User talk:TK13-412-713

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Please work on this text
Moreover, dopamine secretion in the central nervous system has been shown to be inhibited by an increase in melatonin preceding the sensory and motor symptoms in RLS patients. Previous studies have also shown that plasma dopamine and its metabolites change with circadian rhythm. With regard with iron abnormality, the severity of symptoms positively correlated with circadian variations of serum iron and CSF dopamine.

The iron deficiency hypothesis is an important part of the pathophysiological explanations of RLS and has received a broad support through prevalence studies and pharmacological researches. Indeed, low serum iron levels were presented in 25% of patients with severe RLS, and 43% with moderate RLS patients were in an iron deficiency condition. Henceforth, the severity of symptoms has been suggested to be correlated with serum ferritin levels.

A number of MRI neuroimaging studies revealed decreased iron levels in the substantia nigra and putamen, especially prevalent in the most severe cases. While others showed a decrease rather located in the red nucleus, thalamus, and the pallidum. These might be areas of particular interest since a recent study has suggested that under normal circumstances, the brain does not respond to peripheral variations in iron concentrations.

Biochemical studies on the effect of brain iron levels suggested that several iron-containing proteins were implicated in oxidative phosphorylation, oxygen transportation, myelin production and the synthesis and metabolism of neurotransmitters. . As such, iron deficiency can lead to cellular damage by oxidation and modification of cellular compounds. The interactions between impaired neuronal iron uptake and the functions of the neuromelanin-containing and dopamine-producing cells plays important roles in RLS development, indicating that iron deficiency might affect the brain dopaminergic transmissions in different ways

Medial thalamic nuclei also seem to play an important role in RLS. They are part as the limbic system and as such modulated by dopaminergic afferent. A study found thalamic activity changes in the thalamocortical circuit. From this, it was suggested that the uncomfortable symptoms of RLS could be caused by a dopamine dysfunction resulting in impairment of the medial pain system.

Dopaminergic system dysfunctions have mainly been pointed out by substantial improvement of RLS symptoms in patients receiving low-dose dopamine agonists. As mentioned before, the absence of response from the brain to external changes of iron levels suggest that there is a need for the dopamine agonists to cross the blood-brain barrier in order to be effective. Tyrosine hydroxylase being a rate-limiting step enzyme with iron as a cofactor for the conversion of levodopa to dopamine, iron deficiency may once again alter the dopaminergic pathways in the brain.

Current theories postulate that iron deficiency in the brain results in dopaminergic neuronal changes in basal ganglia. While other theories also focus on the importance on peripheral dopaminergic neurons. However, it is also broadly understood that linked to iron deficiency is a decrease in dopamine functions which in turn mediates spinal hyperexcitability leading to the spontaneous sensory and motor movements of RLS. Inversely, it might also result from the decreasing supraspinal inhibition to the spinal cord.

As such, another dopaminergic theory of RLS is that of dopaminergic A11 cell group. Indeed, A11 cell group are almost exclusively at the origin of all dopamine projections to the spinal cord. and motoneuronal site Dopamine A11 cells are located in the midbrain and close to the hypothalamus and have long axons innervating densely to the spinal cord. Recent studies noted the high prevalence of periodic limb movements in patients with spinal injuries highlighting the importance of spinal projections in RLS pathophysiology and the excitatory/inhibitory role of dopamine in motor, sensory and autonomic regulations.