1. Introduction

The conditions of almost each tissue,organ and even cell in the body can be logically defined as four states or levels: normal, dysfunction, illness and tumor. This definition should be also used on the nervous system .But , there is an exception,the sympathetic nervous system(SNS) can only be divided three levels:normal,dysfunction and tumor^[1] .However, theoretically, there is still lacking a definition regarding the illness state ,either the SNS should be defined an illness state or make a clear diagnosis between the dysfunctional and tumor. The SNS is involved in a wide range of physiological activities, metabolisms and function adjustments of organs .The functional states of sympathetic nerve are affected by many factors ,such as psychology, external and internal environment, life styles and metabolic states^[2,3,4,5].Therefore , it is possible to have more chances to get into a kind of illness related to SNS, the functional states of the SNS should theoretically present all four states of health conditions: normal ,dysfunction ,disease ,tumor ^[6,7,8,9].

The lack of diagnosis of the illness might be missing a link or part of the SNS with dysfunction or disease status in theory and might impact widely on clinical practice.Previously, we have published our study, in which we proposed a new concept related to the SNS disease namely as the disease of sympathetic overdrive (DSO)^[10],which is only a hypothesis .In the present review ,we further discuss the symptoms ,risk factors and clinical endpoints of DSO, in order to enrich and improve of the hypothesis of DSO. Figure 1 uses the cards to express conditions of the organs or systems of the body and indeed to focus on the absence of status in the sympathetic nervous system.

Figure 1.The deck of cards of organs’ conditions

*♥ normal ♦ dysfunction ♠ disease ♣ tumor

# HT: Heart AT: Artery BN：Brain LG: Lung SNS: Sympathetic nervous system LV: Liver KD: Kidney IM: Immune

2. The symptoms of DSO in the sympathetic nervous system:

As an important part of the nervous system, the sympathetic nervous system is widely distributed and many problems seem related to the sympathetic nervous system dysfunction or even the illness of DSO.

The early or mild clinical manifestations are excessive sweating, palpitation, shortness of breath, stomach pain, catatonia urinary and fecal incontinence under short terms of stress or anxiety ^{[11,12,13,14,15]}. Many similar mild symptoms are attributed to sympathetic dysfunction, but not considered to be symptoms of DSO .Indeed , more common and serious problems should be recognized and assigned to the framework of DSO^{[16,17,18,19,20,21]}：They should include high normal blood pressure, high resting heart rate, ulcerative colitis, stress, anxiety ^{[22,23,24,25]}. There are more serious psychological and physical problems caused by sympathetic overdrive ^[26,27,28], for example, ventricular fibrillation,ventricular tachycardia ,sudden death ,white hair overnight, syncope, stress disorder ,schizophrenia, need to be unified as the signs or symptoms of DSO^{[29,30,31,32]}.

The symptoms and disorders mentioned above may only be part of clinical manifestations of DSO. It will be very important to identify all of the symptoms related to DSO. The theoretical exploring is just beginning. In the following text, these symptoms are systematically elaborated.

3. The symptoms and disorders of the vascular system of DSO:

To maintain the heart rate, blood pressure, blood volume and myocardium contractility under normal condition are mainly regulating by sympathetic nerve system. The occurrence of many life-threatening diseases,such as arrhythmia, ventricular tachycardia, ventricular fibrillation, acute coronary syndrome, acute myocardial infarction, sudden death and stroke are closely related to the mechanism of short term of the sympathetic overdrive. There are more vascular system problems between normal and end-events, for example, high normal blood pressure, high resting heart rate, myocardial hypertrophy, chronic heart failure, hypertension, carotid plaque and arteriosclerosis, are closely associated with the long-term overdriving of sympathetic nerve system^{[22,23,24,33]} .Although B blockers are widely utilizing in clinical practices, a list of disorders of CVD have not been scientifically classified and summarized into the cardiovascular system performances of DSO in the theoretical level.

In recent years, the diagnostic criteria of hypertension has been discussing and changing, the high normal blood pressure is classified as a part of the hypertension, because the high normal blood pressure is sharing the mechanism of excessive activation of sympathetic nerve, and resulting in cardiac hypertrophy, arrhythmia, sudden death and other endpoints ^[27,31,34]. On the other hand, the high resting heart rate seems to be similar. Many clinical studies show that the existence of high resting heart rate directly reflects the overactivation of sympathetic nerve too. So that,it is significant to create the new coordination and management strategies with a new hypothesis of DSO for hypertension, chronic renal failure , chronic heart failure, ventricular arrhythmia, etc ^{[35,36,37,38,39,40]}.

4. The symptoms of the digestive system of DSO:

The regulation of gastrointestinal function depends on sympathetic and parasympathetic nerves , and both are involved in digestive fluid secretion and gastrointestinal peristalsis^[41,42,43].It is generally believed that the role of parasympathetic nerve is dominantly in gastrointestinal system , but the sympathetic nerve is involved in the body stress ,emotions and the functional regulations of many systems and organs, so it may even affect the gastrointestinal function more often^[44,45,46].

There is an old idiom in China: relieving one's thirsty by thinking of plums is achievable and then quench with self saliva. This reaction typically represents the influence of sympathetic nerve excitement on gastrointestinal exocrine function and peristaltic function. The emotion and sensory nerve act together on the sympathetic nerve system and then to activate gastrointestinal function. In clinical, depression, anxiety and other psychological disorders often induce sympathetic nervous overexcitement and result in binge eating, functional dyspepsia (FD) ,vomiting , irritable bowel syndrome(IBS), hematochezia, obesity, malnutrition and many other disorders of gastrointestinal system^{[42,43,44,47]} .It is suggested that the overdrive of the sympathetic nervous system may be one of the basic reasons evoking those symptoms in the gastrointestinal system. Severe cases might even lead to stress ulcers, melena, shock, malignant gastrointestinal tumors ^[45,46,47].

5. The symptoms of endocrine and metabolic system of DSO

The prevalence of overweight and obesity is rising fast throughout the world ^{[18,20,21,48]} . The obesity almost has become the first endocrine and metabolic disease. Overweight and obesity are associated with increased prevalence of sympathetic excitation ^{[49,50,51,52,53]}. Our research group first proposed that obesity, high resting heart rate and high normal blood pressure are the new triple-high risk factors ^[10], of which the basic pathophysiological manifestation shares the overdrive of sympathetic nerve system ^{[54,55,56,57,58,59,60,61]}.

The diseases of metabolic syndrome , including obesity, lipid disorders, type 2 diabetes(T2DM), etc are closely related to the overdrive of sympathetic nervous system ^[50,52,62].A lot of studies have confirmed that the diseases of metabolic syndrome are due to both of the insulin resistance and the overdrive of sympathetic system .Both of them interact or trigger each other to form a vicious circle and lead to diabetes, obesity, hypertension, arteriosclerosis and various complications^{[58,61,62,63]}. Previous studies of endocrine and metabolic diseases used to focus on cells, cytokines, molecules, and metabolic pathways, unfortunately, the role of sympathetic nervous system in those diseases was rarely involved and neglected

6. Immune function, infection, tumor and DSO：

The correlation between immune system and the sympathetic nervous system seems difficult to understand. It's actually very common around the real world, for example, people suffering from mild stress or sadness in short-term may appear oral herpes, toothache, rhemorrhoids, urinary tract infection and other symptoms^{[29,64,65,66]} . The basic problem of those is that the overdrive of sympathetic system inhibits the functions of immunity system and results in viral or bacterial infection ^{[67,68,69,70,71,72,73]}. The incidence of malignant tumors increased significantly following a long-term and severe depression and deterioration of living conditions ^{[74,75,76,77]}. Epidemiological studies have approved that during bankruptcy, imprisonment, unemployment, and wartimes, the incidences of malignant tumors in relevant populations have definitely increased ^{[78,79,80,81]}, indicating that overdrive of sympathetic system inhibits the immune function and leads to an increase in the incidence rate of tumors.

It has found that the higher level of norepinephrine and sympathetic nerve can affect the function of the immune system by inhibiting the activity of NK cells and activating cytokines ,such as interleukins and tumor necrosis factor(TNF-α)^{[29,69,70,82,83]}, to increase the risk of various infections and malignant tumors^{[71,80,81,84]}.

7. The emotional issues and Psychosocial disorders in DSO：

The phenomenon of the white hair being over a night or Marie Antoinett syndrome is occasional seen, mostly after suffering a huge psychological and spiritual strike .Recent studies have found that norepinephrine can cause degeneration and apoptosis of melanocytes ^[85,86]. Thus cases vividly reflect the process and links of mental disorders, excessive activation of sympathetic nerves, and damage of target organs.

In general, some more serious cases could be seen, such as sudden death, coma and ecstasy ^{[11,12,13,25,87]}, which often occur at the time of extreme fatigue, sadness, happiness, anger and wartimes ^{[26,27,28,30,34,37,88]}. Sudden death is a kind of serious end-point events, the basic or even sole physiopathologic mechanism is the extreme activation of the sympathetic nerve named as sympathetic storm^[58,89,90]. Therefore, sudden death is certainly a serious symptom result of DSO ^{[91,92,93,94,95]}.

8. Major risk factors of DSO：

There are many risk factors of DSO, and they can be divided into environmental factors and self-factors, mutable and immutable factors, lifestyle factors and accidental factors ^{[11,13,23,27,96,97]}. These risk factors of inside and outside stimulate different sensory organs and systems resulting in activation of the sympathetic nerve ^{[98,99,100,101,102]}. If these stimulations are only too strong ,too often, or even overlapping , they could excite sympathetic overdrive , leading a cluster of symptoms of DSO^{[103,104,105]}.The majority of the risk-factors and their sources are listed on the following table 1.

Table 1：The risk factors of mutable factors and immutable factors.

As mentioned above, the risk factors of DSO are so numerous and full of uncertainty and randomness. However, the major part of mutable factors are lifestyle factors, which are extremely difficult to change, such as smoking, drunk, binge-eating, etc^{[106,107,108]} .These problems are so common in the population. therefore, it is reasonable to discuss the hypothesis of DSO,in order to identify all of the risk-factors and symptoms and to find out the new strategies to manage variable risk factors and prevent the disorders of DSO ^{[109,110,111]}.

9. The researches of related mechanisms of DSO：

Since the hypothesis of DSO has just been putting forward and many researches related mechanisms are scattered and fragmented,so far there have been few systematic and comprehensive mechanism studies under the framework of DSO. Therefore, DSO could only be a hypothesis at present. Among them, the cases of following have been studied more clearly：

The sympathetic storms and sudden death ：The sudden death is a kind of tragic events, they are becoming more popular recently. They have been causing by a extreme strong, and sudden overdrive of sympathetic nerve and inducing a rapid ventricular tachycardia or the ventricular fibrillation, of which the sympathetic overdrive is the only pathophysiological mechanism of sudden death ^{[106,107,112]}. According to the basic mechanism or the theory, the best way to stop or avoid the tragic storm is by using B-blockers. Since B-blocker has been widely used on people of high-risks groups to prevent sudden death and lots of lives have been saving throughout the world ^{[108,110,112,113]}.

10. Overweight and obesity：

The persons of overweight and obesity always coexist multiple risk factors of DSO, such as binge eating and lack of exercise^[20,21,48]；Overweight and obesity are always caused by insulin resistance, by which blood sugar fluctuations, sodium and water retention, elevated blood pressure and other internal environmental changes occur in long-term and irregular forms. All of those factors induce excessive activation of sympathetic nerve; On the other hand, insulin resistance（ IR）and sympathetic overdrive correlate or even trigger each other all the time^[49,50,51]. As the result, both of overweight and obesity are more common now, even seem growing by infective-manner in population throughout the world ^{[52,56,57,101]}. Since the higher prevalence of both, the type 2 diabetes (T2DM), target organs damaging, disability and end-point events of DSO are more common now ^{[102,109,114]}.

11. The white hair turns to be over-one-night:

The phenomenon of white hair turns white overnight or Marie Antoinett syndrome has been noting in history, some individual cases could be occasionally appearing in population all the times. It has confirmed whenever overdoses of norepinephrine add to the medium of culture of the hair follicles, the melanocytes undergo degeneration and apoptosis in a short time, and then generate white hairs ^[85,86]. The sign of white hair overnight is occasional happened in population worldwide, by which sudden, strong mental shocks induce the sympathetic overdrive and then the white hairs overnight could be seen ^[103,115].

12. Malignant tumors:

The occurrence of a considerable number of malignant tumors is closely related to the overdrive of sympathetic nerve, including breast cancer, stomach cancer, lung cancer, bladder cancer, etc^[75,76,78]. Because of NK cell activity, interleukin, TNF-ɑ and other cytokines secretion are closely related to function of sympathetic nervous system, as the result, the incidences of various malignant tumors are increased under circumstances of DSO ^[80,81,116].In addition, international studies have found by mean of psychological counseling and the application of β-blockers that the indexes of 5-year cure rate, quality of life and survival times of many patients of cancers could be obviously improved^{[64,66,70,82,117]}, suggesting that inhibiting the overdrive of sympathetic nerve can reduce the incidence rate of malignant tumors significantly.

13. The prospect of hypothesis of DSO：

The hypothesis of DSO is very new, and the framework of the symptoms and risk factors , pathophysiology and epidemiology of DSO is still need to understand and improve . Although this is a new theoretical hypothesis, the disease may have been existing for a long time; the complexity of DSO may be far beyond imagining. Until now,the signs,symptoms, diseases of DSO are isolated ,scattered and fragmented upon on different specialties or departments. Unfortunately, it is too often to deal with one problem and missing many of others related of DSO in daily practice until now ^[34,67,118].

Non-communicable diseases (NCDs) are more and heavy burden around the world. The characteristics of them are a person may have a couple of disorders in different systems with the same mechanism of DSO ^[22,28,119]；On the other hand, there are much more people suffering from the similar disorders among the population to share the common mechanism of DSO.It seems the modern life-style spreading in community could trigger the DSO in population, to impact the most parts of NCDs and manifest the same characteristics of DSO in infectious manner ^{[75,76,77,82,119]}.

At present, more studies of diseases are mainly focusing on the structure and morphology, such as tissues, organs, cells, DNA, RNA, genes, mitochondria, cytokines, molecules, etc ^[23,34,120]; By contrast, there are few systematic studies on the diseases from the perspective of neural regulation. Since there is not a theory similar to the hypothesis proposed of DSO, many complex and interdisciplinary disorders cannot be scientifically and systematically described, classified and managed ^{[73,75,96,97,116,121}]. In order to face those popular illnesses of NCDs,a new hypothesis and theory should be create or established soon^{[31,70,80,122,123]} .Figure 2 presents the outline of DSO: risk factors and their impacts on the organs in human body.

14. Conclusion:

The sympathetic nervous system is a part of the body, and its dysfunction will inevitably lead to diseases. Due to the distribution of sympathetic nerves throughout the body, the DSO certainly involves various organs and systems of the body. Therefore, a new hypothesis or theory on DSO should be established in order to better explore the pathogenesis of such disease and develop precise treatment strategies. Currently, this hypothesis is immature, more studies are needed to be done to continuously improve it.