Demyelination, continued.

The last post got a little long and it included a link to another health writer who was summarizing a large amount of material on the topic of demyelination – it is amazing what you can learn by reading. I only mentioned the article, (22), briefly because it was already a long post and I hadn’t checked the other writer’s references, (it is primarily all medical research from peer reviewed journals (22.1)); and some of his recommendations are not typical, however I had read of them elsewhere so it seemed thorough and well written. The truly intriguing part for me was just how many other conditions there are that may be susceptible to demyelination and increased negative symptoms due to nerve degeneration.

I have a few of the problems that were mentioned and I have had early symptoms of nerve numbness and pain in my extremities – fingertips particularly. Health is easier to maintain then to restore once chronic conditions develop. I have managed to reverse the nerve numbness and occasional pain that I was having in my fingertips but it is with several daily or weekly health habits, not just a simple take-this-medication-once-a-day solution.

The list of psychiatric conditions that may also have demyelination summarized in an article about possible ways to regenerate myelin, (22):

  • Attention deficit hyperactivity disorder
  • Depression 
  • Bipolar disorder 
  • Dyslexia 
  • Language disorders 
  • Stuttering 
  • Autism 
  • Obsessive-compulsive disorder 
  • Cognitive decline 
  • Alzheimer’s disease
  • Tourette’s syndrome 
  • Schizophrenia 
  • Tone deafness
  • Pathological lying
  • (22)

That is quite a list – protect your oligodendrocytes, because they protect your ability to think and communicate, to control your ability to control your movements and to have stable moods, reduce anxiety, and control your ability to be able to read and speak and to be able to control your impulses and ability to prevent yourself from lying or saying things you don’t intend to say, and to be able to understand that your thoughts are your own thoughts, and to be able to hear accurately. The reference given for the information is this article: [45].

Neurology is the study of the nervous system, Psychiatry or Psychology is the study of mental health and neuropsychiatry is the study of mental symptoms caused by neurological conditions.

This topic of psychiatric conditions and other conditions that may also have demyelination is also reviewed in a summary of Neurotoxicology for neurologists: (6.Neurotoxicology). Neurology is the study of the nerves and nervous system. The nervous system includes the brain and spinal cord and all of the nerves throughout the body. It is subdivided into two main categories: the Central Nervous System (CNS) refers to the brain, the spinal cord and nerves of the brain and spinal cord; and the Peripheral Nervous System (PNS) refers to the nerves throughout the rest of the body. Neurologists are medical doctors who specialize in conditions affecting the nervous system. They may focus on a subspeciality within the field of neurology (What is a neurologist?, HealthLine) Interestingly dementia, chronic headaches, and Multiple sclerosis are mentioned as possible conditions they treat but all the other psychiatric conditions mentioned in the list that may involve demyelination are not mentioned.

The overview article on Neurotoxicology does mention that psychiatric symptoms may occur in patients with neurological conditions but that the symptoms tend to be dismissed by neurologists, and are not studied in depth, so more reliable information is needed about psychiatric symptoms presenting with neurological disorders  – see “Psychiatric and behavioural disorders.” (6.Neurotoxicology) An article for neurologists goes into more detail about psychiatric symptoms that might deserve consultation with a neurologist rather than having the patient only see a psychiatrist: Neurological syndromes which can be mistaken for psychiatric conditions. Early symptoms of Multiple sclerosis for example sometimes may be mistaken for a psychiatric condition. (Neurological syndromes) Talk therapy or psychiatric medications are not going to help a patient regenerate their myelin after all. Neuropyschiatrists are neurologists that also have a degree in psychology and specialize in treating patients with mental health and behavioral symptoms related to neurological disorders. (neuropsychiatrists)

PTSD was also mentioned as a psychiatric condition that may have demyelination.[45]

Reading the article that was referenced for the list of psychiatric conditions that may also have demyelination [45] provided an additional condition that was not added to the list in the summary article about potential ways to help regenerate myelin (22) – PTSD also may involve demyelination, and confirmed the rest of the list were mentioned [45] . The article also includes more background information about the function and development of the myelin sheath in learning and behavior.

Nerves with myelin provide a much faster signal and oligodendrocytes myelinate several different nerves so there is additional benefit in signals that work in a coordinated manner to also improve speed of function. The myelination occurs over time so the phrase practice, practice, practice applies. Peak time of life to learn skills is in our youth because that is when the majority of myelination occurs -starting in early childhood and continuing until the early twenties even up to age thirty. Healing after injury or learning a new skill later in life would still require the practice, practice, practice so the speedy pathways between groups of nerve cells develop their myelin sheaths in coordinated connections. [45]

This information may help show the difficulties faced by people with PTSD or other psychiatric conditions – the brain connections are coordinated in patterns learned from traumatic memories or are stuck in Obsessive Compulsive patterns. The problem with impulse control might also make more sense if there is simply “leaky” wiring in the brain. Signals that were intended to do one thing might end up activating other behaviors because the myelin sheath is no longer functioning as expected.

A cognitive therapy technique, involving frequent practice/repetition of new ways to talk to yourself – it might help strengthen more positive neural networks with new myelin sheath connections.

Learning new patterns of thinking, replacing traumatic or anxious thoughts that were learned as a child or during a traumatic phase of life can take time and a lot of repetition but it is possible, just like it can be possible to relearn how to walk or do other basic life skills after a stroke or traumatic physical injury. A book by Shad Helmstetter, PhD discusses how to rephrase your own internal self talk to be more positive and gives examples for a number of different types of concerns. I found the technique helpful for emotional overeating and share phrases that I wrote regarding healthy eating and lifestyle and a link to the book in a previous post: “What to Say When You’re Talking to Yourself.” The recommendation that I followed was to read the statements several times every day – for a while, months even. I don’t remember how long I read them daily but it was for quite a while and I still have the little ring binder of statements that I wrote.

Often changing behavior patterns is easier when the new pattern is created first, rather then trying to stop the old first. Build the new and then the old is no longer needed.  Addition, I found the source of that idea:

“The secret of change is to focus all of your energy not on fighting the old, but on building the new.” – Socrates

A new way to think about demyelination – what is the underlying problem? Possibly excess cell death, at rates above the ability to breakdown and remove nucleotides (ATP, ADP, UTP, UDP).

The article on demyelination and cognitive disorders, [45] , also mentioned that adenosine plays a role in signaling oligodendrocytes to make myelin and an article with more information on the topic mentions that increased amounts of ATP, ADP, UTP, UDP can signal breakdown of myelin. Increased presence of those chemicals was suggested to possibly be due to increased cell death without normal clearing away of the old cellular material. And some types of Multiple sclerosis seems to involve increased levels of the enzyme that breaks down adenosine so there would be less available to signal the production of myelin. (8.adenosine in MS)

Take home point – protect against excessive cell death and/or mitochondria damage by not having excessive glutamate (11.link) or aspartate – excitatory amino acids that may be overly available in the modern processed food diet – and by having adequate magnesium to protect the cells from their interior by providing the needed energy to block ion channels in the cell membrane and prevent excessive amounts of calcium, glutamate or aspartate from being able to cross the cell membrane and enter the cell’s interior.

As usual however, it is not that simple, (not that avoiding glutamate and aspartate in the diet is easy, they are in many processed foods), other things can also cause excessive cell death.

  • Exposure to toxins in the environment or due to drug use, illicit or legal, can cause excessive cell death and lead to demyelination disorders. An overview:(6.Neurotoxicology)
  • Lack of oxygen can also be a cause. Lack of nutrients in general can increase the breakdown of cellular parts to provide enough nutrients however if malnutrition is severe and ongoing the breakdown (autophagy) can become excessive. (7.Metabolic Stress, Autophagy & Cell Death)
  • Traumatic injury and infection can increase the  rate of cell death above the level that the body’s detoxification systems can cope with clearing away the cellular material. Traumatic injury is associated with increased risk for infection for reasons that are not well understood, the immune system is considered functionally suppressed: (10.Immunobiology of Trauma) Also mentioned briefly in the Skeletal Muscle section of this overview: (6.Neurotoxicology).
  • Anything that causes excess oxidative stress may cause increased rates of mitochondria breakdown so protecting against stress is protecting the mitochondria which is protecting the cells. (7.Metabolic Stress, Autophagy & Cell Death) Mitochondria are the main energy producers within cells and make up about thirty percent of the volume of cardiac/heart cells. Other type of mitochondrial problems can also increase risk of their switching from promoting health through energy production into a mode that promotes cell death. One of the roles mitochondria play in normal health is storage of excess intracellular calcium. If the mitochondria become dysfunctional then the extra calcium is released into the cell where it can signal increased activity such as release of cannabinoids from the membranes. (9.mitochondria in CVD)

This is approaching really long again, so I am stopping here for now.

/Disclosure: This information is provided for educational purposes within the guidelines of fair use. While I am a Registered Dietitian this information is not intended to provide individual health guidance. Please see a health professional for individual health care purposes./ 

  1. Jordan Fallis, 27 Proven Ways to Promote the Regeneration of Myelin. Feb. 18, 2017, Optimal Living Dynamics,   https://www.optimallivingdynamics.com/blog/25-proven-ways-to-promote-the-regeneration-of-myelin (22)
  2. Reference list: https://www.optimallivingdynamics.com/myelin-references (22.1)
  3. R. Douglas Fields, White Matter in Learning, Cognition, and Psychiatric DisordersTrends Neurosci. 2008 Jul; 31(7): 361–370.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2486416/ [45]
  4. Butler CZeman AZJ, Neurological syndromes which can be mistaken for psychiatric conditions
  5. Anne Masi, Marilena M. DeMayo, Nicholas Glozier, Adam J. Guastella, An Overview of Autism Spectrum Disorder, Heterogeneity and Treatment Options. Neuroscience Bulletin, Vol 33, Iss 2, pp 183–193, https://link.springer.com/article/10.1007%2Fs12264-017-0100-y (autism link)
  6. Harris JBBlain PG, Neurotoxicology: what the neurologist needs to know.

    (6.Neurotoxicology)

  7. Brian J. Altman, Jeffrey C. Rathmell, Metabolic Stress in Autophagy and Cell Death Pathways. Cold Spring Harb Perspect Biol. 2012 Sep 1;4(9):a008763 http://cshperspectives.cshlp.org/content/4/9/a008763.full (7.Metabolic Stress & Cell Death)
  8. Marek Cieślak, Filip Kukulski, Michał Komoszyński, Emerging Role of Extracellular Nucleotides and Adenosine in Multiple sclerosisPurinergic Signal. 2011 Dec; 7(4): 393–402.   https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3224637/ (8.adenosine in MS)
  9. Sang-Bing Ong, Asa B. Gustafsson, New roles for mitochondria in cell death in the reperfused myocardium. Cardiovascular Research, Vol. 94, Issue 2, 1 May 2012, pp 190–196, https://academic.oup.com/cardiovascres/article/94/2/190/268169 (9.mitochondria in CVD)
  10. Dr. Daniel Remick, pre-ARC Director, Immunobiology of Trauma, pre-Affinity Research Collaborative (ARC), Boston University Medical Center, http://www.bumc.bu.edu/evanscenteribr/files/2009/07/pre-arcimmunologytrauma.pdf  (10.Immunobiology of Trauma)
  11. Howard Prentice, Jigar Pravinchandra Modi, Jang-Yen Wu, Mechanisms of Neuronal Protection against Excitotoxicity, Endoplasmic Reticulum Stress, and Mitochondrial Dysfunction in Stroke and Neurodegenerative Diseases. Oxidative Medicine and Cellular Longevity, Vol. 2015, Article ID 964518, 7 pages,Hindawi.com https://www.hindawi.com/journals/omcl/2015/964518/ (11.link
  12. Blaylock, R.L. (1996). Excitotoxins: The Taste That Kills. Health Press. ISBN 0-929173-25-2
  13. Blaylock, R.L. (a neurosurgeon) podcast Excitotoxinshttp://www.blaylockhealthchannel.com/bhc-ep-18-excitotoxins (Excitotoxins podcast)
  14. Excitotoxicity, Wikipedia, https://en.wikipedia.org/wiki/Excitotoxicity (Excitotoxicity)
  15. Aspartic Acid, Wikipedia, https://en.wikipedia.org/wiki/Aspartic_acid (Aspartic Acid/Aspartate)

Intelligence and the weight of evidence

The “weight of evidence” is a phrase included in the book The Neuroscience of Intelligence by Richard J. Haier (Cambridge University Press, 2017, New York).  In many areas of study including neuroscience research results may vary somewhat or even give opposite results. The concept of evidence-based medicine suggests we should trust the evidence but – which evidence if there is differing results? The National Clearinghouse Guidelines listed in a recent post were screened for quality of evidence – was there a preponderance of studies that had fairly similar results?

In the last post I mentioned that it was good news that the medical use of magnesium or Epsom salts was mentioned as early as the 17th century and written about in a medical journal in the early 1900’s – it suggests a preponderance of evidence – a “weight of evidence” regarding the medical benefit of magnesium.

In the introduction of the book The Neuroscience of Intelligence the author states that the information in the book is screened and included based on three laws that could be applied to most areas of scientific evidence – paraphrased:

  1. no story about medical evidence is simple;
  2. no one research study is adequate to prove a theory on its own;
  3. it generally takes many years to rule out conflicting and inconsistent research results and establish a weight of evidence. (p xiv, The Neuroscience of Intelligence,  Richard J. Haier)

The book is written for the non-neuroscientist who is interested in gaining an in depth overview of the advances made in the study of the intelligence and the brain for the purpose of general knowledge or for creating policies that are based on realistic expectations of human ability. There have been theories that have not been upheld when larger groups were involved. Intelligence can be affected positively or negatively by early childhood experiences and by better nutrition however  by later adolescence and adulthood years the differences are more affected by genetic potential whether parents were rich or poor, whether schools were average or above average. Many genes are involved however, affecting many pathways throughout the brain. Intelligence and creativity isn’t just located in the frontal area of the brain or in just the right hemisphere.

From a magnesium perspective an interesting point that stood out for me was on page 61. Genes that have been found to be involved in intelligence include several that encode glutamate receptors. Background information: Alzheimer’s disease tends to cause more damage in areas of the brain that have a greater number of glutamate receptors – and adequate magnesium is necessary to help protect brain cells from being overexcited by too much glutamate (an amino acid used in flavoring agents, a commonly known type is MSG, Mono sodium glutamate). Glutamate can open the receptors in the cell membranes while the presence of magnesium inside of the cell can keep them closed. NMDA receptors are discussed on pages 101-102 of the book Magnesium and the Central Nervous System and is mentioned 249 times in the book, (the ebook has a useful search feature). (2) 

Excess calcium being allowed to enter the cell can also overexcite cells to the point of cell death. Too much or too little activity of the NMDA receptors can cause problems with health or damage cells. Overexcitatory activity of the NMDA receptors has been associated with damage from ischemic stroke, traumatic brain injury, neonatal brain injury, and neurodegenerative conditions (which include Alzheimer’s Disease, p 104, (2)). Too much magnesium has been known to cause neonatal brain injury when given intravenously or intramuscularly for the expectant mother during preeclampsia/eclampsia to reduce seizures (3), or for other causes of preterm labor – some magnesium is protective for the fetal brain but too much can negatively affect fetal brain cells. (p103, Mg & the CNS, (2)) 

On page 61 of the book The Neuroscience of Intelligence (1)  genes involved with pathways that influence  glutamate binding with NMDA receptors are mentioned including KNCMA1, NRXN1, POU2F3, and SCRT. (1Both books mention that the NMDA receptors and glutamate as a neurotransmitter are involved with learning and memory. (p101, 2) 

A brief look at what might be known about those genes suggests differences in them may be associated with spasticity, (4), “epilepsy, ataxia, mental retardation, and chronic pain,” (7), alcohol abuse, (5), cervical cancer, (6), – a wide variety of conditions not just learning and memory. Take home point – magnesium is important for learning and memory and general health in an adequate amount, but not excessive amount if given intravenously or intramuscularly.

/Disclosure: This information is provided for educational purposes within the guidelines of fair use. While I am a Registered Dietitian this information is not intended to provide individual health guidance. Please see a health professional for individual health care purposes./ 

  1. Richard J. Haier, The Neuroscience of Intelligence, (Cambridge University Press, 2017, New York), http://www.richardhaier.com/the-neuroscience-of-intelligence/ (1)
  2. Robert Vink, Mihai Nechifor, editors, Magnesium in the Central Nervous System, University of Adelaide Press, 2011, adelaide.edu.au, free ebook pdf, https://www.adelaide.edu.au/press/titles/magnesium/magnesium-ebook.pdf  (2) 
  3. Magnesium Sulfate for Seizure Prevention During Pregnancy, American College of Cardiology,  cardiosmart.org,   https://www.cardiosmart.org/healthwise/hw67/281/hw67281 (3)
  4. Baker D., Big conductance calcium-activated potassium channel openers control spasticity without sedation., Queen Mary University of London, https://qmro.qmul.ac.uk/xmlui/bitstream/handle/123456789/24743/BakerBigconductance2017accepted.pdf?sequence=1 (4)
  5. Jill C. Bettinger, Andrew G. Davies, The role of the BK channel in ethanol response behaviors: evidence from model organism and human studies. Front. Physiol., 09 September 2014,   https://www.frontiersin.org/articles/10.3389/fphys.2014.00346/full (5)
  6. Z Zhang, PC Huettner, L Nguyen, M Bidder, MC Funk, J Li, JS Rader, Aberrant promoter methylation and silencing of the POU2F3 gene in cervical cancer, Oncogene vol 25, pp 5436–5445 (31 August 2006), https://www.nature.com/articles/1209530 (6)
  7. C. Contet, S. P. Goulding, D. A. Kuljis, and A. L. Barth, BK Channels in the Central Nervous System, Europe PMC Article,  Int Rev Neurobiol. 2016; 128: 281–342. http://europepmc.org/articles/PMC4902275/ (7)

 

To have optimal Magnesium needs Protein and Phospholipids too

Good news and bad news – magnesium in the form of Epsom salt, magnesium sulfate, has been in use medicinally since the seventeenth century and written about in peer reviewed medical journals since the early nineteenth century. (1) That is both the good and bad news – it is helpful, but it still isn’t used for many conditions where it might be needed. It is not patentable as a pharmaceutical medication because it is a natural substance. It or magnesium chloride and some other forms are in use for a few conditions including preeclampsia, migraines, stroke, and traumatic brain injury. Minor athletic injuries may be treated with Epsom salt soaks (3) and some psychiatric care providers may also recommend the treatment. 

A textbook on the topic of magnesium use for medical conditions reviews the mineral’s role in the body during health and chronic illness or when genetic differences in metabolism are present. It is complex metabolically and just taking a supplement doesn’t always get magnesium to the problem area of the body. Magnesium is primarily found within cells, and most is bound to proteins or phospholipids rather than as free ions, in blood plasma or other extracellular fluid and not all forms can cross the blood brain barrier to help with migraines or other brain injuries.(1) Magnesium sulfate and magnesium chloride have been found helpful for those purposes (1) and both can be used topically which can bypass problems with poor absorption in the digestive system. (3 

Magnesium oxide is a form sometimes used in supplements that has been found to be very poorly absorbed even when the digestive system is in normal health. Only four percent of a dose is likely to be absorbed and the remaining 96% tends to cause loose stools by causing the intestinal muscles to relax too much if the supplement is in a larger dose. (1) Math – a 250 mg supplement of magnesium oxide might only have 10 milligrams absorbed and 240 milligrams pass through in the next bowel movement.  

Magnesium aspartate has been found helpful in some research studies, but the aspartate is an excitatory amino acid that can cause overactivity within brain cells possibly even leading to cell death, so it may not be ideal for people with some conditions such as headaches or brain injury. Other forms of supplements found to typically be well absorbed include magnesium citrate and magnesium glycinate. More recent research is using magnesium threonate as a form that may be more likely to be absorbed through the blood brain barrier. (1) 

Summary points:  

Symptoms of deficiency may include:  

  • Headaches or migraines may be a symptom because magnesium is used within the brain to protect against excess calcium or glutamate entry into brain cells. It is involved in fluid balance so high blood pressure may occur; tiredness and easy weight gain may be symptoms of chronic deficiency as it may cause insulin resistance and is essential within metabolism to turn sugar into a form of usable energy. Muscle cramps are also a common symptom of magnesium deficiency and may include a twitching of the eyelids. Tinnitus, a constant dull ringing sound in the ears, can occur. (1) (2) 

Food sources of magnesium include: 

  • Green leafy vegetables, broccoli, cauliflower, cabbage, sweet potato, squash; fruit, bananas; dark chocolate; beans, tofu; nuts such as cashews & almonds; pumpkin, pomegranate and sesame seeds, tahini; peanuts; brown rice, whole grains; yogurt. (2) 
Magnesium Food Sources and Symptoms of Deficiency.

Topical sources of magnesium include:  

    • Epsom salt, magnesium sulfate, can be used in baths or foot-soaks, or in damp poultices placed on other sore body parts. For a bath, about one cup of salt in a half bath, soak for 20 minutes three times a week, no more than 40 minutes to avoid excess absorption.
      Symptoms of excess absorption can include slowing heart rate, an overly relaxed muscles which can cause loose stools, for up to a day if very excessive. (3)
      An advantage of magnesium sulfate includes the sulfate in a form that doesn’t need sunshine exposure to skin in order for the body to be able to transform sulfur found in foods into the bioactive sulfate form. 
  • Magnesium chloride is available for topical use in body lotions & as an oily feeling liquid solution.People with digestive problems may not be absorbing much magnesium from food or supplements. 
Topical sources of Magnesium and bioactive Sulfate.

Supplemental forms of magnesium may include: 

    • Magnesium citrate, Mg glycinate, Mg L-threonate, Mg lysinate, Mg orotate, Mg malate, and Mg taurate are all fairly well absorbed forms and generally don’t cause side effects when taken in smaller amounts a few times a day (200-250 mg) instead of in a large dose (more than 400 mg in a single dose). People using diuretics or with increased sweat or urine losses for other reasons may need extra magnesium intake to make up for increased loss of magnesium in urine or sweat. People with late stage kidney disease may need to avoid excess Mg intake. (1) (4) 
  • Magnesium sulfate can be taken in water in very small amounts (a few crystals, a very tiny amount) (3), & it or Mg chloride may also be available in capsule form.
    Magnesium aspartate is well absorbed but the aspartate is an excitatory amino acid and may cause headaches for some users. 
  • Magnesium oxide is poorly absorbed (~ only 4%) & may cause loose stools for more users than the other forms. (1) 
Supplemental sources of Magnesium.

 

Food Sources of Phospholipids and other phospho-nutrients:

Hemp seed kernels and oil; Artemisia turanica/wormwood leaf; amaranth seed; asparagus; avocado fruit or the inner kernel, dried and powdered; beans/legumes; cardamom seeds and powder; carrots; celery stalks and leaves; cocoa beans and cocoa powder, baker’s chocolate, dark chocolate and to a lesser amount milk chocolate and chocolate syrup; coconut; cumin seed/powder; fennel seed, flax seed, pine nuts; sesame seeds, pumpkin seed kernels, squash seeds; butternut squash and pumpkin; gingko leaf; grapefruit and orange juice with the pulp; Jerusalem artichoke (this is a root vegetable rather than a green artichoke); lettuce, spinach and mustard leaves and other leafy green vegetables and herbs; nuts/peanuts, cashews, walnuts; oats; okra seeds; onion root, leek leaves, garlic;  parsnip root; pomegranate seeds and pomegranate peel extract;rice, white or brown but the bran is the best source; rosemary; sorghum;  sweet potato or yam; buckwheat (a seed botanically that is not wheat and is gluten free); wheat. (G.26)   

More information about protein and water needs are available in a post about kidney health: Make every day Kidney Appreciation Day.

/Disclosure: This information is provided for educational purposes within the guidelines of fair use. While I am a Registered Dietitian this information is not intended to provide individual health guidance. Please see a health professional for individual health care purposes./ 

  1. Robert Vink, Mihai Nechifor, editors, Magnesium in the Central Nervous System, University of Adelaide Press, 2011, adelaide.edu.au, free ebook pdf, https://www.adelaide.edu.au/press/titles/magnesium/magnesium-ebook.pdf  (1
  2. Rachael Link, MS, RD,Top 10 Magnesium-rich Foods, Plus Proven Benefits, DrAxe.com, https://draxe.com/magnesium-deficient-top-10-magnesium-rich-foods-must-eating/ (2
  3. Magnesium sulfate (Epsom salt) – Side Effects Dosage, Interactions, everydayhealth.com https://www.everydayhealth.com/drugs/magnesium-sulfate (3
  4. Magnesium Types Compared: What is the Best Magnesium for You?, swansonvitamins.com, https://www.swansonvitamins.com/blog/chelsea/magnesium-types-compared  (4