More than 2000 years ago, Roman scholars defined inflammation (in Latin) as a process having color, dolor, rubor, and tumor. These four cardinal signs – heat, pain, redness, and swelling – are the visible manifestations of acute inflammation in the body. But chronic inflammation in our organs does not announce its presence in any such dramatic manner. Far too often we recognise the presence of chronic inflammation only when organs have become dysfunctional. We are now learning to pay closer attention to biomarkers of inflammation in those who suffer from diseases which are multifactorial (having multiple causes). We are also learning that chronic inflammation may be the result of an imbalance in the autonomic nervous system – the part of the brain which controls vital functions, like breathing and heart rate, and which we are usually unaware of.
Diseases are caused by different mechanisms. Hence, diseases are classified as infective diseases (caused by pathogenic microbes), autoimmune diseases (caused by altered immunity), malignant diseases (caused by unchecked cell growth), degenerative diseases (caused by aging or wear and tear), metabolic diseases (caused by disruption of normal cellular metabolism through toxins or deficiencies) and hereditary diseases (caused by defective genes). What is now becoming evident is that the common denominator of all diseases is inflammation. Inflammation always begins as a protective response to keep the organism safe from harm. Damage and dysfunction occur when inflammation becomes self-perpetuating and prolonged.
In that most mysterious of organs, the brain, there are cells called microglia. Once dismissed as having only a supporting role in keeping neurons together (‘glia’ comes from the Greek meaning glue), we now know that these cells function in the same way as macrophages in the peripheral blood. They are meant for damage-control. Microglia respond to changes in neuronal integrity by transforming from a dormant state to an activated state. They then secrete chemicals called cytokines to recruit other inflammatory cells to keep the brain safe. When severe or prolonged, the inflammation mounted by these microglia can damage normal brain tissue. Evidence of activated microglia and increased amounts of inflammation-producing molecules (like interleukins 1 and 6, and tumour necrosis factor) have been noted in the brains of patients with neurodegenerative disorders such as Alzheimer’s and Parkinsonism. Like the question about the chicken and the egg, the difficulty is always in determining which came first. Did the inflammation cause the disease or is the observed inflammation because of the disease?
In a paper titled ‘Inflammation as a central mechanism in Alzheimer’s disease’ (published in the journal called Alzheimer’s and Dementia in September 2018), the authors provide research evidence to support the hypothesis that persistent inflammatory activity in the brain can be one reason for the appearance of amyloid deposits and neurofibrillary tangles in the brains of those with Alzheimer’s disease. Mood disturbances and challenging behaviours are often associated with Alzheimer’s disease. Are these also related to chronic inflammation? The answer may be yes. In 2009, a paper in the journal of Biological Psychiatry suggested that chronic inflammation may have an etiological role in major neuropsychiatric disorders too. The authors showed evidence of increased inflammatory biomarkers (cytokines) in the peripheral blood of those with major depression. They also noted that depressed patients with higher levels of inflammatory markers are more likely to be resistant to anti-depressant treatment.
What is it that triggers the chronic inflammation which insidiously damages brain tissue? Many factors can be responsible. In February 2022, a paper published in the International Journal of Molecular Sciences discussed the interplay between the autonomic nervous system and the immune system. The gist of the article was: when the balance between the sympathetic and parasympathetic nervous systems is skewed towards persistently increased sympathetic activity, conditions are in place for chronic inflammation to develop. Which is why, the authors say, vagal stimulation techniques have emerged in recent years as a method to increase parasympathetic activity and restore balance in the autonomic nervous system. Increased sympathetic activity will not only stimulate release of pro-inflammatory hormones and chemical mediators but will also adversely affect the gut microbiota which has an important role in immune regulation.
A publication in Stroke (a journal from the American Heart Association) in April 2021 discussed the findings in their study related to risk of stroke and dementia in those with preexisting autonomic imbalance. They concluded that “some measures of autonomic imbalance may precede dementia and stroke in older adults”. They used resting heart rate and heart rate variability as parameters of cardiac autonomic imbalance.
In the same way that cholesterol in our blood is not the sole cause of heart disease, but a marker for increased probability of developing heart disease, we can say that an autonomic nervous system skewed towards consistently increased sympathetic activity will increase the probability of insidious brain damage leading to neurodegenerative diseases and mood disorders. And, just as we pay attention to diet and exercise for protecting the heart, we can learn to pay attention to factors that optimise gut microbiota and learn techniques (slow-paced breathing, for example) to regulate the autonomic nervous system.
Nature has programmed us for survival by using a default brain setting called the ‘fight or flight’ response mediated through the sympathetic nervous system. It is not a surprise that this same system also mediates inflammation which is, first and foremost, a protective mechanism. However, inflammation is a double-edged sword and can become too much of a good thing. We are now learning that the autonomic nervous system may have a role to play in initiating and in maintaining chronic inflammation in the brain. This knowledge can help us. We may be able to reduce the risk of developing neurodegenerative diseases like Alzheimer’s, and mood disorders like anxiety-depression, by learning ways to increase parasympathetic activity and balance the autonomic nervous system. In short, chronic inflammation is the fire within the brain that we must learn to extinguish.
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Good morning Sir.
An excellent article on the role of inflammation in various Neurological disorders through overactive Immune system or the imbalance of the ANS.
Incedently there is a book on Autoimmune Encephalitis written by a patient, named ' "Brain On Fire "
Most of the advances in Neurological disorders and Newer medications are in the sphere of Inflammation of the brain.
Your article has simplified it so beautifully, that anyone can understand this complex concept easily.