pH, Brain Function and the importance of the motor skeletal respiratory muscles and nerves

Dr Emile Kraepelin, towards the end of his career in 1926, hypothesized that patients with [untreated] manic depressive insanity [bipolar illness] were suffering from metabolic dysfunction.Because of his research findings, Kraepelin suspected a Respiratory acid base problem affecting locomotor activity, mood and brain function. * Kraepelin measured respiratory rates, blood pressure, heart rate and body temperature of his manic depressive patients and found abnormal baseline patterns at rest; he mentions depressed respiratory rates during untreated bipolar depressed stages of the syndrome. * Chapter 3, Bodily Signs, Manic Depressive Insanity, 1926 Emile Kraepelin

Paula and I, like Kraepelin, also suspect a Respiratory acid base problem resulting in chronic hypercapnia, which can cause cognitive decline, pH changes to brain tissue, and neuro-inflammation. We followed Kraepelins methods and measured Paula’s vital signs, and we included measuring the respiratory rates. We found that Paula’s respiratory rates were also depressed and that the rest of the vital signs were abnormal in the same pattern as Kraepelin found, when Paula was in the depressed stage of bipolar illness.

Respiratory acidosis leads to decreased brain pH. Patients with chronic pulmonary disorders may exhibit lethargy, confusion, memory loss and stupor. Hypercapnic Encephalopathy – Basic Neurochemistry – NCBI https://www.ncbi.nlm.nih.gov › books › NBK28164

Cognitive impairment is associated with multiple human diseases that have in common chronic hypercapnia. However, the mechanisms leading to chronic hypercapnia-induced cognitive decline are not known……… data suggest that chronic hypercapnia leads to CNS site-dependent acute inflammatory responses and shifts in select glutamate receptor expression/phosphorylation in brain regions contributing to cognitive function. Such changes may be indicative of alterations in glutamatergic receptor-mediated signaling and neuronal dysfunction that contribute to declines in cognitive function associated with human diseases defined or marked by chronic CO2 retention. H.V.Forster Midbrain and cerebral inflammatory and glutamatergic adaptations during chronic hypercapnia in goats Brain Res. 2019 Dec 1;1724:146437.

Today, with new modern scientific tools, scientist are finding evidence of lowered pH in the brains of patients suffering from bipolar illness, schizophrenia, neuromuscular disorders, and conditions such as Parkinson’s and Alzeihmers. Decreased pH in the aging brain and Alzheimer’s disease            K. Fassbender et al   Neurobiol Aging  . 2021 May;101:40-49 Decreased Brain pH as a Shared Endophenotype of Psychiatric Disorders  T. Miyakawa et al   Neuropsychopharmacology   2018 Feb;43(3):459-468.

Scientists are also finding evidence of chronic neuro-inflammation in these same neurodegenerative and neuropsychiatric diseases.. Innate Immunity: A Common Denominator between Neurodegenerative and Neuropsychiatric Diseases G. Donato et al, Int J Mol Sci. 2020 Feb; 21(3): 1115. Published online 2020 Feb 7.   Neuroinflammation in Bipolar Depression ont. Psychiatry, 26 February 2020 R. Furlan et al

 Why not investigate chronic hypercapnia as a cause of these stable yet changeable dose related signs and symptoms? Why not at least check out the neuro-motor ventilatory system and baseline respiratory rate to see if anything is amiss. It is easy to mindfully and carefully count the respiratory rate to see if it is normal or not. * Baseline respiratory rates are the most sensitive of the vital signs in detecting illness and deterioration [mental and physical]. * The value of vital sign trends in predicting and monitoring clinical deterioration: A systematic review M. Braband et al PLoS One. 2019; 14(1): e0210875.

Abnormal and stable baseline respiratory rates can lead to [hidden] stable, dose related levels of hypercapnic ventilatory failure during periods of respiratory muscle weakness and increased load.

Abnormal baseline respiratory rates can lead to lowered brain pH and chronic neuro-inflammation, especially during chronic periods of exacerbations.

Abnormal respiratory rates can lead thus, to abnormal brain function and abnormal states of consciousness [hyper-awakeness/ difficulty sleeping/ sympathetic arousal/ awake-sensations of distress, fear, dyspnea/sleepiness/stupor/brain fog, etc]… and abnormal function of mind [cognitive impairment/amnesia for personal facts and skills] and abnormal locomotor activity and speed [psychomotor dullness/psychomotor excitement/abnormal spinal reflex arcs [too slow, too fast]/muscle stiffness].

Abnormal baseline respiratory rates will affect pH [intracellular and extracellular] which will affect all functions of the body and brain.

Abnormal baseline respiratory rates AND periods of altered mental state, altered cognition, altered memory, loss of previously known skills and knowledge, altered personality, altered speech, altered feeding, loss of appetite, altered locomotor activity and speed etc.. definitely suggests that pH is disturbed, affecting intracellular/extracellular processes in brain cells and tissues and in muscle tissues [skeletal and smooth and cardiac] requiring, , at the very least,, at the very least, further medical [noninvasive] investigation [minute ventilation] and more. The effects of chronically disturbed baseline ventilation can be investigated and even treated in the 21st century. Damage to the ventilatory system of peripheral nerves and muscle fibres probably cannot be repaired but supportive medical, nutritional and rehabilitative treatments can be given in the current century, and baseline mental status potentially restored.

Dr Kraepelin understood the implications of his findings of stable but abnormal baseline breathing rates [depressed and excited] in both depressive psychosis and manic psychosis. He mentioned depressed breathing rates in depressive insanity. He knew he was describing a a type of respiratory failure that results in an acidosis, He also mentioned a rapid, chaotic pattern of breathing in mania. Abnormal breathing rate, breathing depth and breathing pattern is a known cause of respiratory acid base disorders and acid base affects every cell in the body, and neutrons are particularly sensitive. The importance of acid base balance was understood in Kraepelin’s time and Kraepelin understood physiology and biology very well, he worked with physiologist William Wundt, Wundt himself trained by W. Hemholtz., physicist and physiologist. .

Abnormal respiratory rates can suggest the possibility of a chronic hypercapnia due to depressed ventilation and possible hypoventilation of the alveoli in the lungs, resulting in inflammation of the brain and declines in cognitive function…..due to cerebral vasodilation effects of endogenous CO2 and most likely affecting cerebral blood flow and raising intracranial pressure.

Abstract: …….These data suggest that chronic hypercapnia leads to CNS site-dependent acute inflammatory responses and shifts in select glutamate receptor expression/phosphorylation in brain regions contributing to cognitive function. Such changes may be indicative of alterations in glutamatergic receptor-mediated signaling and neuronal dysfunction that contribute to declines in cognitive function associated with human diseases defined or marked by chronic CO2 retention. H. V.Forster Midbrain and cerebral inflammatory and glutamatergic adaptations during chronic hypercapnia in goats Brain Res 2019 Dec 1;1724:146437.

The brain monitors endogenous CO2 [and CO2 in the air] in order to regulate breathing. But what if it can’t. What if some of the parts of the peripheral motor ventilatory system are broken – having suffered damage? What if some of the deeper muscles in the motor skeletal ventilatory system are weaker and more difficult to move or react? This could explain why Paula’s baseline respiratory rate at rest is depressed. During exercise – her rate of ventilation rises only sluggishly. It appears that Paula’s brain cannot regulate her breathing normally. Paula seems to depend a lot on increasing the depth of her breath [through increased accessory muscle use and effort] more than increasing the rate, even with exercise, which increases her work of breathing and is not a normal pattern of breathing. Maybe she can’t increase her rate of breathing without a very strong stimulus or by using different undamaged nerve pathways. Paula also may use her locomotor muscles during manic attacks to aid her breathing when it becomes absolutely necessary to avoid hypoxia and further hypercapnia. It turns out that the locomotor limb muscles are very important in breathing. Paula’s unconscious brain [eg the brain stem] may sometimes choose to regulate respiratory motor output by stimulation of limb muscles when control of brain H+ becomes an emergency and there is no other way, even though mood, cognition and memory may still be abnormal and erratic. This would certainly explain the madness of mania.

Breathing constantly adapts to environmental, metabolic or behavioral changes by responding to different sensory information, including afferent feedback from muscles. Importantly, not just respiratory muscle feedback influences respiratory activity. Afferent sensory information from rhythmically moving limbs has also been shown to play an essential role in the breathing. The present review will discuss the neuronal mechanisms of respiratory modulation by activation of peripheral muscles that usually occurs during locomotion or exercise. An understanding of these mechanisms and finding the most effective approaches to regulate respiratory motor output by stimulation of limb muscles could be extremely beneficial for people with respiratory dysfunctions. Specific attention in the present review is given to the muscle stimulation to treat respiratory deficits following cervical spinal cord injury.Modulation of Respiratory System by Limb Muscle Afferents in Intact and Injured Spinal Cord T. Bezdudnaya et al Front. Neurosci., 26 March 2019 

Why does Paula breath this way? We do not really know. This needs more study, especially given Kraepelin’s observations and and ours. If we had to guess, we would look more closely at the “the neural and motor circuits underlying central command and muscle afferent control of breathing. ” These “remain elusive and represent a fertile area for future investigation.” see Abstract in this post: D. Bayliss et al Neural Control of Breathing and CO2 Homeostasis Neuron  2015 Sep 2;87(5):946-61

Despite Paula’s chronically stable sensations of anguish, distress and extreme anxiety during her attack, her baseline respiratory rate stayed depressed at rest. This does not fit with the body’s normal reaction to stress or in this case distress. Fear and distress typically cause the respiratory rate to rise.

What is the body’s reaction to stress? When you feel threatened, a chemical reaction occurs in your body that allows you to act in a way to prevent injury. This reaction is known as “fight-or-flight,” or the stress response. During stress response, your heart rate increases, breathing quickens, muscles tighten, and blood pressure rises. Aug 19, 2021 Stress https://www.webmd.com/balance/stress-management/stress-symptoms-effects_of-stress-on-the-body

During Paula’s extreme sensation of fear and stress during her depressive attack, YES, her heart rate did increase, YES, her muscles did tighten, YES, her blood pressure did rise a lot AND NO, her breathing rate DID NOT increase as expected, despite extreme sympathetic activation. In fact her respiratory rate stayed stuck and it stayed depressed. [by the way, when Paula recovered, her breathing rate remained depressed and her heart rate, blood pressure and muscles became normal. It seems that her body has accommodated to her baseline depressed breathing condition and she only reacts with sympathetic activation and brain/mind dysfunction during exacerbations and increased levels of retention of more endogenous/exogenous CO2.

This needs further exploration. It makes no sense…..unless we understand more. This is not how the [fight of fight] sympathetic nervous system works …unless something in Paula is broken, explaining the respiratory rates and patterns that we are measuring and that Paula is unaware of

Control of Breathing requires intact peripheral nerve and muscle fibres of the skeletal motor ventilator system- the Respiratory Pump. .

As shown below, there are many parts and it is very complex.

Vagal control of the breathing pattern

  It has long been recognized that section of the vagi in the neck (before entrance into the vertebral column) has a major effect on the breathing pattern; breathing frequency is reduced and tidal volume increased .

3.1. Vagal reflexes 
    The vagus, tenth cranial nerve, is a mixed (sensory and motor) bilateral nerve. Its sensory neurons have their body in the nodus and petrosus ganglions, and the afferent fibers, partly myelinated and mostly not-myelinated, innervate a variety of thoracic and abdominal organs [Fig.7]. 

[ Explanation: Afferent neurons are sensory neurons that carry nerve impulses from sensory stimuli towards the central nervous system and brain, while efferent neurons are motor neurons that carry neural impulses away from the central nervous system and towards muscles to cause movement. AP Biology : Understanding Afferent and Efferent Neurons]

Fig. 7

Fig 7 : RESTING BREATHING PATTERN and ITS PERIPHERAL MODULATION, Vagal Control of the Breathing Pattern. https://www.medicine.mcgill.ca/physio/resp-web/TEXT4.htm

It bears repeating… “It has long been recognized that section of the vagi in the neck (before entrance into the vertebral column) has a major effect on the breathing pattern; breathing frequency is reduced and tidal volume increased . ”

Does Paula have damage to the peripheral ganglions of the vagus nerve? or to other parts of the vagus nerve controlling breathing pattern?

Or maybe she has damage to the [many] afferents of the chest wall? Or damage to muscle fibres anchored to the chest wall?

Nerves

The muscles that comprise the thoracic wall and the posterior thorax are innervated by the intercostal nerves, which mainly come from the anterior rami of spinal nerves T1 to T11. The anterior ramus of spinal nerve T12 is a subcostal nerve. Each intercostal nerve supplies a dermatome and a myotome. Their afferent fibers provide sensory information to the overlying skin while their efferent fibers conduct motor information to the muscles of inspiration. Of note, only a portion of the anterior ramus of spinal nerve T1 forms the lower trunk of the brachial plexus whereas the remaining intercostal nerves do not form plexuses.[1][2]

Innervation to the muscles of the anterior thorax arises from different branches of the brachial plexus. Innervation of the pectoralis major is by both the lateral pectoral nerve, which innervates the clavicular head, and the medial pectoral nerve, which innervates the sternocostal head. The pectoralis minor receives its innervation by the medial pectoral nerve. The lateral pectoral nerve branches from the lateral cord of the brachial plexus while the medial pectoral nerve comes from the medial cord.[4][8] The nerve to the subclavius innervates the subclavius muscle, which arises from the superior trunk of the C5 to C6 nerve roots. If present, the accessory phrenic nerve, mostly a C5 contribution, may also provide motor innervation to the subclavius muscle.[5] Last, the serratus anterior is innervated by the long thoracic nerve, which originates from the anterior rami of C5 to C7.[6]

Innervation to the diaphragm comes from both the right and left phrenic nerves, which originate from the anterior rami of C3 to C5. The phrenic nerve provides both the motor innervation to allow the diaphragm to contract during inspiration and sensory innervation to the parietal pleura and peritoneum covering the central aspect of the diaphragm. The lower six intercostal nerves provide sensory innervation to the periphery of the diaphragm.[3][5] Anatomy, Thorax, Muscles StatPearls [Internet]. https://www.ncbi.nlm.nih.gov/books/NBK538321/

And then there is the possibility of hidden muscle damage involving the muscle fibres;

Muscles

The muscles of the thorax discussed in this article include the following:

  • Thoracic Wall
    • Intercostal muscles
      • External intercostal muscle
      • Internal intercostal muscle
      • Innermost intercostal muscle
    • Subcostalis
    • Transversus thoracis
  • Posterior Thorax
    • Levatores costarum
    • Serratus posterior superior and inferior muscles
  • Anterior/Superficial Thorax
    • Pectoralis major and minor muscles
    • Subclavius
    • Serratus anterior
  • Floor
    • Diaphragm

Physiologic Variants

Multiple studies have reported the existence of anatomical variations of the muscles of the thorax either in the case of supernumerary muscles or congenital anomalies .  Anatomy, Thorax, Muscles StatPearls [Internet]. https://www.ncbi.nlm.nih.gov/books/NBK538321/

What about non progressive muscle weakness from an injury or accident?

Respiratory muscle weakness is a common complication in many neuromuscular and chest wall conditions, and although it may occasionally be a presenting feature of the underlying disorder, it generally is a complication of an already established diagnosis. In view of the impact of chronic respiratory failure on health-related quality of life and the potential life-threatening consequences of respiratory muscle weakness, respiratory muscle function should be monitored at regular intervals with noninvasive respiratory muscle tests in patients with progressive neuromuscular disease. Furthermore, patients with neuromuscular disease or chest wall disease, or both, who present with unexplained dyspnea should be referred for formal respiratory assessment. This evaluation will include a detailed history and clinical examination with a focus on symptoms suggestive of significant muscle weakness, sleep-disordered breathing, and associated complications such as bulbar symptoms. Other components of the evaluation will include a basic lung volume measurement, noninvasive respiratory muscle testing, and, in special circumstances, invasive respiratory muscle testing. It is well to be mindful, however, of the limitations of performing a single measure of respiratory muscle strength in attempting to diagnose respiratory muscle weakness . Diseases of the Thoracic Cage and Respiratory Muscles Michelle Ramsay, … Nicholas Hart, in Clinical Respiratory Medicine (Fourth Edition), 2012 in https://www.sciencedirect.com/topics/medicine-and-dentistry/respiratory-muscle

The ventilatory system responsible forgiving air in and out of the body is very complex and can become damaged in a number of different ways, especially in the more fragile, relatively unprotected periphery.

Kraepelin thought, based on his observations, that manic depressive patients had a non progressive respiratory defect or injury making control of acid base inside the brain and body tissues and cells more difficult. This certainly seems to be the case with Paula. Paula does not seem to be able to regulate her breathing normally.

If asked, Paula would say she did experience difficulty breathing or “dyspnea” during her experience of fear and distress. “Although several sensory receptors located throughout the respiratory system are considered to be responsible for generation of dyspnoea, there is no afferent receptor solely responsible for the sensation of dyspnoea. Afferent information from the sensory receptors is processed at the cortex along with the respiratory motor command from the cortex and brainstem, and a mismatch between the motor command and the incoming afferent information may result in dyspnoea.” T. Nishino Dyspnoea: underlying mechanisms and treatment BJA: British Journal of Anaesthesia, Volume 106, Issue 4, April 2011, Pages 463–474,

In Paula’s case there is definitely a mismatch between motor command and the incoming afferent information; her respiratory pump muscles are unable to increase their rate, even with the help of the extra abdominal muscles, during an internal or external stress, at rest and even have difficulty with exercise. It is likely, we think that peripheral nerve or muscle injury, affecting the ventilatory system is at fault. We think that the brain stem is working normally and that the brain stem must freak out when it cannot raise the breathing rate normally in times of need. Hypercapnia affecting the brain would explain the tremendous fear and distress and dyspnea experienced in this situation by Paula. And unfortunately the brain stem doesn’t speak and so Paula has no words to explain this and of course, is not aware of damage to the nerves or muscle afferents of the ventilatory system. This needs to be studied.

Abstract

Recent advances have clarified how the brain detects CO2 to regulate breathing (central respiratory chemoreception). These mechanisms are reviewed and their significance is presented in the general context of CO2/pH homeostasis through breathing. At rest, respiratory chemoreflexes initiated at peripheral and central sites mediate rapid stabilization of arterial PCO2 and pH. Specific brainstem neurons (e.g., retrotrapezoid nucleus, RTN; serotonergic) are activated by PCO2 and stimulate breathing. RTN neurons detect CO2 via intrinsic proton receptors (TASK-2, GPR4), synaptic input from peripheral chemoreceptors and signals from astrocytes. Respiratory chemoreflexes are arousal state dependent whereas chemoreceptor stimulation produces arousal.…. …During exercise, central command and reflexes from exercising muscles produce the breathing stimulation required to maintain arterial PCO2 and pH despite elevated metabolic activity. The neural circuits underlying central command and muscle afferent control of breathing remain elusive and represent a fertile area for future investigation. D. Bayliss et al Neural Control of Breathing and CO2 Homeostasis Neuron  2015 Sep 2;87(5):946-61

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