The Progressive Connection among Stress, Anxiety, Sleep, and Neurological Disorders

Abstract

Many conditions that can cause “sleep disturbance” for many different health conditions, where normal constant sleep is interrupted since altering falling asleep to a frequent disturbance for a long time duration, usually implicit for a wide range of causes including environment alteration, health problems that affect physical or mental body functions, and others. Finding causes for “sleep disturbances or sleep disorders” is not an easy task, even for medical professionals. At this time, where humanity is confronting a huge amount of disasters due to climate change, bacteria and viruses of different kinds have been evolving as a treat with a long pandemic time, and economic impacts do not present a near sign of stabilization; technological advances based on artificial intelligence are making frequent changes in our way of living, which usually widen the amount of information that we receive and process. These factors and others are misdirecting the basic survival needs of human beings, such as food, water, air quality, and the necessary and confronting need to sleep. These altered facts overuse our brains and, as a consequence, maximize their normal functions. Including natural biology tools such as the “circadian clock” that regulate all brain sub-structures, the nervous system expresses its frustration as a progressive brain structural deterioration.

1. Introduction

There are many conditions that can cause “sleep disturbance” for many different health conditions where “normal constant sleep” is interrupted since altering “falling asleep” to a “frequent disturbance for a long duration of time” usually implicit for a wide range of causes including environment alteration, health problems that affect physical or mental body functions, and others. Typically, the affected person with a “sleep disorder” tries to resolve the problem by paying attention to the “effect,” and intending to avoid the disturbing conditions with temporal reachable solutions such as “traditional home remedies,” that is, tea. If the situation continues, then they use “off-the-counter drugs” as sleep pills, that is, melatonin, and finally, when the situation is getting worse, they request professional medical help to find the “cause” of their unmanageable and possible “sleep disorder.” Finding the cause of “sleep disturbance” and/or “sleep disorders” is not an easy task, even for medical professionals. In this time where humanity is confronting a huge amount of disasters due to “climate changes” with environmental changes that even have increased earth temperature, bacteria and viruses of different kinds have been evolving as a treat with a long pandemic time, and economic impacts do not present a near sign of stabilization; technological advances based on artificial intelligence that are making frequent changes in our way of living usually widen the amount of information that we receive and have to process. All these factors and many others are misdirecting the “basic survival need for the human being as amount and food, water, air quality, and the necessary and confronting need to sleep.” All these facts have altered the pressure of the process and tried to find solutions to stabilize our situation, overusing our “brain and, by consequence, maximizing its normal functions.” Including our natural biology tools, such as the “circadian clock,” that regulate all the brain sub-structure is needed to process all the information and situations ASAP. Our nervous system by itself expresses its frustration as “progressive brain structural deterioration” generating different abnormal behaviors as “stress” (a physical, mental, and emotional factor), “anxiety” (an additional factor to stress reflecting as an emotion such as tension, excessive nervousness, fear, increased blood pressure), and many others as “depression.”

All these factors are evolving into “sleep disorders,” where frequently genetic factors are altered by “sleep change patterns” due to adjustments of shift of our own “circadian clock” by a big diversity of alteration as stress, and its response is detectable as anxiety and many others, including but not limited to aging, hormonal level changes, mood, sleep apnea, snoring, lifestyles, environment changes, restless leg syndrome, and many other reasons. If all these brain responses are not attended to, the possibility of permanent and destructive changes in our neuronal circuits can explain many abnormal behaviors in “neurological disorders” [1]. The research of all these factors is the main objective of this book chapter, “Sleep Medicine - Asleep or Awake.”

2. Circadian clock, circadian rhythms, and physiological functions

The “circadian clock” is a biochemical oscillator clock or internal pacemaker in most living things that cycles with a stable phase and is synchronized with the solar time, It helps organisms and humans anticipate daily environmental changes of the day-night cycle and adjust their daily biology routines and behavior accordingly. “Circadian clock” is the central mechanism to drive “circadian rhythms.” Some examples of circadian rhythms are sleep and wake cycles, hormonal activity, body temperature rhythm, eating, and digesting.

In humans, the “circadian clock” is slightly greater than 24 hours, and, earth’s 24-hour rotation creates temporal variations, including light/dark cycles with temperature oscillations, which forces humans and other organisms to adapt to the cyclic environmental changes activate compensatory mechanisms and redundancy to maintain the function of the clock, providing “circadian rhythms,” for many behaviors and physiological functions [2]: “sleep/wake cycle,” “endocrine system,” “metabolism,” “immunity,” and “mood.” Where:

• The “sleep/wake cycle” is triggered by chemicals called “neurotransmitters” to send messages to different nerve cells in the brain to define “sleep/wake homeostasis,” which handles the tendency to a relatively stable equilibrium between interdependent elements. The longer that we are awake, the greater our body senses the need to sleep at the end of the day, but our “circadian clock” causes highs and lows of sleepiness and wakefulness throughout the day. But plenty of regular sleep each night can help balance out these sleepy lows [3].

• The “endocrine system” is a network of glands in our body that make hormones to help cells talk to each other. A gland is an organ that makes and puts out hormones that do a specific job in your body. Endocrine and exocrine glands release the substances they make into your bloodstream, and they are responsible for almost every cell, organ, and function of our body by regulating the complexity of life in an organized way and other factors. The endocrine system is comprised of several glands. In many places in our body, including the human brain, there are three important glands:

  1. “hypothalamus,” which connects your endocrine system with your nervous system.

  2. “Pituitary gland,” which is attached to the “hypothalamus,” indicates when the pituitary gland starts or stops making hormones, and

  3. “Pineal glands” make a chemical hormone called “melatonin” in response to darkness that helps your body get ready to go to sleep, and it has been linked to the regulation of circadian rhythms.

• “Metabolism” refers to the chemical processes that take place in our body to convert foods and drinks into energy. It is a complex process that combines calories and oxygen to create and release energy. This energy fuels body functions.

• “Immunity” is defined as the ability to resist infections or toxins by the action of antibodies or sensitized white blood cells.

• “Mood” is a temporary state of mind or feeling such as stress, anxiety, and many others. People who regularly experience mood swings are more likely to experience psychiatric disorders such as depression, anxiety, post-traumatic stress disorder, bipolar disorder, and borderline personality disorder. Mood swings in humans are likely caused in part by their genetics and their key developmental experiences, showing “high neuroticism,” and they are just more likely to enter moods of anxiety and depression, particularly in response to stress [4].

REMARK: In a general way, we can say that if we alter the “circadian clock” as the central mechanism that drives “circadian rhythms,” the alteration is reflected on the “sleep/wake homeostasis,” driven by the “endocrine system” glands as the “hypothalamus” that connects the endocrine system with the nervous system, and is attached to the “pituitary gland,” indicating when to start or stop making hormones. This alters the release of “melatonin” to initiate the normal “sleep cycle,” and by consequence, this alters the release of “melatonin” to initiate the normal “sleep cycle,” altering the nervous system that can be detected with “mood swing” showing as stress, anxiety, and other moods.

3. Brain waves and sleep stages

Our brain is always producing bursts of electrical activity identified as “electrical pulses” in the brain cell nerves known as “neurons.” The “electrical pulses “are the way the neurons communicate to each other in their neuronal pathways to send orders or receive information, generating “wave activity” that can be detected and measured with a device known as an “electroencephalogram (EEG)” that evaluates the electric activity in the brain and records it in waves measured in cycles per second identified as “hertz (Hz).” Basically, the brain waves have a different speed from the fastest to the slowest frequency. There are five different types: gamma, beta, alpha, theta, and delta, as shown in Table 1.

Brain waves	Gamma	Beta	Alpha	Theta	Delta
Frequency	Up to 100 Hz	12–38 Hz	8–12 Hz	4–8 Hz	0.5–4 Hz
Brain state; Sleep stage	Awake; Receptive and concentrated	Awake; Busy and focused	Awake to sleepy; Alert with calm awareness	Sleepy; Stages 1–2; N1 & N2 NREM	Deep sleep Stages 3 NREM & 4 REM

Table 1.

General brain wave types and brain states.

“Sleep” is defined as the normal condition of body and mind, such as that which typically recurs for several hours every night, in which the nervous system is relatively inactive, the eyes are closed, the postural muscles are relaxed, and consciousness is practically suspended. The normal “sleep stages” are four, three of them with “non-rapid eye movements (NREM)” and one with “rapid eye movements (REM)” as indicated in Table 1, where the duration for each step is different at different ages.

• Stage one, or N1 (sleep type NREM from 1 to 5 mins): “Sleep” begins with a “lighter sleep” that can last from seconds up to 7 minutes, like a “short nap” where we can be easily woken, while the brain produces “alpha” and “theta” waves, and your eye movements slow down.

• Stage two, or N2 (sleep type NREM from 10 to 60 mins): It is also similar to a “light sleep” resembling a “larger nap,” where we can wake up if we want. Here, if the brain produces a sudden increase in brain waves known as “sleep spindles,” then the brain waves slow down.

• Stage three, or N3, or slow-wave sleep (sleep type NREM from 20 to 40 mins): It is the beginning of “deep sleep” and becomes a little harder to wake up because the body becomes less responsive to external stimulus. Here, the brain begins producing slower “delta waves” which are characterized by “no movement active in the eyes or muscles.”

• Stage four, or N4 (sleep type REM from 10 to 60 mins): It moves to a “deeper sleep,” and it is harder to wake up. Here, the brain is more active, producing more “delta waves” allowing a necessary “restorative stage,” where the body repairs muscles, tissues, and tiny bone fractures, diminishes pain, stimulates growth and development, boosts immune function, and builds up energy for the next day.

Initially falling asleep, a “rapid eye movement (REM)” is observed, where the eyes make sudden movements in different directions, heart rate and blood pressure increase, and breathing becomes fast, irregular, and shallow. “REM” can last up to an hour, and an adult can have five or six of these cycles with intervals: “REM” and “non-rapid eye movement (NREM is also known as “progressive rapid eye movements (pREM)),” where the brain consolidates and processes information from the day before so that it can be stored in your long-term memory; these “pREM intervals are very important to maintain the brain in good standing.” Besides, “sleep spindles” are a type of brainwave that come in bursts, and they are described as an oscillatory activity of the brain that is mostly said to happen during stage 2, which is identified as “non-rapid eye movement NREM sleep,” indicated as sleepy stages 1–2 in Table 1, and additionally occurs during deep sleep stages 3–4. “Sleep spindles” are described based on the frequency of waves as slow or fast: “slow spindles” occur between 9 and 12 Hz and originate in the frontal brain areas, and “fast spindles” have a range of 12 to 16 Hz from the central nervous system and peripheral parts.

REMARK: The “circadian clock” generates the “sleep circadian rhythm” initiated by the release of “melatonin” for the “sleep cycle” that has four stages: in the first 2 from awake to sleepy generating “alpha” and “theta” brain waves, and in the last 2 with “deep sleep generating Delta” brain waves where the brain consolidates, and processes information accumulated during the day and moves from a short-term memory to a long-term memory through “pREM intervals” are very important to maintain the brain restored.

4. Introduction to neuroscience and circadian neuroscience

“Neuroscience” is the scientific study of the nervous system, including the brain, spinal cord, and peripheral nervous system, and its functions. “Circadian neuroscience” is a branch of neuroscience and chronobiology that looks at the neurological mechanisms that maintain “circadian rhythms” and investigates their subsequent effects on processes in the nervous system [5].

The human internal clock is controlled by the “Suprachiasmatic Nucleus (SCN)” located in a forward region of the brain area identified as the “hypothalamus” that connects your endocrine system with your nervous system, as explained in the last section. “SCN” contains a group of “neurons or nerve cells” that control the human body’s “circadian rhythm.” When the morning light is received by the eyes, an optical nerve senses it and sends the signal through neurons in the “SCN” that are sensitive to the light and release hormones such as “cortisol” that make an order for wake-up. At night, darkness is detected in the eyes, and the SCN sends a signal to the “pineal gland” that releases the chemical hormone that initiates the process of sleep, making our body feel sleepy [6].

5. Stress-anxiety take to sleep alteration

“Stress” is defined as a physical, mental, or emotional factor that causes bodily or mental tension. Stress can be external or internal. Where:

• External factors such as the environment, psychological, or social situations.

• Internal factors caused by illness, pain, or a medical procedure.

REMARK: “Stress” is unavoidably something that everyone experiences throughout their lives. While some stress can pass quickly or feel acute, the most important thing is how we handle it.

“Anxiety” is an emotion characterized by feelings of tension, worried thoughts that lead to excessive nervousness, fear, apprehension, and inclusive physical symptoms such as increased blood pressure and others that may seriously affect day-to-day living.

REMARK: “Anxiety” is the human brain’s natural response to the “stress” accumulated.

Sleep alteration is an evolution of stress into anxiety, and this can be triggered by internal and external factors, as shown in Figure 1.

Figure 1.

Sleep alteration is an evolution of the stress to anxiety, this can be triggered by internal and external factors as indicated.

“Sleep Internal Alteration”: Some frequent examples that cause “sleep change patterns” are: “inflammation,” “injuries,” “pain,” “aging,” “and other factors.”

• “Inflammation” is a protective response of body tissues against stimuli such as pathogens, damaged cells, and irritants that are perceived as harmful.

• “Injuries” are defined as damages to the body caused by trauma by an external force or even internal factors such as inflammation.

• “Pain” is physical suffering or discomfort caused by illness or injury.

• “Aging” is generally accepted as an progressive function deterioration, and the “circadian clock” function and its rhythmic behavior decline, affecting the metabolism with changes such as glucose intolerance, nutrient sensing dysregulation, and mitochondrial dysfunction [2].

REMARK: Aging body declination functions are reflected in metabolic disorders [7], such as obesity, diabetes, hypertension, and other changes that cause the human body to develop “sleep disorders.”

“Sleep external alteration” examples that cause “sleep change patterns” could be in many ways, the most common are “artificial intelligence algorithms inspired by behaviorist psychology,” “smart device screens and their blue light,” and prescribed medicine side effects.” Where:

• “Artificial Intelligence algorithms inspired by behaviorist psychology apps such as email, chats, text, social networking, running on all smart devices that we use every day as: mobile phones, tablets, computers, etc. These apps constantly make interruptions to alter our natural behaviors applying AI algorithms as “reinforce learning” that are deigned to keep our attention constantly by activities based on rewards of different types with the purpose of creating addiction on us for different purposes from statistics, commercial, political, etc., for example:

  • “Search engines online” such as Google, Microsoft Bing, Yahoo, Baidu, Ask.com, and many more to search information on webpages, images, news, research papers, books, etc.

  • “Social media,” such as Instagram, Facebook, Snapchat, Twitter, TikTok, YouTube, and many others, are controlling the lives of their users. On a daily basis, they frequently control users by checking their notifications and sighing in dissatisfaction because they have not gotten enough likes on your profile picture or comments.

  • “News websites” are always updating, generating, and adding new news to meet the need to be informed. These websites analyze the traffic and your activities and, with statistics, detect what is of more general interest, and if they have your username, they personalize the news for them, to maintain their attention and force them to check frequently for updates that are important for them, such as stock prices, public health, to accomplish user awareness.

• “Smart devices Screen and their blue light.” The problem with the display on smart devices LED (light-emitting diode) flat panel that emits blue light beside others from small displays and more large-scale video displays. It uses an array of LED units known as modules, consisting of many small LED chips placed on a printed circuit board (PCB) substrate. On a natural rainbow, we see the visual light spectrum; these are the colors visible to the human eye and include red, blue, and green “wavelengths.” All light we see is a combination of these wavelengths, including light from the sun and exposure to blue light from the sun as well as our screens, which boost mood and alertness, that is, sunrise signals to our brain that it is time to wake up. In the evening, these flat screens can disrupt “our body’s natural sleep cycle,” known as the “circadian rhythm,” which synchronizes the “sleep-awake cycle” with night and day. By slowing the natural production of “melatonin.” It is a natural hormone that is produced by the “pineal gland in the brain” and then released into the bloodstream to make us follow the natural “circadian rhythm” cycle [9].

• “Medicines side effects”: many of them may cause “sleep deprivation” as “anti-arrhythmic,” “beta-blockers” for high blood pressure, or heart rhythm problems or angina; “chemotherapy” for cancer; “clonidine” for high blood pressure; “corticosteroids” for inflammation or asthma; “diuretics” for high blood pressure; “medications containing drugs” as headaches or pain relievers; “sedating antihistamines” for cold, allergy, or motion sickness; “selective serotonin reuptake inhibitors” for depression or anxiety; “sympathomimetic stimulants” for attention deficit disorder; “theophylline” for asthma; “thyroid hormone” for hypothyroidism, and many others [10].

  • “Anti-arrhythmic” for heart rhythm problems There are four classes of antiarrhythmics, based on the Vaughan-Williams (VW) classification system [11]:

    1. Class I sodium channel blockers to slow electrical impulses in heart muscles include disopyramide, flecainide, mexiletine, propafenone, and quinidine.

    2. Class II beta blockers slow down the heart rate, often by blocking hormones such as adrenaline. that is, acebutolol, atenolol, bisoprolol, metoprolol, nadolol, and propranolol.

    3. Class III potassium channel blockers slow down electrical impulses in all of the heart’s cells, that is, amiodarone, bretylium, dofetilide, dronedarone, ibutilide, and sotalol.

    4. Class IV, nondihydropyridine calcium channel blockers to decrease heart rate and contractions, such as diltiazem and verapamil,

    5. Other antiarrhythmic drugs not included in the VW classification are adenosine, digoxin, and blood thinners.

  • “Beta-blockers” to control heart rhythm, treat angina, and reduce high blood pressure, that is, Acebutolol, Atenolol, Betaxolol, Bisoprolol (Zebeta, Ziac) Carteolol, Carvedilol, Labetalol (Normodyne, Trandate).

  • “Chemotherapy” is a type of cancer treatment that uses one or more anticancer drugs as chemotherapeutic agents, alkylating agents, or others [12]. It is important to know that not all medicines and drugs to treat cancer work the same way. Other drugs to treat cancer work differently, such as “targeted therapy,” “hormone therapy,” and “immunotherapy.”

  • “Clonidine” is used alone or with other medications to treat high blood pressure (hypertension). Brand Names: Catapres-TTS-2; Catapres-TTS-3; Catapres-TTS-1.

  • “Corticosteroids” are any group of steroid hormones produced in the adrenal cortex or made synthetically. There are two kinds: glucocorticoids and mineralocorticoids. They have various metabolic functions, and some are used to treat inflammation. Some corticosteroid medicines include cortisone, prednisone, and methylprednisolone. Prednisone is the most commonly used type of steroid to treat certain rheumatologic diseases (like rheumatoid arthritis or lupus) [13].

  • “Diuretics” are substances that promote diuresis, the increased production of urine, helping rid the body of salt (sodium) and water. Help your kidneys release more sodium into your urine. The sodium helps remove water from your blood, decreasing the amount of fluid flowing through your veins and arteries. This reduces blood pressure. As shown in [14].

    1. Thiazide types include chlorothiazide, chlorthalidone, hydrochlorothiazide, indapamide, and metolazone.

    2. Loop type: bumetanide (Bumex), ethacrynic acid (Edecrin), furosemide (Lasix), and torsemide (Soaanz).

    3. Potassium sparing types include bumetanide (Bumex), ethacrynic acid (Edecrin), furosemide (lasix), torsemide (Soaanz).

  • “Medications containing drugs” for different purposes as headaches or pain relievers include “alcohol” (for cough, cold, and flu), “caffeine” (for headaches and other pain), “nicotine replacement” (avoid smoking), and others.

  • “Sedating antihistamines” for colds, allergies, or motion sickness,

  • “Selective serotonin reuptake inhibitors” for depression or anxiety,

  • “Sympathomimetic stimulants” for attention deficit disorder,

  • “Theophylline” for asthma,

  • “Thyroid hormone” for hypothyroidism,

  • and many others.

REMARK: “Artificial intelligence algorithms inspired by behaviorist psychology” running on smart devices create “addiction,” which is handled by the need to stay up-to-date to try to relax the anxiety generated by “stress.” The main problem is that we expend part of our energy on unimportant things that do not benefit our important daily duties, at the end of the day, we feel more nervous, and these thoughts alter our daily sleep [8].

REMARK: Almost everyone has an occasional night with little or low-quality sleep. But when sleep problems start to affect your “quality of life,” you may develop a “sleep disorder.” The most common sleep disorder caused by too much exposure to “smart device screen blue light” is “insomnia,” which refers to habitual sleeplessness, and it is the most common “sleep disorder” in the world. Besides, “insomnia” is more common as you get older, and it can affect your life in a number of ways, including daytime fatigue, poor concentration, and low mood.

REMARK: If prescribed medicines are affecting your “sleep pattern,” it is strongly recommended to inform your healthcare provider to correct this issue ASAP.; IMPORTANT: Never take medicine for sleep without a medical prescription and follow-up medical supervision.

6. Sleep-wake and circadian disorders and neurological disorders

“Central nervous system (CNS)” lesions appear by disrupting continuously the “sleep-wake cycle” based on constant alteration of the human “circadian clock” developing into “circadian disorders.” These are identified as “sleep-wake and circadian disorders (SWCD),” leading primary to lesioning specific cell types or structures generating or regulating sleep, wake, and circadian functions or through nonspecific lesioning of diffuse neural networks. In addition, “SWCD” can arise secondarily from complications of “CNS” lesions such as spasticity, “muscle stiffness and spasms,” “pain,” and even “depression.”

As explained in Section: Introduction to Neuroscience and Circadian Neuroscience, “Circadian rhythms” signals from the “Suprachiasmatic Nucleus (SCN)” are distributed in the brain and the entire body by two main cell-brain connections identified as pathways: the “Hormonal rhythms control pathway” and the “Euro humoral pathway” [15]. These are:

1. “Hormonal rhythms control pathways” transmitted by terminals of the SCN from the brain to organs with the release of neurotransmitters and a group of them known as “neuropeptides” [16].

2. “Euro humoral pathway” involving secretion of diffusible output signals regulating preferentially the rest-activity rhythm as: heart rate, muscular strength, insulin, leptin, and glycemia. Where:

   1. “Heart rate rhythm” is a healthy “sinoatrial (SA) node” a special cardiac muscle in the upper back wall of the right atrium made up of cells known as “pacemaker cells.” It has an intrinsic heartbeat generation rate of 60 to 80. If the atrium fails to generate a heartbeat, then a healthy “atrioventricular node (AV)” can do so at a rate of about 40, and if needed, the ventricles themselves can generate heartbeats at a rate of about 20 per minute.

   2. “Muscular strength rhythm” is the “circadian rhythm” in muscle force that has also been described for maximal dynamic contractions and isometric contractions. The “acrophase” (time of the maximal level of the rhythm) of the muscle capacity to develop maximal force has been found in the evening compared with the morning. The diurnal variations in muscle performance can be influenced by several factors, such as core temperature, sleep deprivation, warm-up duration, and hormone concentrations such as cortisol and catecholamine [17].

   3. “Insulin rhythm”: levels of both insulin and the counterregulatory hormones, which work against the action of insulin, are influenced by a “circadian rhythm.” The counterregulatory hormones, which include glucagon, epinephrine (adrenaline), growth hormone, and cortisol, raise blood glucose levels when needed [18].

   4. “Leptin rhythm,” where leptin is a pleiotropic protein hormone produced mainly by fat cells, regulates metabolic activity and many other physiological functions. The intrinsic circadian rhythm of blood leptin is modulated by gender, development, feeding, fasting, sleep, obesity, and endocrine disorders [19]

   5. “Glycemia rhythm” refers to the concentration of sugar or glucose in the blood. Glycemia is measured by a number called the glycemic index, which reflects how much an individual’s blood sugar level rises after consuming 50 grams of carbohydrate compared with someone without diabetes who has consumed 50 grams of carbohydrate.

In many cases, the “sleep-wake and circadian disorders” may worsen over time, leading primary to lesioning specific cell types or structures on the brain. That could present the first manifestations of an underlying neurologic disorder such as “dream enactment behavior in Parkinson disease (PD),” “excessive daytime sleepiness (EDS) in hypothalamic disorders,” or “insomnia in Alzheimer disease (AD)” [20]. Finally, through time it is evolving as an identifiable “progressive neurologic disease.”

REMARK: The brain is the one that drives sleep and wakefulness through the “circadian clock,” which acts as a natural pacemaker, adjusting our daily lives with day-night based on the detection of solar light, allowing us to do our routines and behaviors that are driven by “circadian rhythms.” Their continuous alterations are reflected in “sleep-wake and circadian disorders,” which sooner or later affect neural brain networks, memory, circadian preferences, neural development, and unresponsiveness to outside events. All these changes are ways to develop and could be associated with “progressive neurologic diseases” with abnormalities such as insomnia, schizophrenia, epilepsy, mental retardation, and mental health issues observed in Parkinson’s, Alzheimer’s, and other diseases.

7. How to analyze sleep-wake and circadian disorders

The “sleep-wake-circadian pathologies” are generally underdiagnosed in neurologic patients despite their major impact on the onset, evolution, and outcome of neurodevelopmental disorders in the sense of an illness that disrupts normal physical or mental functions, including attention-deficit hyperactivity disorder (ADHD), autism spectrum disorders (ASDs), Prader-Willi syndrome (PWS), and Smith-Magenis syndrome (SMS), and diseases as progressive disorders with abnormal conditions that negatively affect the structure or function of all or part of an organism, and that is not immediately due to any external or internal injury, such as Parkinson’s, Alzheimer, and many more. The main key in this research paper is to focus on accessible technologies and methodologies that are necessary for the periodic evaluation of “sleep-wake and circadian disorders.” These are summarized in Figure 2. With the purpose of measuring the progression effect or efficacy of their therapeutic interventions and helping to evaluate the progression of “sleep-wake and circadian disorders” that could lead to neurologic disorders and diseases, separated on four instrument types: “personal home monitor,” “lab studying testing,” and “neuroimaging.”

• “Personal home monitors” are devices characterized for their low cost, allowing personal home sleep monitors to:

  • “Actigraphy” or “actometer” is worn on the nondominant wrist or ankle to record acceleration or deceleration of body movements. It is worn for days or weeks and complements a daily sleep log for the diagnostic “circadian rhythm sleep disorders” and other primary sleep disorders such as insomnia and idiopathic hypersomnia.

  • “Smart watches.” Today, some smart watches include a clinical-grade “actigraph” used for sleep and activity home monitoring, showing an easy-to-follow and understand graph with automatic daily recordings, with high accuracy and sensitivity, very useful as primary personal feedback, that allows you to take the information collected to the medical doctor with valid information on your personal “sleep/wake cycle” for an initial diagnostic of “circadian rhythm sleep disorders.” Please be sure to buy a clinically validated smart watch for sleep monitoring [21].

• “Labs studying testing” are labs studying combining specialized monitor instruments for evaluation of sleep tests, breathing, movements, and others based on specialized medical instruments that must be handled by specialized people to place the sensor and run the test as specified by medical specifications using a diversity of them defined in general as “Polysomnography” [22]:

  • “Electroencephalogram (EEG)” to measure electrical activity in the brain using electrodes attached to the scalp, for detecting and analyzing several polygraphic physiologies during sleep.

  • “Chin electromyogram (EMG)” to assess the health of muscles and the nerve cells that control the chin and allow determination of sleep stages.

  • “Limb EMG” for leg muscle evaluation, detecting and analyzing periodic leg movements that may disrupt sleep as “restless legs syndrome,” and other evaluations.

  • “Oronasal thermal airflow sensors” use thermistors or thermocouples to measure and analyze thermal airflow, reading the difference between the temperature of exhaled and ambient air to estimate airflow and detect mouth breathing. Interrupt during sleep as “sleep apnea,” and other issues.

  • “Electrocardiography” is the process of producing an electrocardiogram (ECG or EKG) recording the heart’s electrical activity.

  • “Electrooculogram” for measuring the cornea-retinal standing potential that exists between the front and the back of the human eye and detection of eye movements.

  • And many other instruments, such as “pulse oximetry” for measuring arterial oxygen saturation and “audiovisual recordings,” enhance the diagnostic utility of polysomnography.

    “Polysomnography” is used to diagnose sleep-disordered breathing, movement disorders, and abnormal behavior during sleep, such as “REM sleep behavior disorder” and arousal disorders.

• “Neuroimaging analyzing” is the process of producing images of the structure or activity of the brain or other part of the nervous system by biomedical instruments such as “magnetic resonance imaging (MIR)” or “computerized tomography (CT)” and other neuroimaging technologies. Neuroimaging approaches can be broadly divided into three types:

  • “Structural imaging,” which visualizes brain anatomy and pathology and measures volume and other tissue characteristics,

  • “Functional neuroimaging,” measuring brain activity, blood flow, and glucose metabolism; and

  • “Molecular imaging” focuses on information on biologic processes, including protein aggregation, neuroinflammation, and related processes.

REMARK: “Polysomnography” is very useful to analyze the sleep architecture process for the wakefulness stage, Stage W, and NREM and REM sleep stages, as shown in Table 1.

Figure 2.

Sleep-wake cycle circadian disorders instruments for evaluation of progression and sleep-wake cycle circadian pathologies.

The development of “functional neuroimaging” consists of all techniques that can generate images of brain activity. In humans, such techniques usually include “single photon emission computed tomography (SPECT),” “positron emission tomography (PET),” “functional magnetic resonance imaging (fMRI),” “optical imaging,” “diffusion tensor imaging (DTI),” “multichannel electroencephalography (EEG),” “magnetoencephalography (MEG),” and others. Each technique has its own advantages and drawbacks in terms of spatial and temporal resolution, accessibility, safety, and cost [23]. Applying AI algorithms detected following:

• “Sleep-wake cycle,” detecting brain activity throughout the brain in this cycle.

  • “Regional brain activity” identifies them when they are influenced by incoming stimuli as well as by previous waking experience.

  • “Neural correlates of sleep-wake regulation tend toward a relatively stable equilibrium between interdependent elements for sleep pressure and the non-visual effect of light.”

  • “Functional imaging of patients with sleep disorders: studying their neural system changes across the sleep-awake cycle.”

Many researchers applying “neuroimaging techniques” have discovered the relation of the “sleep-wake cycle” with neurological diseases such as: “REM sleep behavior disorder,” “isolated rapid eye movement (REM) sleep behavior disorder,” “type 2 diabetes mellitus and sleep disorders,”

• “REM sleep behavior disorder (RBD)” may be idiopathic or associated with other neurologic disorders, and there is a strong association between RBD and “α-synucleinopathy” which are neurodegenerative diseases characterized by the abnormal accumulation of aggregates of alpha-synuclein protein in neurons, nerve fibers, or glial cells. They have observed groups for sleep disorders and signs at the clinical onset of neurodegenerative disease by studying and comparing structural and functional MRI to identify brain changes that progress over time in patients [24].

• “Isolated rapid eye movement (REM) sleep behavior disorder (iRBD)” was detected in patients with neurology symptoms of “Mild Cognitive Impairment (MCI)” presenting long-term verbal memory and visuospatial functions, as well as attentional-executive impairment “reduced cerebral glucose consumption in brain areas critical for cognition” and a more severe deafferentation of the “nigro-striatal” regions in the brain. Then, there is the importance of identifying iRBD patients with MCI for urgent neuroprotective trials [25]. “Wakefulness” is associated mainly with the following brain structures: the frontal and parietal polymodal associative cortices.

• “Type 2 diabetes mellitus (T2DM) and sleep disorders (SD)” are both common diseases related to brain functional and structural abnormalities involving the “hypothalamic-pituitary-adrenal (HPA)” axis. “T2DM” is a chronic metabolic and inflammatory disease accompanied by insulin resistance, hyperglycemia, and defective insulin secretion from the pancreas. All included studies showed that alternative interventions improved sleep quality, glucose levels, blood lipids, hypertension, and weight management, but whether acupuncture and other alternative treatments for long-term T2DM and SD can decrease disease-associated risks and complications is yet to be determined. Sleep disturbances in T2DM patients are related to the brain organs, and “obesity” manifests with sleep problems as “insomnia.”

  • “Obesity,” Neuroimaging analysis demonstrated that there were altered interactions in the brain networks of obese individuals in response to food cues [26], particularly in the frontal-mesolimbic network [27].

  • In “insomnia,” the main affected brain areas are the “ascending reticular activating system,” “hippocampus,” “amygdala,” “insular cortex,” and “medial prefrontal cortices” [28].

“Molecular Imaging (MI)” is a growing biomedical research discipline that enables the visualization, characterization, and quantification of biologic processes taking place at the cellular and subcellular levels within intact living patients in their own psychological environment. Examples of progressive neurologic diseases are “Parkinson’s disease,” “Alzheimer’s disease,” “frontotemporal dementia,” “multiple system atrophy,” and many more related to disturbances in the “sleep/wake cycle.”

• “Parkinson’s disease (PD)” in patients has a high degree of sleep problems, one of “two common accumulations of proteins” related to different types of Parkinson’s identified as “idiopathy Parkinson’s,” the most common at about 85%, and “atypical Parkinson’s,” the least common at about 15% [29]. Both types of “PD” have a bidirectional relationship with sleep through the accumulation of proteins in the neuron cells: “α-synuclein” and “Tau.”

  • “α-synuclein or synuclein alpha” is also known by the alias “SNCA or NACP or PARK1 or PARK4 or PD1.” “α-synuclein” is a neuronal protein that regulates synaptic vesicle trafficking and subsequent neurotransmitter release. It is abundant in the brain, mainly in the axon terminals of presynaptic neurons, and

  • “Tau or tubulin,” also known by the alias “MAPT (microtubule-associated protein tau) or DDPAC or FTDP-17 or MAPTL or MSTD or MTBT1 or MTBT2 or PPND or PPP1R103 or microtubule-associated protein tau ortau-40,” is a group of six highly soluble protein isoforms produced by alternative splicing from the gene MAPT. They have roles primarily in maintaining the stability of microtubules in axons and are abundant in the neurons of the “central nervous system (CNS),” where the cerebral cortex has the highest abundance. It is found in atypical Parkinson’s known as “Progressive Supranuclear Palsy,” which often shows “midbrain” and “superior cerebellar peduncular atrophy” and cell loss in a specific distribution, particularly affecting the “subthalamic nucleus,” “globus pallidus,” “substantia nigra,” and “pretectal area of the midbrain” [30].

• “Alzheimer’s disease (AD)” is the most prevalent neurodegenerative disorder and the most common cause of dementia with abnormal “tau protein accumulation.” Disturbances of the “sleep/wake” cycle in “AD” are very common, frequently precede cognitive decline, and tend to worsen with disease progression. “Sleep-wake cycles” are regulated by neuromodulator centers located in the “brainstem,” “hypothalamus,” and “basal forebrain,” many of which are vulnerable to the accumulation of abnormal protein deposits associated with neurodegenerative conditions. There is evidence that “tau” protein accumulation-driven neuropathology is a primary driver of sleep disturbance in AD [31].

• “Frontotemporal dementia (FTD)” is the second most common cause of young-onset dementia. Our understanding of FTD and its related syndromes has advanced significantly in recent years. Among the most prominent areas of progress is the overlap between FTD, motor neuron diseases (MND), and other neurodegenerative conditions at a clinicopathologic and genetic level. There is emerging evidence that “hypothalamic” dysfunction, manifesting as disturbances in sleep and metabolism, is an integral component of neurodegeneration [32].

• “Multiple system atrophy (MSA)” is a sporadic and progressive neurodegenerative disorder characterized by abnormal “α-synuclein” aggregation in oligodendroglia and neuronal loss in multiple areas of the central nervous system, and many report sleep-related breathing disorders as inspiratory sighs that are considered a diagnostic red flag for the parkinsonian form of MSA [33].

And many other neurologic diseases usually present sleep disturbances.

REMARKS: Sleep and mental health are closely connected. Sleep deprivation affects our psychological state and mental health. And they are particularly common in patients with anxiety, depression, bipolar disorder, and attention deficit hyperactivity disorder, and also have connections with neurologic disease.

8. Conclusions and comments

“Sleep quality” is critical for the maintenance of a stable equilibrium of body function driven by “circadian function,” especially for “neuronal cells and pathways” in the brain, endocrine system, metabolism, immunity, and others. If we leave unattended the importance of normal “sleep/wake cycles,” our human body is taken to the next step, presenting “chronic sleep disturbances” through the increment of undesirable “mood swings,” presenting symptoms of stress, anxiety, and many others. People who regularly experience “mood swings” are more likely to experience “psychiatric disorders” such as “anxiety,” “depression,” “post-traumatic stress disorder,” “bipolar disorder,” and “borderline personality disorder.” And with time, the same situations grow to have significant “cognitive” and “physical health” consequences that likely exacerbate disease severity as “neurological disorders.” Today, there are technologies that can detect and evaluate “sleep-wake and circadian disorders,” measuring and tracking the severity of the damage with “specialized lab tests,” such as “polysomnography,” that combine specialized monitor instruments for evaluation of sleep tests, breathing, movements, and others. Technologic advances based on “neuroimaging analyzing,” “functional neuroimaging,” and “molecular imaging” that allow the discovery of new “genetic mutations” as well as the development of “potential biomarkers” may serve to further expand knowledge to help with “sleep quality” that is affecting millions of people and continues growing around the world.

The odds of being “sleep deprived with less than 6 hours a night for adults” have increased significantly over the past 30 years as the lines between work and home have become blurred and digital technology has firmly become part of our lifestyles [34].

FINAL REMARK: “Sleep quality” is affecting millions of people and continues to grow around the world. Today, there are technologies that can detect and evaluate “sleep-wake and circadian disorders” before they cause chaos on our neuronal circuits, creating endless multiple neurologic responses that could take us to “degenerative diseases that still have no cure.”

Please sleep well.

Thanks.

Dr. Jorge Garza- Ulloa.

More information: https://garzaulloa.org

Notices: Knowledge and best practice in this field are constantly changing as new research and experience broaden our understanding, and changes in research methods, professional practices, or medical treatment may become necessary. To the fullest extent of the law, neither the publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence, or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein.