The Best Nutrition Tips To Manage Depression After Brain Injury

The Best Nutrition Tips To Manage Depression After Brain Injury

Detoxifying vegetables and fruits

After sustaining a brain injury there is a variety of symptoms and issues a person must face – not only the challenges of headaches, dizziness, mental fatigue and cognitive problems, but also mental health issues as well.

In fact, sustaining a brain injury increases a person’s risk of developing depression by 59% (1). Research also shows that sustaining even a mild traumatic brain injury can increase an individual’s risk of developing a mental health issue such as depression by 20% in the six months after their injury (2).

The mechanisms of action for the correlation between brain injury and mental health challenges are not clearly understood. That said, one significant factor is the life adjustment, which includes not being able to do the same things as they did before, taking extra-ordinary time and effort to complete tasks that were easy to do before their injury, and changes to relationships and roles in their life. In addition, there are changes in brain chemistry following a brain injury that can also predispose someone to depression.

So, what can we do to help avoid or manage depression after someone has sustained a brain injury?

Nutrition can play an important role. Research has shown that poor mental health is linked to poor diet quality. People who ate more unhealthy food were more likely to report psychological distress compared with people who ate a healthy diet. In fact, research by Jim E. Banta, Ph.D., et. al (2019) showed that eating fried foods or foods containing too much sugar and processed grains is linked to depression. Unfortunately, following a brain injury it is these quick and easy processed foods that often people gravitate to.

Below we’ll share our best nutrition tips to help avoid or manage depression after brain injury:

10 Best Foods to Combat Depression

The World Journal of Psychiatry in 2018 completed a comprehensive analysis of foods and their impact on mood and depression. They assigned a score to the food based on the nutrients that they contain that help play a role in preventing and promoting the recovery of depression.

Their results showed that the best animal food sources for depression were:

  1. Oysters
  2. Liver and other organ meats
  3. Clams and mussels
  4. Octopus
  5. Crab

They identified that the top 5 plant foods for fighting depression were:

  1. Watercress
  2. Spinach
  3. Mustard, turnip and beet greens
  4. Swiss Chard
  5. Fresh herbs (cilantro, basil and parsley)

The Best Food to Avoid

Although this seems like a no brainer (no pun intended), sugar is extremely detrimental to brain health and mood.

Sugar is inflammatory to the body and brain and can be toxic to brain cells in large doses, which can negatively impact neurological health. This, in turn, can impact our mood causing depression, anxiety and unrest. So, avoiding sugar is advised.

However, this can be tough for a lot of people because the brain requires higher amounts of glucose (energy) following a brain injury, and because sugar is hidden in so many foods. With cognitive and physical fatigue following an injury, we can’t help but gravitate to sugar and sugar-laden products.

There is a whole host of issues and problems that sugar contributes to in the body but one of them (if consumed in high amounts) is the increase in a process called glycation. Glycation is the process when sugars attach to proteins creating advanced glycation end products otherwise called AGE’s. The problem with AGE’s is that they interfere with nerve cell communication and disrupt the mitochondria in the cell (battery/energy). In the Brain Research Review 2003, it reported that glycation is a slow process that advances over time, but it catches up with us as we age and especially if we have genetic susceptibilities.

Glycation also contributes to production of free radicals or oxidative stress, inflammation, and nerve toxins. These are all issues that an injured brain is already dealing with so adding AGE’s to the mix with increased sugar intake only compounds this even more. This will contribute to not only depression, but mood swings, anxiety, and irritability. It is best to avoid foods such as cookies, candy, ice cream, pop, and baked goods.

The Best Cooking Methods for Brain Injury

AGE’s is not just formed by increase sugar intake but also by the way we cook the food. So, we can reduce our AGE’s and subsequent inflammation and free radicals by incorporating better cooking methods when preparing our meals.

The best cooking methods for brain and overall health is to cook with water. For example:

  • Boiling
  • Steaming
  • Poaching
  • Stewing

The reason why these are the best methods is that presence of moisture helps keep AGE’s formed in cooking to a minimum. The worst cooking methods is cooking without water so using the BBQ, oven, and deep frying foods will help to generate a lot more AGE’s.

To give you an example, below we examine the AGE’s formed in chicken breast cooked using four different methods. It is important to know that the amount of AGE’s are expressed as kilo units – so cooking a chicken breast in different ways can significantly impact the amount of AGE’s being formed.

  • Deep fried chicken breast is 9,000 ku
  • Broiled chicken breast is 5,250 ku
  • Roasted chicken breast is 4,300 ku
  • Boiled (soup) chicken breast is 1,000 ku

Best Diet for Depression and Brain Injury

There are so many diets out in the world today, commercial-based diets like weightwatchers, cultural diets, the latest fad weight loss diets such as keto, and so on. It is overwhelming and confusing. But, one diet that has truly stood the test of time, can easily be incorporated into a person’s life, and has a ton of research to back it up – is the Mediterranean diet.

In the Journal of BMC Medicine 2017 a study was completed with individuals that were diagnosed with mild to severe depression. It found those that who were coached and followed the Mediterranean diet for 12 weeks experienced significant improvements in mood compared to those who received social support but not dietary advice. At the end of the study 30% of the participants no longer experienced depression compared to only 8% that just received the social support.

The reason why the Mediterranean diet has been rated the #1 diet multiple years in a row is due to a number of factors. The Mediterranean diet is based on whole foods and contains a high fat content due to the inclusion of fish, olives and olive oil, Greek yoghurt, and feta cheese.  Our brain loves and needs fats so this is crucial for healthy brain function and mood. It also contains tons of fresh fruits, vegetables, and whole grains; but none of the sugar, refined grains, and processed foods. It is an easy diet to stick to, in part because you likely won’t feel hungry (because of the high fat content which supports satiety) and because you are getting a full spectrum of nutrients.

Summary

Depression is a common problem among individuals that have sustained a brain injury. By avoiding sugar, implementing the Mediterranean diet, cooking your food in the presence of water, and consuming a variety of dark leafy greens, organ meats and seafood you will be well on your way to supporting a happier and healthier brain.

References

  1. https://www.scientificamerican.com/article/head-injury-may-cause-mental-illness/
  2. https://www.nih.gov/news-events/news-releases/mental-health-disorders-common-following-mild-head-injury

 

Top 10 Brain-Boosting Foods

Top 10 Brain-Boosting Foods

Detoxifying vegetables and fruits

Whether you’ve suffered a brain injury, or are experiencing brain fog, or just struggling to concentrate and focus … we’ve got you covered with this list! Brain foods not only can help with supporting better cognitive functioning, but help can help boost mood, support sleep, and help with better focus and memory for school or work.

Let’s explore our top 10 brain-boosting foods!

1. Turmeric

This eye-catching, gold-coloured spice is a common component in curries. Turmeric’s most well-known active constituent is curcumin, which has been shown to have many supportive benefits for cognitive functioning. Curcumin is an antioxidant and anti-inflammatory compound that has the ability to cross the blood-brain-barrier, a protective barricade that defends our brain from toxins in our body. Once in the brain, curcumin acts to reduce oxidative stress and neuroinflammation (1). With inflammation reduced, your neurons are able to communicate more effectively, increasing cognitive capacity.

Turmeric is a spice that is an easy addition to many dishes. For an inspiring new take on an old dish, take a look at our Turmeric Hummus recipe. 

2. Kale/Leafy Greens

Eating your daily greens is essential for brain health! Cruciferous vegetables, including kale, spinach, broccoli, and Brussels sprouts are packed full of essential vitamins, such as notable amounts of vitamin K. Vitamin K is a fat-soluble vitamin that is critical for brain health. Vitamin K helps to build strong fat cells in the brain, which improves the structure and communication of our brain cells, otherwise known as neurons (2). Research has shown that individuals who have higher levels of vitamin K, achieved through consuming their leafy greens, have less memory challenges than those with lower levels of vitamin K (3).

If you are looking for a fun way to incorporate more leafy greens in your diet, try these Quinoa and Kale Fritters for a new lunch idea!

3. Eggs

Eggs are packed with brain supporting nutrients such as Vitamin B6, B12, choline and folate. Deficiencies in B12 and folate have been linked to depression. Because eggs are high in the B vitamins, they are good at helping to reduce mental decline as we age.

Eggs are a powerhouse source of choline, a nutrient important for strong cognitive performance. Studies that looked at individual cognitive performance (on tests of memory and attention) and choline levels demonstrated that higher choline levels correlated with better cognitive performance (4). It is suggested that since choline is a major component in the neurotransmitter acetylcholine, high levels help neurons communicate with each other during activities involving memory and attention. While choline is not yet used as a direct treatment in humans, animal studies indicate that choline treatment help reduce memory deficits in animal models of traumatic brain injury (5).

The National Academic press indicates that choline is an important micronutrient that your body uses to create acetylcholine, a neurotransmitter that helps regulate mood and memory. Two studies found that higher intakes of choline were linked to better memory and mental function (Nurk, Resfum, et al 2013) (Poly et al 2011).

Eggs are economical, and quick and easy to make for any meal of the day. In case cholesterol is a concern, we want to share the The Mayo clinic indicates that although chicken eggs are high in cholesterol, the effect of egg consumption on blood cholesterol is minimal when compared with the effect of trans fats. Most healthy people can eat up to seven eggs a week with no increase in their risk of heart disease. Some studies have shown that this level of egg consumption may actually prevent some types of strokes.

Eggs yolks, specifically, are where high levels of choline are found. For a new way to prepare your morning eggs, check our Pesto Baked Egg Cups recipe. This recipe also contains kale – another brain superfood! 

4. Oily Fish

Fat is a very important component of your brain. Your brain is made up of billions of specialized cells, called neurons, and each neuron is wrapped in a fatty sheath. This fatty sheath helps the neurons send messages to each other quickly. The faster these neurons can communicate, the better our thinking skills including memory and attention. Unfortunately, after a brain injury, this fatty sheath can become damaged and impair communication between neurons (6)

Oily fish, including salmon and trout, are wonderful sources of fat that go straight to the brain. Particularly, omega-3 fatty acids are found in these fish are used to help build up the fatty sheaths around neurons (7). Due to this process, incorporation of oily fish is believed to be beneficial in the cognitive recovery process after a traumatic brain injury. 

5. Pumpkin Seeds & Squash Seeds

Pumpkin seeds are filled with the amino acid tyrosine. Consuming this amino acid is important because it is used to create neurotransmitters, the chemicals that our brain communicates with. Specifically, tyrosine is important for creating norepinephrine, which is responsible for responding to acute stress scenarios. When stress is addressed with norepinephrine, it allows our brain to focus on the task at hand without feeling worried or losing focus. Multiple studies have shown that consumption of tyrosine can boost cognitive performance in a stressful situations (8). 

Pumpkin and squash seeds are a wonderful source of tyrosine. In fact, estimates show that one handful can have as much as 35% of the recommended daily intake for tyrosine (9). Consider having these seeds as a snack on the go to keep your thinking skills sharp, even on a stressful day! Check out our coconut yogurt clusters recipe for a tasty way to consume pumpkin seeds!

6. Coffee

Many of us are all too familiar with the daily pick-me-up that appears to come loaded in our daily cup of coffee. However, coffee, specifically caffeine, does more than increase wakefulness; caffeine has benefits for our learning and memory too! When consumed, caffeine interacts with specific receptors in the areas of our brain responsible for learning and memory. After a traumatic brain injury, this interaction becomes particularly important. Researchers suggest that long-term exposure of caffeine can indeed increase the number of these receptors having a positive impact on thinking skills such as memory (10).

Remember, that caffeine can also impact your sleep cycle and potentially exacerbate stress and anxiety, so these are important factors to consider before consumption. 

7. Green Tea

If coffee isn’t for you, then perhaps you’d like to try green tea. Green tea is famous for promoting relaxation and mental clarity and it is increasing in popularity around the world.

Similar to coffee, green tea also contains smaller amounts of caffeine, which promotes thinking skills such as learning and memory. However, there’s another important secret ingredient in green tea… groups of polyphenols! Polyphenols are micronutrients that are found in plant foods. Polyphenols are powerful antioxidants that help to fight inflammation in the brain. Due to these anti-inflammatory properties, researchers support the consumption of polyphenols through the diet to facilitate the complex recovery process after a traumatic brain injury (11).

L-theanine, is an amino acid found in green tea. This amino acid can cross the blood-brain barrier and increase the activity of the neurotransmitter GABA, which helps reduce anxiety and makes us feel more relaxed. Although caffeine in green tea can help increase our mental alertness, the L-theanine helps us to avoid getting the “jitters” and nervous energy that coffee can sometimes give us.

So switch out your coffee for green tea and if you are not a hot green tea fan – brew a pot and put it in the fridge to cool and add stevia for a healthy iced tea beverage.

Of course green tea can be sipped hot as a tea, but you can also enjoy it cool from the fridge with a bit of stevia for a healthy iced beverage, or maybe you’d be interested in making it into a 2-ingredient ice cream!

8. Blueberries

Blueberries are small, but mighty, when it comes to protecting your brain! They contain phytochemicals, which are non-nutrient compounds that provide health benefits. Blueberries are high in a particular phytochemical group known has flavonoids. Along with producing that vivid blue colour, flavonoids are strong antioxidants, which protect against free-radicals and neuro-inflammation.

Additionally, a six-year Nurse’s health study in over 16,000 older individuals found that consuming 2 or more half cup servings of blueberries and strawberries a week were linked to slower mental decline and delays in mental aging by up to 2.5 years. Another study identified nine older adults with mild cognitive impairment who consumed blueberry juice every day. After 12 weeks, they experienced improvements in several markers of brain function (Kroikorian 2010).

The studies on blueberries and brain health seem almost endless! To share one more, Tufts scientists have found that the addition of blueberries to the diet in animal studies improved short-term memory, navigational skills, balance and coordination. Compounds in blueberries seem to jump-start the brain in ways that get aging neurons to communicate again.

Human studies have shown that consumption of blueberries promotes the growth of neurons, combatting memory loss (12). In animal brain-injury models, when taken as a powered supplement, blueberries have been found to have positive impacts on learning and memory challenges. It is believed that their anti-inflammatory effects, promote brain plasticity, fostering learning (13).

For your daily dose of berries, check out our Berry Beet Smoothie Bowl!

9. Walnuts

Given that these nuts look like a little brain themselves, it makes sense that they support brain health! Walnuts contain a host of healthy fats, which play an essential role in brain health. Research has shown these healthy fats reduce oxidative stress, maintain the structure of the neuron, and promote the generation of new neurons (14).

Did you know that 60% of our brain is made up of fat? This includes saturated as well as polyunsaturated fats. Omega 3 is a very important fat for our brain and we just do not get enough in our diets due to poor food choices, consuming processed foods and poor cooking and heating methods. Omega 3’s surround our nerves and protect them. They ensure that our nerves can transmit a smooth signal. Believe it or not, these good fats help regulate the release and performance of neurotransmitters. If we don’t consume enough of these good fats in our diet we can experience depression, memory and learning problems, difficulty concentrating, inflammation and even schizophrenia (Holford 2004). We mentioned above that consuming oily fish provides Omega 3, but so does eating raw nuts like walnuts!

In addition to these fats, walnuts contain various nutrients including polyphenols, vitamin E, flavonoids, and more. These components allow walnuts to protect the brain against inflammation and mitigate cognitive challenges (13).  Who knew that so much power could be packed inside one little nut! 

10. Dark Chocolate

Who doesn’t love hearing that dark chocolate can be a brain health food! Dark chocolate packs a triple punch containing levels of caffeine, antioxidants, and flavonoids. Just like in blueberries, the flavonoids in dark chocolate are strong antioxidants which fight against oxidative stress and neuroinflammation. This helps to slow cognitive decline and protect against neurocognitive diseases14. One study looked at over 900 participants and found that more regular dark chocolate consumption was associated with a stronger cognitive performance (15).

The flavonoids in chocolate gather in the areas of the brain that deal with learning and memory. Researchers say these compounds may enhance memory and also help slow down age-related mental decline (Sokolov, Pavlova et al, 2013). Chocolate is also high in magnesium which helps to calm the mind and promote relaxation. In fact, craving chocolate can be a sign of a magnesium deficiency.

In case you need one more reason to enjoy some chocolate, it also contains a chemical, phenyethylamine (PEA), which can help to elevate mood and feelings of love, while suppressing appetite and improving memory and learning. Feel the love and eat some dark chocolate!

Remember, we are talking about dark chocolate here and not candy bars or milk chocolate bars, which are full with sugar and artificial colourings and flavourings. Our Cranberry Pistachio Bark, Hot Cocoa Elixir, or Black Bean Brownies are all great way to consume dark chocolate!

In Summary

We can see from this list than there are many foods available to support brain function after a traumatic brain injury. Of course, these strategies are relevant to those of us who haven’t suffered an injury as well, as these foods support a healthy brain for improved mood and memory.

It is important to remember that a healthy balance of all these recommended foods, and others, is the most important to optimize cognitive performance. Don’t forget, that many lifestyle factors, such as sleep and stress, impact how our brain functions too! These should be considered in addition to dietary factors to support our brain during recovery or to prevent premature aging.

If you’re looking for help navigating brain injury recovery or other cognitive symptoms, please reach out! Our Nutritionists and Dietitians would be happy to guide you along your health journey!

References 

  1. Misra, S., & Palanivelu, K. (2008). The effect of curcumin (turmeric) on Alzheimer’s Disease: An Overview, Annals of Indian Academy of Neurology, 11(1), 13-19. doi: 10.4103/0972-2327.40220
  2. Ferland, G. (2012). Vitamin K and the Nervous System: An Overview of its Actions. Advances in Nutrition, 3(2), 204-212. doi: 10.3945/an.111.001784
  3. Soutif-Veillon, A., Ferland, G., Rolland, Y., Presse, N., Boucher, K., Feart, C., & Annweiler, C. (2016). Increased dietary vitamin K intake is associated with less severe subjective memory complaint among older adults. Maturitas, 93, 131-136. doi: 10.1016/j.maturitas.2016.02.004
  4. Nurk, E., Refsum, H., Bjelland, I., Drevon, C., Tell, G., Ueland, P., … & Vollset, S. (2013). Plasma free choline, betaine and cognitive performance: the Hordaland Health Study. The British Journal of Nutrition, 109(3), 511-519. doi: 10.1017/S0007114512001249.
  5. Dixon, C., Ma, X., & Marion, D. (2009). Effects of CDP-Choline Treatment on Neurobehavioural Deficits after TBI and on Hippocampal and Neocortical Acetylcholine Release. Journal of Neurotrauma, 14(3), 161-169. doi: 10.1089/neu.1997.14.161
  6. Mierzwa, A., Marion, C., Sullivan, G., McDaniel, D., & Armstrong, R. (2015). Components of myelin damage and repair in the progression of white matter pathology after mild traumatic brain injury. Journal of Neuropathology and Experimental Neurology, 74(3), 218-232. doi: 10.1097/NEN.0000000000000165
  7. Wysoczanski, T., Sokola-Wysoczanska, E., Pekala, J., Lochynski, S., Czyz, K., Bodkowski, R., … & Librowski, T. (2016). Omega-3 Fatty Acids and their Role in Central Nervous System – A Review. Current Medical Chemistry, 23(8), 816-831. doi: 10.2174/0929867323666160122114439.
  8. Lieberman, H. (2003). Nutrition, brain function and cognitive performance. Appetite, 40(3), 245-254. doi: 10.1016/S0195-6663(03)00010-2
  9. My Food Data. Roasted Squash And Pumpkin Seeds (Unsalted). https://tools.myfooddata.com/nutrition-facts/170557/wt2
  10. Sachse, K., Jackson, E., Wisniewski, S., Gillespiie, D., Puccio, A., Clark, R., … & Kochanek, P. (2007). Increases in Cerebrospinal Fluid Caffeine Concentration are Associated with Favourable Outcome after Severe Traumatic Brain injury in Humans. Journal of Cerebral Blood Flow & Metabolism, 28(2), 395-401. doi: 10.1038/sj.jcbfm.9600539
  11. Erdman, J., Oria, M., & Pillsbury, L. (2011). Nutrition and Traumatic Brain Injury: Improving Acute and Subacute Outcomes in Miliiatary Personnel.  National Academies Press (US). Washington, DC.
  12. Krishna, G., Ying, Z., & Gomez-Pinilla. (2019). Blueberry Supplementation Mitigates Altered Brain Plasticity and Behaviour after Traumatic Brain Injury in Rats. Molecular Nutrition and Food Research, 63(15), 1-8. doi: 10.1002/mnfr.201801055
  13. Chauhan, A., & Chauhan, V. (2020). Beneficial Effects of Walnuts on Cognition and Brain Health. Nutrients, 12(2), 550-555. doi: 10.3390/nu12020550
  14. Sokolov, A., Pavlova, M., Klosterhalfen, S., & Enck, P. (2013). Chocolate and the brain: neurobiological impact of cocoa flavanols on cognition and behaviour. Neuroscience and Behavioural Reviews, 37(10), 2445-2453. doi: 10.1016/j.neubiorev.2013.06.013
  15. Crichron, G., Elias, M., & Alkerwi, A. (2016). Chocolate intake is associated with better cognitive function: The Maine-Syracuse Longitudinal Study. Appetite, 100, 126-132. doi: 10.1016/j.appet.2016.02.01

 

How Nutrition Can Support or Hinder Brain Injury Recovery

How Nutrition Can Support or Hinder Brain Injury Recovery

Top 5 Foods to Boost Brain Power Blueberries Koru Nutrition

The human brain requires a huge amount of energy to function efficiently. After a traumatic brain injury, the brain requires even more energy to allow repair to occur. Following a brain injury one major key to recovery is to promote neuroplasticity – that is, enabling the brain to make new connections and pathways to regain function.

Nutrition is often overlooked as a factor that can either support or hinder brain injury recovery, depending on an individual’s eating habits. We know there are specific compounds in foods that effect the production of Brain-Derived Neurotropic Factor (BDNF), which is a protein in the family of growth factors that is produced by the human body and plays an integral role in the survival and growth of brain cells.¹ BDNF contributes to the plasticity of neurons, which is essential for recovery, learning and memory.

Let’s look more closely at how food can support or hinder brain injury recovery!

Top 2 Foods To Avoid Post-Brain Injury

These Foods Reduce Neuroplasticity

1. Alcohol

We’ve probably all heard the adage that “alcohol kills brain cells”. The science is a bit more complicated than that, but it’s true that even moderate alcohol intake can decrease neuroplasticity as well as increasing inflammation within the brain.² This is important to know because sustained inflammation within the brain leads to further damage and impairments in cognitive function.

2. Sugar

Sugar increases inflammation and oxidative stress (an imbalance of free radicals and antioxidant in the body that can lead to tissue damage). Diets high in refined sugar down-regulate several key factors needed for brain function and repair including neurotransmitters. A diet high in refined sugars also impairs the gut microbiome (the bacteria and fungi that live in our guts), which directly impacts the brain via the gut-brain axis. Put plainly, anything damaging the gut is also harming the brain, and vice versa.³

Top 4 Foods To Consume Post-Brain Injury

These Foods improve Neuroplasticity

1. Berries

Berries as a group are high antioxidants and known for their protective effects. The antioxidants present in berries can help protect the brain from secondary damage and functional decline, as well as reduce inflammation.

2. Egg Yolk

Egg yolk is high in the nutrient choline, which is an essential component of all cell membranes and especially critical for communication between brain cells. Choline has neuroprotective effects and promotes rapid repair of damaged cells – exactly what is required post-brain injury!4

3. Non-starchy vegetables

Caloric restriction may benefit individual’s post-brain injury as their body focuses on recovery. In fact, research shows that calorie restriction has beneficial effects on brain plasticity and neuronal vulnerability to injury and can stimulate production of BDNF.5 As such, vegetables like kale, broccoli, asparagus, celery, or cucumber, that provide dense nutrition and satiety without an abundance of calories should be considered as the base of an individual’s diet.6

4. Oily Fish

One of the most important and well-researched dietary factors that relates to brain health is fish-derived Omega 3 fatty acids. Not only do Omega 3 fats assist in reducing inflammation within the brain and helping to prevent secondary damage, but DHA (one specific Omega 3 fat) is known to facilitate brain cell recovery and the development of new brain pathways post-injury.7

If you or someone you know has suffered a traumatic brain injury, please consider the significant positive impact that changes in nutrition can have on recovery. A skilled dietitian or nutritionist, like those at Koru Nutrition, can help you navigate what dietary changes are best for you, and provide you with the tools and skills to implement new habits. Get in touch by email or book a session now, we’re here to help!

 

References:

¹ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4697050/

² https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4342330/

³ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6025245/

https://www.ncbi.nlm.nih.gov/books/NBK209327/

https://link.springer.com/article/10.1385/JMN:16:1:1

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4672013/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3225186/