Theory of Stress-Anxiety-Sleep Disorders-Neural Damage Cyclic Chain and the Progression of Parkinson’s Disease

“Parkinson’ disease” is a neurologic complex disease that affect the functionality if the brain modifying the neural connectivity due to cell death, that still don’t have cure. All actual medication and procedures available today only help to improve the quality of life of the patients. The main objective of this research paper is to conclude a theory for the relation of “Stress”, “Anxiety” and “Sleep disorders” and an additional factor identify as “neural damage”, and relation between them and others additional factors like genetic disorders with the progression of “Parkinson’s disease”, supported with many published research papers that are currently available, personal interviews with PD patients, caregivers, PD families, neurologists, others peoples involves in their PD health team, and my own experience as a Biomedical Engineering researcher and caregiver for my wife with PD.

B. "Neuron" is a specialized cell known as the basic unit of the "human nervous system". These cells make a up a massive network of "specialized nerve cells" connected with the purpose of transmit messages very rapidly, from one part of the body to another, creating complex interconnected circuits known as: "neural pathways".
A zoomed illustration of two neurons connected are shown in Figure 1b, to introduce the concept of "Neural Pathways".

Figure 1:
The relation between human nervous system, neurons, neural pathways, and synapse: a) Human Nervous System and two Neural Pathways, 2) Two neurons connected as a part of the Neural Pathway in the brain, and c) Synapse between two neurons that are part of a Neural Pathway. C. "Neural pathway" is a cluster of "neurons" connection from one part of the nervous system to another using "synapses" in each neurons union. The brain under the right conditions can change hundreds of millions and possibly billions of the connections between the nerve cells in our "neural pathways" as we learn, and process new information [8]. The "Neural pathways" created in the brain are updated continuously based on "neurons" connection process known as "synapse", there are an estimated of 100 billon neurons making a total of 100 trillion neural connections, that process information and they can send orders to body movement known as "motor pathways", and receive information from humans senses known as "sensory pathways". D. "Synapse" is the structure that permits a "neuron" to pass an electrical to chemical signal from one neuron to another. The "synapse" is located in the union between two "neurons" that are part of a "neural pathway", as indicated in Figure 1c zooming of a "synapse" where, a

Copy@ Jorge Garza-Ulloa
"neuron" is connected through the "Axon Terminal of the Neuron Transmitter" to another "neuron" through the "Dendrite of the Neuron Receptor". "Neurons basic functions" can be categorized as Sensory, Motor and Interneurons. Where: a. "Sensory that carry information from the sensory receptor cells as eyes, nose, tongue, and skin throughout the body to the brain", b. "Motor that transmit information from the brain and spinal cord to the muscles of the body to achieve movements on them", and c. "Interneurons that convey information by transmitting messages to other neurons".
"Neuron activities" are of two kinds Electrical and Chemical. Where: a. "Electrical that is used to transmit signals within neurons", and b. "Chemical that is used to transmit signal between neurons through the synaptic space".
The "synapse chemical activity" trigger the release of "neurotransmitters" which carry the impulse across the synapse to the next neuron. Once a nerve impulse has triggered the release of "neurotransmitter", these chemical messengers cross the tiny "synaptic space" and taken up by specialized receptors on the surface of the next cell. "This process converts the chemical signal back into electrical signal", if the signal is strong enough, it will be propagated down to the next neuron until once again reaches another "synapse" and the process is repeated once more, and so on until reach the destination.
The "neurotransmitters" than cross the "synapse" as indicated in Figure 1c are received by other nerve cells, where the "axon terminal from the neuron transmitter" is also responsible for the reuptake of any excessive "neurotransmitters" released during this process. Different "neurotransmitters" fulfill different functions in the brain as: "excitatory neurotransmitters" that acts to stimulate the firing in the "synapse", and "inhibitory neurotransmitters" that tend to block it in the responding cell. There are different types of small molecules manufactured in different kind of axon terminals, known generally as "neurotransmitters", some of them are: "acetylcholine", "dopamine", "GABA"," glutamate", "glycine", "norepinephrine", "epinephrine or adrenaline", "serotonin", and many more. Where [7]: 1. "Acetylcholine (Ach)" is used by spinal cord motor neurons to cause muscle contraction, and many neurons in the brain to regulate memory. In most instances, "acetylcholine" is excitatory function.
2. "Dopamine (DA)" is responsible for transmitting signals between the nerve cells in the brain. The brain includes several distinct "neural dopamine pathways" that play a major role in regulate movement, attention, learning, emotional responses the motivational component of reward-motivated behavior and also play a role in addiction. "Dopamine" functions as both "inhibitory and excitatory neurotransmitter" depending upon where in the brain and at which receptor site it binds to.
3. "GABA or (Gamma-aminobutyric acid) "is the major "inhibitory neurotransmitter" in the brain. It is important in producing sleep, reducing anxiety, and forming memory.

"Glutamate
(Glu)" is the most "excitatory neurotransmitter" in the brain. It is important in learning and memory.
5. "Glycine (Gly)" is used mainly by "neurons" in the "spinal cord". It is probably always act as "inhibitory neurotransmitter".
6. "Norepinephrine (NE)" acts as a "neurotransmitter and a hormone". In the peripherical nervous system, it is part of the "fight-or-flight response", and in the brain, it acts a "neurotransmitter" regulating blood pressure and calmness. NE is usually excitatory, but it is inhibitory in a few brain areas.
7. "Epinephrine or adrenaline" is also a hormone responsible for concentration, attention, mood and both physical and mental arousal 8. "Serotonin (5-HT)" is involved in many functions including mood, appetite, and sensory perception. In the spinal cord, serotonin is inhibitory in pain.
9. And many more additional "neurotransmitters", where the action of all of them help to regulate many human body functions of different types.
It is very import to notice that each "neurotransmitter" work alone or with others to handle a big diversity of body functions that affect the three types of "Parkinson's symptoms" as indicated in Table 1. "non-motors" Epinephrine commonly known as adrenaline Responsible for concentration, attention, mood and both physical and mental arousal "non-motors"

Serotonin
Regulating mood, appetite, and sensory perception, and inhibitory of pain "non-motors"
ii. "Parkinson's disease" patients report "disturbed sleep patterns long before motor dysfunction" in the research paper from

"Jorge S.Valadas et al. ER Lipid Defects in Neuropeptidergic
Neurons Impair Sleep Patterns in Parkinson's Disease" [10]. ii. "Sleep loss" affects many aspects of cognition, and memory consolidation processes occurring in the brain specially in the "hippocampus" that seem particularly vulnerable to sleep loss, from the research paper of "James E. Delorme et.al. Sleep loss disrupts Arc expression in dentate gyrus neurons" [12].
iii. "Parkinson's disease" is the most common movement A population-based longitudinal study" [15].

Progression of PD
Parkinson's progression is usually quite gradual as it is a progressive illness, with symptoms slowly growing worse over time.
Many people with Parkinson's believe they had the condition for some time -often two to three years -before they look for a formal diagnosis. Often it is only when symptoms become obvious or start to interfere with daily life that people visit the doctor. Symptoms and responses to treatment vary from person to person, so it is not possible to accurately predict how Parkinson's will progress. For some people it may take many years for the condition to develop, for others it may take less time [16].

Types of Parkinson's
Based on "Parkinson's disease" is a typical movement disorder [17] and the 2nd most common neurodegenerative condition after "Alzheimer's disease". PD is a continuous neurological disorder where the symptoms continue to worsen gradually [18]. PD is a highly variable disease, meaning that different patients have different combination of symptoms, and those symptoms can be at varying severity levels. There are basically two general "Parkinson's types": "Idiopathic Parkinson's" and "atypical parkinsonism" [19]. Where: a. "Idiopathic Parkinson's" because of their unknown source. It is the most common form of "Parkinsonism". It is a tremor predominant disorder that involves shaking and trembling. About 85% of people with parkinsonism have "idiopathic Parkinson's". This type of "Parkinson's disease" can begin at an earlier age but progresses more slowly. It has a lower risk of cognitive (brain function) decline, but the tremors may be more difficult to treat than other symptoms [20].
b. "Atypical parkinsonism" is less common; it is an instability and gait disorder that present more trouble with walking and balance. About 15% of people with parkinsonism have Atypical parkinsonism disorders, these are rarer conditions and more difficult to treat. This type of Parkinson's disease happens at an older age but tends to progress quickly. Although people may experience fewer tremors or no tremors at all, they have a higher risk of cognitive decline.

Factors for risk of Parkinson's disease
Nobody know the specific cause for "Parkinson's diseases" except that about 20% are presumed to be "genetic variations" in the genetic combination of certain genes elevate the risk of PD. Generally, scientists speculate that the interaction between gene mutations and environmental exposures can contribute to PD progression. Studies have listed few modifiable risk factors for PD, the following factors are considered as some of the causative factors of PD [24,25] are: Exposure to pesticides, herbicides, some solvents, well-water drinking, metals as manganese, calcium intake, age, gender, and many more factors [1]. The cause of idiopathic Parkinson's disease has been hypothesized to involve an external agent, for example a pathogen, and one potential route of entry for such an agent could be via the gastrointestinal system. The It can be explained as follow: "Stress" is defined as a normal feeling of response to an emotional or physical tension, and it is very frequently on "PD patients".
Their body's reaction to the everyday challenges or demand in actions that has been altered, when patient's thing, feel or affront their physical and cognitive limitation that are diminished for the PD. Also, it could come from any event as "thoughts that increase frustration", "angry", "pain" or "nervousness". The most common symptoms for "PD stress" are: Excessive worries in your mind producing physical effects as: "Stress on PD patients have many reasons", but the biggest one is usually due to the overwhelm feeling of losing control of their bodies, being each time more dependable of others persons, that they need to take control of the situations and knowing before that PD is a neurodegenerative disorder and still there is not cure for it. Additional thinking in them generate an immense stress on them, deducting that their PD could affect even more their physical body functions and present mental issues, and the increase of their disabilities.
There is enough evidence that "stress rise the level of PD symptoms" as "tremors", "cognitive decline", "mood", "behavior", and many PD symptoms [14]. The reality is that "stress" make for them the situation worst to deal with it.
"Anxiety" is the normal reaction to stress, but in PD patients it is more detectable by physical effects and mental situation that are on the next level, as: c. Showing easy fatigue due to irritability, pain that cannot explain where, or due to muscle tension.
d. Detecting that "multitasking" and "multiprocessing "as ability for doing more of one task at once, or thinking many things is being damage or lost in PD.
e. Perceiving that the "planning" of action to do is each time more difficult to program and follow in PD.
There is enough evidence that "stress and anxiety increase faster the level of PD symptoms" as "tremors", "cognitive decline", "mood", "behavior", and many others PD symptoms [29]. The reality is that "Stress and Anxiety" make for them the situation worse and almost impossible to deal by themselves.
"Sleep disorders" are conditions that result in sleep changes that are affecting the overall health, safety and quality of life. Research has shown the effects of "poor sleep", such as reduced mood and concentration as well as increasing the risk of serious conditions such as obesity, heart disease, diabetes and other neurological diseases as PD.
"The theory that sleep is necessary to reset connections between brain cells and process information from the previous day is gaining credibility trough time as the results of many research and clinical trial are obtained, and now the observation in many neurological diseases are suggesting that sleep is essential for clearing damaged proteins and waste from the brain". This insight could lead to new ways of treating a range of diseases that may be linked to "Stress-Anxiety-Sleep disorders-neural damage cyclic chain" such as "Parkinson's diseases", "Alzheimer's disease", and many others neurologic diseases.
The more common "sleep disorders" are: a) "Sleep apnea" as abnormal sleep patterns in breathing.

Copy@ Jorge Garza-Ulloa
It is important to mention that there are several types of sleep apnea. b) "Restless legs syndrome (RLS)" also known as "Willis-Ekbom disease", causes an uncomfortable sensation and an urge to move the legs while trying to sleep. c) "Narcolepsy" is a condition characterized by extreme sleepiness during the day and falling asleep suddenly during the day. d) "Insomnia" is characterized by having difficult to falling sleep or staying asleep throughout the night.
On PD "Sleep disorders", they are the consequence of the next level of the chain "Stress-Anxiety-Sleep disorders" by the following reasons: a) PD patients reports "disturbed sleep patterns" long before motor dysfunction [10].
b) PD patients are affecting their "quality of life" and presents many aspects of "cognition deterioration" [12]. c) PD patients presents "NREM sleep instability" even in earlier stages [11]. "Neural damage" is the stage where the response of the normal brain cells is altered. PD is caused by the impairment or "death of dopamine-produced in nerve cells (neurons) in a region of the brain called the substantia nigra", which controls the body's balance and movement, with a big probably cause by "sleep disorders" that didn't allow the need of clearing damaged proteins and waste from the brain cells in many neural pathways" [31]. Table 1, the "dopamine" is a chemical that acts as a messenger transmitting nerve signals from one neuron to another in the brain to control body movements as indicate in Figure 1c. It is also involved in behavior and cognition, memory and learning, sleep, and mood. The loss of these "neurotransmitter in the neurons" by the results of sequences of "Stress-Anxiety-Sleep disorders-neural cyclic chain", alter the production of many "neurotransmitters" that are reflected as "Parkinson's disease symptoms". the decreased specially on "dopamine", lead to abnormal brain activity and the symptoms of the PD such as: abnormal muscle movements, cognitive impairment and others PD symptoms. Neuropathological studies demonstrate significant damage in brain regions and their causes as stated in the following research reports:

As shown in
a. In the research paper from: William P. Flavin et.al., "Endocytic vesicle rupture is a conserved mechanism of cellular invasion by amyloid proteins" [32,33]. c. In the research paper from: Nicolaas I. Bohnen et al.

"Sleep Disturbance as Potential Risk and Progression
Factor for Parkinson's Disease" [31]: "Sleep behavior disorder (RBD)"is common among the α-synucleinopathy disorders of PD, dementia with Lewy bodies (DLB) and Multiple System Atrophy (MSA) probably because in these diseases cell loss is common within neuronal structures regulating Rapid Eye Movement (REM), that is an sleep disturbance " [35].
d. In the research paper from: Eti Ben Simon et al.
"Overanxious and under-slept" [29]. "Deep sleep" restores the "medial prefrontal cortex" mechanisms that restore "emotion". This lowers emotional and physiological reactivity, "preventing the escalation of stress and anxiety". After a night of no sleep, brain scans showed a shutdown of the "medial prefrontal cortex", which normally helps keep our "anxiety" in check, while the brain's deeper emotional centers were overactive. "Our study strongly suggests that insufficient sleep amplifies levels of anxiety and, conversely, that deep sleep helps reduce such stress". "Deep sleep" seems to be a "natural anxiolytic (anxiety inhibitor)", so long as we get it each and every night" e. In the research paper source from: University of Rochester Medical Center "Immune cells rewire and repair the brain while we sleep" [36]. Science tells us that a lot of good things happen in our brains while we sleep -"learning and memories are consolidated and waste is removed, among Parkinson's disease" that can be explain as shown in Table 2.

1
When the "synapse chemical activity" on many "neurons synapses" in the "neural pathway" is affected in some degree for factors as: "Stress-Anxiety-Sleep disorders" and factor as genetics and others, then the release of "neurotransmitters" as: "dopamine, "GABA", and many others, the release of "neurotransmitters" are diminished or stopped. a.
"Stress "is very frequently but no necessary the first stage, defined as the natural body's reaction from PD patients to a challenge or demand in their actions that has been limited by any physical, cognitive diminished for the neurological disease. That also, it could come from any event or thoughts that increase frustration, angry, pain or nervousness. The "Stress" can indirectly alter the synapse chemical activity in neurons" [14,32]. b.
"Anxiety" as the normal reaction to "stress". Where "PD Anxiety" is more noticeable with physical effects and mental situation on the next level as: difficulty of controlling worries, exaggerated feeling for sudden shock or alarm that producing physical and cognitive effects that can take them to deeper levels like "depression" and generate more cognitive declinations. "Anxiety" can indirectly alter even more the synapse chemical activity in neurons" [1,2,27]. c.
"Sleep disorders" are based in sleep changes due to multiple factors, on PD patients mainly are reactions to: "stress"," anxiety", and "declination on the overall health including pain, desperation as sudden sensation of fear and others". "sleep deprivation disrupts in the PD brain cells, the ability to communicate with each other, leading to temporary mental lapses that affect memory and visual perception, leading for cognitive lapses in how to perceive the world and their reactions". Definitively "Sleep disorders" affect the chemical activities and release of the neurotransmitters in synapses" [2,4,5,8,9,10,11,12,13,19,24,30,31,34]. d.
"Neural damage" is the stage where the response of the normal brain cell is "altered to the limitation in the release of many necessary" neurotransmitters during the synapses". PD is caused mainly by the "impairment or death of many neurotransmitters, with specially emphasis in the dopamine-produced in nerve cells (neurons) in a region of the brain called the substantia nigra", which controls the body's balance and movement, with a big probably caused by genetic alterations or sleep disorders that didn't allow the "need of clearing damaged proteins and waste from the brain cells in many neural pathways" [30]. "and also affecting cognition by avoiding the memory consolidation needed during a deep sleep" [19,28,29,30].

e.
After the "Stress-Anxiety-Sleep Disorders-Neural Damage chain in PD patients" is completed, initiated in any step by many external or internal reasons, the chain is reinitiated to a higher level forming a bigger cyclic chain as shown in figure 2 represented with dash circles indicating the progression in Parkinson's disease.

5
The proposed, "Theory of Stress-Anxiety-Sleep Disorders-Neural Damage cyclic chain and the progression of Parkinson's disease" is repeated undefinedly worsening the symptoms of Parkinson's disease that are only detected after 70-80 percent of nerve cells in the "substantia nigra" have been lost [8,37].

Recommendations to Implement the "The Theory of Stress-Anxiety-Sleep Disorders-Neural Damage Cyclic
Chain and the Progression of Parkinson's Disease".

Based on "The Theory of Stress-Anxiety-Sleep Disorders-Neural
Damage cyclic chain and the progression of Parkinson's disease " shown in Figure 2, explained in the last section, stated in Table   2, and taking into account that Parkinson's doesn't affect only the person diagnosed with the disease; it can impact loves ones, family members, friends and caregivers too. I can deduct the following "7 more important recommendations for PD patients and their caregivers" for a good implementation of the theory and achieve the decreased progression of this neurological disease. The basic recommendations are indicated in the following Table 3.  "Each day is different for PD patients" "Accept the fact that there are good days, and bad days".
"Every day count your blessings; you will find many more than you knew, be proud and grateful for them".
2) "Eat healthy" "PD patients need good energy from real food! say goodbye to junk food" "Grease, fast food and proteins make harder to your body to digest and absorbs your PD medications".
"Eat Healthy food based on fruits grains and vegetables, fish with omega 3, poultry and eat little red meat".

3) "Stress and Anxiety handle"
"Recognize that all PD patients need incremental help from others as: family members, friends, take givers, medical doctors, and that there are many therapies can help you to handle the "stress and anxiety", "Write down your negative thoughts and ask if they are true, because root in stresses and anxiety mind can be distort the severity of the real situation, and analyze if it is possible to take back control of them, if not don't worry time will say how" "Forget multitasking and multiprocessing, PD patients must be concentrated in doing and thinking only one thing at the time to avoid unnecessary stress" "Maintain as possible positive attitude with good humor as frequently as possible".

4) "Sleep well"
"Recognize that deep sleep is something necessary for your mind and body specially in PD patients to control the progression of the disease!" "Try first home remedies and relaxing techniques to sleep", "Gives thanks every day for all blessing received thought your life".
"Sleep disturbances, it is very common for PD patients; don't' be afraid to ask medical help support if you cannot handle your daily situations and tasks due to sleep deprivation"

5) "Exercise body and mind"
"Moderate daily exercise according to the disease progression", exercise releases feel-good chemicals that are necessary in your brain", "do mind games and keeping learning thing to boost the creation of new neural pathways in your brain".
6) "Medicines always in time and keep a record of their intakes, specially the combination of medicines" "Keeping a record of medicines intake with the purpose of detect on time side effects, register any change observed, time off /time off, each fall and why happen and how can be avoided, analyze them frequently and give the feedback to your healthcare team and neurologist".
"Never add new medicines/suddenly increment / decrement or discontinue the doses of these PD medications without supervision from your healthcare team and your neurologist". 7) "Socialize and stay busy" "Isolation never help with PD", "Be involved in any conversation around, everybody learns from each other!" "Always thing in other's needs " "Maintain up to date on advances on PD new treatments" "Stay busy according to the level of the disease" Do that special easy things that recomfort you as: listen to music, coloring book, drawing, hobbies, gardens and nature activities, watching movies, browsing internet, cards game, and others",

Conclusion
Parkinson' disease is a neurologic disease that affect the functionality if the brain modifying the neural connectivity due to There are many more issues to resolve on the development of these disease that affect PD patients. There are necessity for new biomarkers, and new methods for early detection on Parkinson's disease, new techniques for follow-up the progression to achieve more understanding of this neurological disease and others.
We need to know the real PD causes, where PD begins and why, find new biomarkers to measure the damage level from early stages, develop more stable and effective PD medications, new PD surgical treatment, better mathematical tools and smart computer algorithms for the correct analysis, diagnostic and prescription and many mores issues to understand and resolve the issues of this highly varied disease. We need more from you: Please share your information about your PD journey, possible causes that you believe, about your progression, all your symptoms, and many things, sent that information to PD researches like: garzaulloa.org, michaeljfox.