Neuro Endocrinol Lett. . 2011;32(1):7-24.
Depression’s multiple comorbidities explained by (neuro)inflammatory and oxidative & nitrosative stress pathways
Michael Maes 1, Marta Kubera, Ewa Obuchowiczwa, Lisa Goehler, Joanna Brzeszcz
There is now evidence that depression, as characterized by melancholic symptoms, anxiety, and fatigue and somatic (F&S) symptoms, is the clinical expression of peripheral cell-mediated activation, inflammation and induction of oxidative and nitrosative stress (IO&NS) pathways and of central microglial activation, decreased neurogenesis and increased apoptosis. This review gives an explanation for the multiple “co-morbidities” between depression and a large variety of a) brain disorders related to neurodegeneration, e.g. Alzheimer’s, Parkinson’s and Huntington’s disease, multiple sclerosis and stroke; b) medical disorders, such as cardiovascular disorder, chronic fatigue syndrome, chronic obstructive pulmonary disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, inflammatory bowel disease, irritable bowel syndrome, leaky gut, diabetes type 1 and 2, obesity and the metabolic syndrome, and HIV infection; and c) conditions, such as hemodialysis, interferon-α-based immunotherapy, the postnatal period and psychosocial stressors. The common denominator of all those disorders/conditions is the presence of microglial activation and/or activation of peripheral IO&NS pathways. There is evidence that shared peripheral and / or central IO&NS pathways underpin the pathophysiology of depression and the previously mentioned disorders and that activation of these IO&NS pathways contributes to shared risk. The IO&NS pathways function as a smoke sensor that detect threats in the peripheral and central parts of the body and signal these threats as melancholic, anxiety, and fatigue and somatic (F&S) symptoms. The presence of concomitant depression is strongly associated with a lower quality of life and increased morbidity and mortality in medical disorders. This may be explained since depression contributes to increased (neuro)inflammatory burden and may therefore drive the inflammatory and degenerative progression. It is concluded that the activation of peripheral and / or central IO&NS pathways may explain the co-occurrence of depression with the above disorders. This shows that depression belongs to the spectrum of inflammatory and degenerative disorders.
Well, if indeed it turns out that “depression belongs to the spectrum of inflammatory and degenerative disorders“, then the question that Paula and I have is…whether inflammation can change motor systems such as movement and breathing?
…...to be continued…..
We know that delirium has strong motor components due to existence of stereotyped motor subtypes of delirium. The motor subtypes are similar to bipolar subtypes in ambulatory patients. It seems that bot delirium and bipolar disorder may be due to the same thing- systemic peripheral or central inflammation.
Inflammation consists of reflex responses in the body and blood
Nature. . 2002 Dec;420(6917):853-9.
The inflammatory reflex
Inflammation is a local, protective response to microbial invasion or injury. It must be fine-tuned and regulated precisely, because deficiencies or excesses of the inflammatory response cause morbidity and shorten lifespan. The discovery that cholinergic neurons inhibit acute inflammation has qualitatively expanded our understanding of how the nervous system modulates immune responses. The nervous system reflexively regulates the inflammatory response in real time, just as it controls heart rate and other vital functions. The opportunity now exists to apply this insight to the treatment of inflammation through selective and reversible ‘hard-wired’ neural systems.
Not only is there an Inflammatory Reflex to protect us from viruses or injury, there is also a Respiratory Reflex to protect us, as well.
D.R. McCrimmon, … G.F. Alheid, in Encyclopedia of Neuroscience, 2009. in science direct; https://www.sciencedirect.com/topics/neuroscience/breathing-reflex
Sensory receptors related to breathing have essential regulatory and airway-protective roles. Coughing, sneezing, mucus secretion, and airway constriction protect the airways from irritants and facilitate the removal of inhaled substances that are potentially harmful to the lungs and airways. Sensory feedback from arterial and central chemoreceptors as well as lung mechanoreceptors modulates the breathing pattern (e.g., tidal volume and breathing frequency) and is essential for matching ventilation to changing metabolic requirements. Feedback is also essential for adapting respiratory motor output to other behaviors such as changes in posture or locomotion.
Receptors in the Nasal Passages and Pharynx
Respiratory reflexes can be evoked from the nasal cavities via receptors in the mucous membrane. Sensory information is transmitted largely via branches of the trigeminal nerve, including the anterior ethmoidal nerve and branches of the maxillary nerve. Nasal receptors respond to inhaled irritants such as ammonia, cigarette smoke, and volatile anesthetics, as well as to cold and decreased pressure associated with respiratory airflow. Irritants elicit various cardiorespiratory reactions, including sneezing, mucus secretion, bradycardia, hypertension, and inhibition of breathing. https://www.sciencedirect.com/topics/neuroscience/breathing-reflex
You will remember that Dr Emile Kraepelin noted that ventilation was abnormal in bipolar depressive stages and different yet abnormal in mania. Abnormal rates, rhythms and patterns of ventilation may be directly related to emotion, thinking, locomotion and to managing PaC02 and and pH.
Abnormal ventilation and acute onset of mental confusion/cognitive impairment with locomotor changes are likely to be intimately linked. The motor act of breathing and the reflexes controlling endogenous carbon dioxide produced by metabolism of food affect the gases in the blood in the entire body. The brain is part of the body. The ventilatory system of the body, the responses of the blood and the circulation and the brain are intimately linked.
The fact that Paula has depressed ventilation and has had episodes of quiet sustained delirium or serious sustained depression [same thing] is significant! The fact that Kraepelin also saw important links between incapacitated patients with bipolar depression and very abnormal [we think depressed] ventilation in thousands of unmedicated patients in the asylums suggests that Paula is one more patient in Kraepelin’s sample. One more patient of thousands with abnormal control of breathing which is easy to measure if one cares to.
But again I ask, are inflammation and changes in baseline ventilation related ?
Well, research is now suggesting that inflammation during sensitive times can affect the “control of breathing”.
One bout of neonatal inflammation impairs adult respiratory motor plasticity in male and female rats
- Austin D Hocker,
- Sarah A Beyeler,
- Alyssa N Gardner,
- Stephen M Johnson,
- Jyoti J Watters,
- Adrianne G Huxtable
Mar 22, 2019
Neonatal inflammation is common and has lasting consequences for adult health. We investigated the lasting effects of a single bout of neonatal inflammation on adult respiratory control in the form of respiratory motor plasticity induced by acute intermittent hypoxia, which likely compensates and stabilizes breathing during injury or disease and has significant therapeutic potential. Lipopolysaccharide-induced inflammation at postnatal day four induced lasting impairments in two distinct pathways to adult respiratory plasticity in male and female rats. Despite a lack of adult pro-inflammatory gene expression or alterations in glial morphology, one mechanistic pathway to plasticity was restored by acute, adult anti-inflammatory treatment, suggesting ongoing inflammatory signaling after neonatal inflammation. An alternative pathway to plasticity was not restored by anti-inflammatory treatment, but was evoked by exogenous adenosine receptor agonism, suggesting upstream impairment, likely astrocytic-dependent. Thus, the respiratory control network is vulnerable to early-life inflammation, limiting respiratory compensation to adult disease or injury.
So it is significant that Paula had a hypoxic birth and needed resuscitation and transfusion. It may follow that structures involved in the motor act of ventilation [moving air in and out of the body in the correct proportions] might have been damaged, forcing changes and adaptations to control of breathing and limiting reflexes involving PaC02 and pH.
Researchers and doctors could have reached this conclusion over 100 years ago, had they listened to Kraepelin and tried replicating his findings on the motor act of breathing in the different stages of bipolar illness. [or, as I am suggesting, bipolar illness being a form of chronic delirium [all motor subtypes].
But no……….doctors insisted in believing that the brain and the mind were different from the body and refused to look for simple physical signs i.e. vital signs. Vital signs, if abnormal-especially breathing rate and pattern at rest, suggests that bipolar illness is due to damage to a an organic homeostatic system, where the ability to breathe is more important than anything else, even more important than cognition, memory or making sense.
If you, the reader, ever lose your mind, you will be disgusted at the foolishness of psychiatrists in whose hands you will be delivered.
to be continued……………
to be continued