“Inflammation can be defined as a type of immunoresponse to tissue injuries. In the past, it could only be diagnosed based on visual findings or changes in white-blood-cell counts, but even microinflammation can be measured today using substances released by cells during inflammation, such as cytokines or CRP, as markers. As a result, a considerable amount of research has been directed toward the measurement of the underlying inflammatory changes in several psychiatric disorders, including depression, and the link between physical and mental diseases is being interpreted in relation to inflammation.” J Inflamm Res. 2018; 11: 179–192. Published online 2018 May 8. doi: 10.2147/JIR.S141033 The role of neuroinflammation and neurovascular dysfunction in major depressive disorder Sang Won Jeon1 and Yong-Ku Kim2
“A growing body of evidence now highlights a key role for inflammation in mediating sickness behaviors and depression. Systemic inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, and chronic liver disease have high comorbidity with depression. How the periphery communicates with the brain to mediate changes in neurotransmission and thereby behavior is not completely understood. Traditional routes of communication between the periphery and the brain involve neural and humoral pathways with TNFα, IL-1β, and IL-6 being the three main cytokines that have primarily been implicated in mediating signaling via these pathways. However, in recent years communication via peripheral immune-cell-to-brain and the gut-microbiota-to-brain routes have received increasing attention for their ability to modulate brain function. In this chapter we discuss periphery-to-brain communication pathways and their potential role in mediating inflammation-associated sickness behaviors and depression. ” Immune-to-Brain Communication Pathways in Inflammation-Associated Sickness and Depression. Curr Top Behav Neurosci 2017;31:73-94. doi: 10.1007/7854_2016_37. Charlotte D’Mello 1, Mark G Swain PMID: 27677781 DOI: 10.1007/7854_2016_37
“The immune-inflammation hypothesis has attracted much attention, suggesting that the interactions between inflammatory pathways and neural circuits and neurotransmitters are involved in the pathogenesis and pathophysiological processes of depression. Early evidence found that patients with autoimmune or infectious diseases are more likely to develop depression than the general population . In addition, individuals without depression may display depressive symptoms after treatment with cytokines or cytokine inducers, while antidepressants relieve these symptoms [55, 56]. There is a complex interaction between the peripheral and central immune systems. Previous evidence suggested that peripheral inflammation/infection may spread to the central nervous system in some way and cause a neuroimmune response [55, 57]: (1) Some cytokines produced in the peripheral immune response, such as IL-6 and IL-1 β, can leak into the brain through the blood-brain barrier (BBB). (2) Cytokines entering the central nervous system act directly on astrocytes, small stromal cells, and neurons. (3) Some peripheral immune cells can cross the BBB through specific transporters, such as monocytes. (4) Cytokines and chemokines in the circulation activate the central nervous system by regulating the surface receptors of astrocytes and endothelial cells at the BBB. (5) As an intermediary pathway, the immune inflammatory response transmits peripheral danger signals to the center, amplifies the signals, and shows the external phenotype of depressive behavior associated with stress/trauma/infection. (6) Cytokines and chemokines may act directly on neurons, change their plasticity and promote depression-like behavior.……..
…………Patients with depression show the core feature of the immune-inflammatory response, that is, increased concentrations of pro-inflammatory cytokines and their receptors, chemokines, and soluble adhesion molecules in peripheral blood and cerebrospinal fluid [58–60]. Peripheral immune-inflammatory response markers not only change the immune activation state in the brain that affects explicit behavior, but also can be used as an evaluation index or biological index of antidepressant therapy [61, 62]. Li et al. showed that the level of TNF-α in patients with depression prior to treatment was higher than that in healthy controls. After treatment with venlafaxine, the level of TNF-α in patients with depression decreased significantly, and the level of TNF-α in the effective group decreased more . A recent meta-analysis of 1,517 patients found that antidepressants significantly reduced peripheral IL-6, TNF-α, IL-10, and CCL-2, suggesting that antidepressants reduce markers of peripheral inflammatory factors . Recently, Syed et al. also confirmed that untreated patients with depression had higher levels of inflammatory markers and increased levels of anti-inflammatory cytokines after antidepressant treatment, while increased levels of pro-inflammatory cytokines were found in non-responders . Clinical studies have also found that anti-inflammatory cytokines, such as monoclonal antibodies and other cytokine inhibitors, may play an antidepressant role by blocking cytokines. The imbalance of pro-inflammatory and anti-inflammatory cytokines may be involved in the pathophysiological process of depression.……..
……….In addition, a recent study showed that microglia contribute to neuronal plasticity and neuroimmune interaction that are involved in the pathophysiology of depression . When activated microglia promote inflammation, especially the excessive production of pro-inflammatory factors and cytotoxins in the central nervous system, depression-like behavior can gradually develop [65, 66]. However, microglia change polarization as two types under different inflammatory states, regulating the balance of pro- and anti-inflammatory factors. These two types are M1 and M2 microglia; the former produces large number of pro-inflammatory cytokines after activation, and the latter produces anti-inflammatory cytokines. An imbalance of M1/M2 polarization of microglia may contribute to the pathophysiology of depression .” Major Depressive Disorder: Advances in Neuroscience Research and Translational Applications Zezhi Li,1,2Meihua Ruan,3Jun Chen,1,5 and Yiru Fang Neurosci Bull. 2021 Jun; 37(6): 863–880. Published online 2021 Feb 13. doi: 10.1007/s12264-021-00638-3
“Neuroinflammation, defined as inflammation of nervous tissue, is initiated in response to a variety of endogenous and exogenous sources including invading pathogens, neuronal injury, and toxic compounds. It is characterized by glial cell activation, the release of inflammatory molecules, increased blood-brain barrier permeability, and recruitment of peripheral immune cells into the brain. Neuroinflammation is initiated by microglia, which are the resident immune cells of the central nervous system. Under steady-state conditions, microglia are maintained in a “resting” state through interactions with cell surface and soluble factors from surrounding cells. Microglia become activated following exposure to pathogen-associated molecular patterns (PAMPs) and/or endogenous damage-associated molecular patterns (DAMPs), and removal of the immune-suppressive signals. Activated microglia can acquire different phenotypes depending on cues in its surrounding environment. M1 microglia are initially present following an insult as they promote a proinflammatory response. Over time, the response is shifted to be anti-inflammatory, which is mediated by M2 microglia. In truth, current research has suggested that microglia activation is more complex than originally believed. It has been suggested that there is a range of microglia activation states that span from the M1 to M2 phenotypes, with each phenotype displaying different markers, secreting different compounds, and exhibiting different functions.” Microglia Activation During Neuroinflammation: Overview https://www.rndsystems.com/pathways/microglia-activation-during-neuroinflammation-overview
Inflammation in the brain has been linked to memory loss and cognitive disorders, including Alzheimer’s disease. When inflammation has occurred after an infection, injury, stroke, or even after a surgical procedure, the resulting memory loss can be profound and prolonged. Sep. 20, 2012 Memory loss caused by inflammation may be reversible
Paula’s memory loss was profound and prolonged, including autobiographical memory loss. Her “control of breathing” mechanism is abnormal, depressing her ventilatory responses. Endogenous and/or exogenous carbon dioxide in excess is a toxin, with dose related effects. Endogenous C02, when in excess, is a toxin, with dose related effects and could definitely cause neuroinflammation and activation of the glia .
Diagnosing the possibility of excess carbon dioxide in the blood is simple and is non invasive. All one has to do is check if the respiration rate is normal. Counting respirations at rest for one minute with a stopwatch will tell you if respiration is normal. Paula’s respiration rate at rest is 3-5 breathes per minute. A normal respiration rate at rest is between 12-16 breaths per minute. Paula’s breathing rate is very depressed and does not rise normally with exercise or with exposure to high C02 environments. “During quiet breathing, there is little or no muscle contraction involved in exhalation; this process is simply driven by the elastic recoil of the lungs. When forceful exhalation is required, or when the elasticity of the lungs is reduced (as in emphysema), active exhalation can be achieved by contraction of the abdominal wall muscles (rectus abdominis, transverse abdominis, external oblique muscle and internal oblique muscle). These press the abdominal organs cranially (upward) into the diaphragm, reducing the volume of the thoracic cavity.” Muscles of Respiration Wikipedia
Paula uses forceful exhaling; she uses her abdominal muscles to exhale with every breath. This is not normal. Paula is at risk for attacks of hypercapnia due to respiratory failure, because of her depressed breathing and because of needing sting voluntary muscles to breathe out excess C02. . These attacks are most likely the cause of inflammation occurring after an infection. And inflammation affecting the brain is most likely the cause of her autobiographical memory loss after a significant infection. Paula cannot recover easily once her ventilatory system is weakened by physical illness. She will need supportive medical care until her memory recovers.
Paula’s memory and cognitive skills did return without supportive medical care, but it took a long time -too long.
Because no one checked her vital signs when she got sick and got seemingly depressed. No one counted her respiration rate. No one knew her breathing was depressed. Paula did not know that her breathing was depressed.
And so she had to figure it out herself, with my help and that of Dr Emile Kraepelin and his careful studies.
Dr Kraepelin did measure respiratory rates at rest in 1926 in thousands of patients similar to Paula.
No one listened to him, just as no one is listening today.
This is the reason why we decided to write this blog.