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Some molecular changes in the brain under hyperthermia that affect the development of the brain.

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• Nitric Oxide (NO): 

Hyperthermic brain injury is associated with a marked upregulation of nitric oxide synthase (NOS), which produces nitric oxide (NO) [72].  NO is an important signaling molecule that is widely used in the nervous system [73]. However, it is a radical gas and a highly reactive molecule with an unpaired electron, which takes an electron from another molecule and destabilizes that molecule. In a high level of NO toxicity, it acts in the nucleus and in the membranes of cells, damaging molecules such as DNA, proteins, carbohydrates, and lipids during the whole life cycle of the cell [74, 75], and not only during the period of cell division. It means that a baby who is 3 months old for example, whose head is massaged with the hot water, would still suffer from death of neuron due to the nitric oxide toxicity induced by the hot water massage, even though the baby passed already the sensitive period of neurogenesis that occurs in the first few weeks. Not only during the first few weeks of the life of a baby the brain would produce less nerve cells, but by continuing the hot water massage into the second and third month of the life of a baby, nerve cells that the baby already produced are destroyed, leading to even smaller brains and slower cognition, or thinking.

 

• Serotonin (5-hydroxytryptamine, 5-HT):

An elevation of Serotonin (5-hydroxytryptamine, 5-HT) in all brain regions along with a high plasma level in the blood was observed in animals subjected to hyperthermia induced by the exposure of 4 hours heat at 38 degrees Celsius [76]. Serotonin is known to influence every single developmental process in the brain including, neurogenesis, cell and neuronal migration, axon guidance, dendritogenesis, and synaptogenesis [77, 78, 79,  80]. Neuronal migration is a critical early step in construction of the neural circuit in the cortex (cortical circuits), ultimately determining the positioning of differentiated neurons in the distinct cortical layers. Abnormal positioning of the distinct types of neurons is likely to impair the functions of the cortical circuits [81]. An excess of serotonin decreases the migration speed of the cortical neurons. The development and migration of the important excitatory pyramidal neurons in the cortical layers during the first postnatal week [84] is an early developmental process, which is necessary for the subsequent formation of the neocortical circuits [82, 83]. Alterations in the neuronal migration of pyramidal cells due to the excess of serotonin could contribute to the delicate changes in the thickness of the cortical layers [83]. 

Increasing 5-HT levels during neuronal migration was sufficient to disturb the clustering of axons and the organization of neurons into columnar/pillars and caused axons to extend abnormally into wrong cortical layers. These happened due to defective terminal branching of axons and a failure of dendritic orientation towards the target layer neurons. It meant changes in the cortical microcircuits [83, 85]. Hot water massage to the head of a baby increases the level of serotonin causing changes in the position of the neurons in the cortical layers and their axon and dendrite branching. This would affect different cognitive functions such as attention, perception, awareness, and consciousness among others.

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• Additional factors that can elevate Serotonin level in the brain:

It is worth mentioning another factor that affects the elevation of serotonin during pregnancy, and therefore, affects the brain development of a baby. Also, medications against depression for women during pregnancy and after delivery have the same effect, but through a different mechanism. Serotonin re-uptake inhibitors (SRI) medications prevent the reabsorption of serotonin thus leading to a high level of serum serotonin. Exposure of offspring of rodents during the first postnatal week to SRI, reduced dendrites of prefrontal dendritic branching [86]. Reduction in the dendrites branching of neurons affects the neural circuit complexity. One way to check such an effect on the activity of human brain is through electroencephalography (EEG). This method was used to observe changes in activity of human neonatal brains that were suspected to have disruption of dendrites branching due to the intake of SRI medication by their mother during the pregnancy. Lower EEG activity in different areas of the brain including the frontal area, which is the last of the cortical regions to mature, suggested more long-lasting developmental effects by the elevation of serotonin due to prenatal SRI exposure [87]. Such ever lasting effect can be expected from the hot water massage that lasts several months. 

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• Glutamate:

Glutamate is an amino acid, and it is the most abundant excitatory neurotransmitter. It acts in over 90% of all synaptic connections in human brain.

​In hyperthermia of 40 to 42 degrees Celsius the level of blood glutamate in a body increases sharply and as a result of that also the level of glutamate in a brain [155]. A high level of glutamate in a brain disturbs the balance between the excitatory neurotransmitter glutamate and the inhibitory neurotransmitter GABA. This damages the neural circuit of a brain. It must be noted here that application of Robb ointment on the head of a baby can affect this delicate balance too, see "Robb ointment effect" page. 

Glutamate is also essential for a wide variety of functions. It is responsible among others, on opening the non-selective cation (ion charged positive) canals in the nerve cells [153].  In the blood vessels, ion channels such as Ca++ canals are important contributors to the control of smooth muscles contraction that determines the diameter of blood vessels. The activity of calcium ion canals contributes to the reduction in the diameter of blood vessels, which means that blood vessels become narrow [157]. The changes in the constriction of blood vessels are called the vascular tone. A high vascular tone means that constriction of smooth muscle in the blood vessels is high. While low vascular tone means that the constriction of smooth muscle in the blood vessel is low. These changes in the vascular tone affect the perfusion (the passage of fluid through blood vessels to a tissue).

In normal situation there is a balance between widening and narrowing of blood vessels that allows an adequate supply of nutrition and oxygen to a tissue. If a high level of Ca++ is released as a result of increase in the level of glutamate as a result of hyperthermia, blood vessels will be narrow more than necessarily and the brain perfusion will be low too. It means that neurons in a brain will not get enough nutrition and oxygen from the blood [154]. Eventually it will cause fainting [45], as was the case with Kofi. The mechanism that causes fainting in hyperthermia (Figure 1), appears also in head injury [156]. We can therefore say that any time hot water is applied on the head of a baby it is as if the baby got a hard blow on his or her head and he or she suffers from head injury.

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 Figure 1: The effect of hyperthermia on glutamate level in the brain that eventually can cause fainting.

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