilation. Physiol Rep. 2019 Apr; 7(8): e14035. Glutamate receptor plasticity in brainstem respiratory nuclei following chronic hypercapnia in goats Nicholas J. Burgraff, ¹ Suzanne E. Neumueller, ¹ Kirstyn J. Buchholz, ¹ Matthew R. Hodges, ^{1 , 3} Lawrence Pan, ² and Hubert V. Forster ^{1 , 3 , 4}

Paula’s resting breathing rate of 3 breathes per minute with active exhaling most likely represents a new ” set point “of ventilation with changes to glutamatergic signalling within brain stem nuclei or to the mesencephalic Locomotor Region or MLR. [see the next post].

Patients that retain CO ₂ in respiratory diseases such as chronic obstructive pulmonary disease (COPD) have worse prognoses and higher mortality rates than those with equal impairment of lung function without hypercapnia. We do not think that Paula has COPD or any lung issues. We think that this is why she has done so well. We know that she has a “control of breathing” issue affecting her manner and speed of ventilating. . We recently characterized the time‐dependent physiologic effects of chronic hypercapnia in goats, which suggested potential neuroplastic shifts in ventilatory control mechanisms. However, little is known about how chronic hypercapnia affects brainstem respiratory nuclei (BRN) that control multiple physiologic functions including breathing. Since many CNS neuroplastic mechanisms include changes in glutamate (AMPA (GluR) and NMDA (GluN)) receptor expression and/or phosphorylation state to modulate synaptic strength and network excitability, herein we tested the hypothesis that changes occur in glutamatergic signaling within BRN during chronically elevated inspired CO ₂ (InCO ₂)‐hypercapnia.  Physiol Rep. 2019 Apr; 7(8): e14035. Glutamate receptor plasticity in brainstem respiratory nuclei following chronic hypercapnia in goats Nicholas J. Burgraff, ¹ Suzanne E. Neumueller, ¹ Kirstyn J. Buchholz, ¹ Matthew R. Hodges, ^{1 , 3} Lawrence Pan, ² and Hubert V. Forster ^{1 , 3 , 4}

C02 levels are sensed by all cells and play an essential role in behaviour.

CO₂ sensing in cells and organisms

Chemoreception, the recognition of soluble and volatile chemicals by cells, plays an essential role in the behaviour and survival of most organisms. CO₂ is a by-product of metabolism and is an important signal for a variety of animal behaviours, including feeding, ventilation, mating and avoiding predators and harmful substances. The ability to sense CO₂ has been described in many eukaryotes ranging from fungi to human beings.

Why aren’t we researching the effects of metabolic carbon dioxide in stereotypic animal and human behaviours such as increased and decreased motor activity and speed? Especially now that we know that metabolic ” C02 is an important signal for a variety of animal behaviours, including feeding, ventilation, mating and avoiding predators and harmful substances.“

CO₂ sensing in mammalian neuronal cells

From a physiological standpoint, some of the most important CO₂ sensors are those that control breathing in mammals. …. What happens if broken neurons in the neck or torso or somewhere in the unprotected periphery prevent a fast or an effective response to retention of C02 due to upper respiratory illness or due to fatigue and loss of substate from malnutrition or dehydration or whatever? This seems to be the problem with Paula. Kraepelin referred to such problems in chapter 3, Bodily Changes, Manic Depressive Insanity, last updated in 1926, when he died. ….. Changes in CO₂ and CO₂/H⁺ levels are sensed in special chemosensitive neurons located peripherally in the carotid body and centrally in the central nervous system. The peripheral carotid neurons detect arterial CO₂ and pH, as well as variations in O₂ levels in arterial blood [21]. The central neurons reside in several regions of the hindbrain and detect CO₂ and pH in the cerebrospinal fluid [22]. J Cell Mol Med. 2009 Nov-Dec; 13(11-12): 4304–4318.  Sensing, physiological effects and molecular response to elevated CO₂ levels in eukaryotes Kfir Sharabi,^a,# Emilia Lecuona,^b,# Iiro Taneli Helenius,^b,c,# Greg J Beitel,^c,# Jacob Iasha Sznajder,^b,# and Yosef Gruenbaum^a,#*

So again I ask…. Why aren’t we researching the effects of metabolic carbon dioxide in stereotypic animal and human behaviours such as increased and decreased motor activity and speed? Especially now that we know that metabolic C02 is an important signal for a variety of animal behaviours, including feeding, ventilation, mating and avoiding predators and harmful substances.

……..”The caudal hypothalamus is a major site for ‘central command’, or the parallel activation of locomotion and respiration“.

Abstract

Despite focus on brainstem areas in central respiratory control, regions rostral to the medulla and pons are now recognized as being important in modulating respiratory outflow during various physiological states. The focus of this review is to highlight the role that suprapontine areas of the mammalian brain play in ventilatory control mechanisms. New imaging techniques have become invaluable in confirming and broadening our understanding of the manner in which the cerebral cortex of humans contributes to respiratory control during volitional breathing. In the diencephalon, the integration of respiratory output in relation to changes in homeostasis occurs in the caudal hypothalamic region of mammals. Most importantly, neurons in this region are strongly sensitive to perturbations in oxygen tension which modulates their level of excitation. In addition, the caudal hypothalamus is a major site for ‘central command’, or the parallel activation of locomotion and respiration. Furthermore, midbrain regions such as the periaqueductal gray and mesencephalic locomotor region function in similar fashion as the caudal hypothalamus with regard to locomotion and more especially the defense reaction. Together these suprapontine regions exert a strong modulation upon the basic respiratory drive generated in the brainstem. Respiration Physiology Volume 114, Issue 3, December 1998, Pages 201-211 Suprapontine control of respiration Eric M.HornTony G.Waldrop

There is also evidence that the mesencephalic locomotor region (MLR), is involved in the parallel activation of locomotion and respiration . [and of course glutamate is involved].

Wait, it gets more complicated…………

Abstract

When animals move, respiration increases to adapt for increased energy demands; the underlying mechanisms are still not understood. We investigated the neural substrates underlying the respiratory changes in relation to movement in lampreys. We showed that respiration increases following stimulation of the mesencephalic locomotor region (MLR) in an in vitro isolated preparation, an effect that persists in the absence of the spinal cord and caudal brainstem. By using electrophysiological and anatomical techniques, including whole-cell patch recordings, we identified a subset of neurons located in the dorsal MLR that send direct inputs to neurons in the respiratory generator. In semi-intact preparations, blockade of this region with 6-cyano-7-nitroquinoxaline-2,3-dione and (2R)-amino-5-phosphonovaleric acid greatly reduced the respiratory increases without affecting the locomotor movements. These results show that neurons in the respiratory generator receive direct glutamatergic connections from the MLR and that a subpopulation of MLR neurons plays a key role in the respiratory changes linked to movement. PNAS December 12, 2011 109 (2) E84-E92 https://doi.org/10.1073/pnas.1113002109 Specific neural substrate linking respiration to locomotion Jean-François Gariépy, Kianoush Missaghi, Stéphanie Chevallier, +4 , Shannon Chartré, Maxime Robert, François Auclair, James P. Lund, and Réjean Dubuc 

Paula breathing rate does increase with motor activity but not as much as others, since it starts from a lower baseline. During some activities her breathing rate can be as high as anyone’s so she is able to sustain very fast breathing for a short period of time, if need be. Why? How? No one knows.

If C02 response is impaired in people like Paula or if C02 is retained during illness, the body and brain have an integrated physiological system to cope, including involuntary and stereotyped motor activity; increased motor activity to help “blow Off” C02 or to reduced motor activity in order to save energy.

The complete picture of the integrated physiological system to deal with a physical stressor will involve some variation of the one described below by Dr Desborough:

The stress response is the name given to the hormonal and metabolic changes which follow injury or trauma…. This obviously includes the body’s reaction to the injury inflicted by hypercapnic respiratory failure [retention of metabolic C02] ….This response is part of the systemic reaction to injury which encompasses a wide range of endocrinological, immunological and hae- matological effects (Table 1). 

Table 1 Systemic responses to surgery

Sympathetic nervous system activation, Endocrine `stress response’, pituitary hormone secretion, insulin resistance, Immunological and haematological changes, cytokine production, acute phase reaction, neutrophil leucocytosis, lymphocyte proliferation.

The endocrine response to surgery

The endocrine stress response to surgery is characterized by increased secretion of pituitary hormones and activation of the sympathetic nervous system.13 The changes in pituitary secretion have secondary effects on hormone secretion from target organs (Table 2). For example, release of cortico- trophin from the pituitary stimulates cortisol secretion from the adrenal cortex. Arginine vasopressin is secreted from the posterior pituitary and has effects on the kidney. In the pancreas, glucagon is released and insulin secretion may be diminished. The overall metabolic effect of the hormonal changes is increased catabolism which mobilizes substrates to provide energy sources, and a mechanism to retain salt and water and maintain ̄uid volume and cardiovascular homeostasis. British Journal of Anaesthesia 85 (1): 109±17 (2000) The stress response to trauma and surgery J. P. Desborou

Paula has breathing that is chronically altered, making it harder for her to maintain homeostasis. She is thus prone to hidden hypercapnic respiratory failure which is not visible because she is not able to have shortness of breath, unless the cause is a cardiac one.

The devil is in the details. Not counting her respirations carefully will obscure the role of hypercapnia in bipolar depression and mania.

Gaseous imbalance is complex and invisible and fascinating and very relevant to reversible attacks of manic depressive insanity and explains the cognitive impairment and the stereotypic motor patterns of bipolar illness.