We have all heard about the 'Fight or Flight' response in the Neanderthal context.  This basically refers to the hormonal changes  triggered when a caveman met a wild beast.  It was designed to preserve the species.  He, or she, was suddenly forced to fight the beast or leg it out and out-run or out-climb the more powerful animal.  The response being referred to involves the activation of a set of neuro-endocrine pathways designed to enhance performance in what was usually a short term yet very intense struggle.

Another, possibly more precise way of describing these neuro-endocrine responses is to characterize them as sympatho-adrenal.  'Sympatho' refers to activation of the sympathetic nervous system.  Activation of the sympathetic nervous system (SNS) causes the release of epinephrine (adrenalin) and norepinephrine into the bloodstream.  These have a panoply of metabolic actions including the elevation of blood pressure and blood glucose.  Increased propensity of the blood to coagulate is another indirect effect which would act to stem bleeding from an artery that might be injured.  Activation of the SNS also produces a rise in serum triglyceride levels.  Triglyceride-rich particles facilitate the neutralization of multiple hostile invaders such as bacteria, viruses and protozoans.  As is apparent, these responses are designed to maximize outcomes in the field of battle. 

The 'adrenal' part of the sympatho-adrenal response refers to release of the stress hormone cortisol into the bloodstream from the adrenal gland.  Because of this, serum cortisol levels rise.  Cortisol is in the category of 'glucocorticoid' hormones.  'Gluco' refers to the link with sugar and  the subsequent elevation of blood sugar levels caused by cortisol.  The benefit of enhanced blood glucose availability is that the muscles (those organs necessary for transporting you away from an angry tiger) will then have an uninterrupted supply of the fuel source they rely on.

In the past, most serious threats were usually resolved one way or another relatively rapidly.  However, in modern times the typical triggers of this primordial hormonal response are chronic in nature and thus produce a prolonged activation of the hormonal responses just described. They were never designed for chronic use.  Modern day stressors are the primary triggers of the fight or flight hormonal response.  In most circumstances stress develops not from crossing paths with a wild animal, but from the unremitting demands at home or at work, financial pressures, lack of sleep and trying to cram too much into too little time.  The hormonal responses are then activated in a continuous fashion.  The persistence of these hormonal responses is at the root of many modern day illnesses including high blood pressure, weight gain, weak bones and heart disease.  This observation is especially germane for the brain.  When exposed to persistently elevated cortisol levels, neurons suffer.  They lose contacts with their neighbors, shrink, and are less resistant to the daily insults all cells are continuously exposed to.  In rodent studies, when infused for just three weeks with the rat equivalent of cortisol, brains wither and memory suffers.  This is in only three weeks!  Imagine how many of us are exposed to chronic stress lasting for months or years.  In the animal studies, the amazing observation is that if the stress hormone infusion is stopped, the brain atrophy reverses!  If this didn't happen, there would be little more to discuss.  However, because it does reverse the question remains, "What can be done about modern brains exposed to chronic stress?"

This is where complete understanding of the flight or fight response is important.  As it evolved over millions of years, it consisted of two related phases. The first phase involves the stress response and subsequent hormonal activation.  It is followed almost immediately by the second phase, the flight response-the most likely reaction to the (generally) physical stressor.  The flight response involves running, jumping, climbing or other similar strenuous activities.  These are identical to what we refer to today as exercise!  When we exercise we trigger the same physiological responses.  They tend to counteract the effects of the stress inducer.  That is the beauty of the combination of stress and vigorous physical activity.  As a result, blood pressure falls, glucose levels fall and triglycerides fall after exercise.  Exercise even reverses the hormonal changes.  It appears to provide the best and most natural antidote for stress.  When the two phases of the fight or flight response are dissociated, or uncoupled, and one is engaged without the other (the situation occurring in most of us today) we experience only the bad effects and it takes its toll on our health. Hence, the optimal way to reverse the ill effects of our stressful lives and the associated adverse impact on our health is to exercise vigorously on a daily basis.  By understanding our ingrained physiology (the fight or flight response) and what goes awry when it is only partially turned on (especially in a continuous fashion), it is clear what the best approach is to address the problem.  Daily exercise is Mother Nature's solution to one aspect of our modern day lifestyles.        

Sounds pretty healthy at first blush, doesn't it?  How could anything having to do with fruit be anything but healthy?  After all, it is recommended that we consume five to eight servings of fruits and vegetables each day.  They contain many healthy nutrients such as antioxidants-the compounds that counteract the harmful effects of 'free radicals', those damaging compounds that age cells, injure the genetic material they depend on, and cause clumping of our functional proteins and lipids- those fatty compounds that enhance function in each cell in the body.  For example, grapes contain resveratrol, a unique ingredient that has been purported to lengthen the life span of various organisms.  I believe there are many healthy nutrients in fruits and veggies.  However, try to imagine in your mind's eye how these foodstuffs might have appeared in the distant past.  For example, take an apple.  It would clearly not have been the large, succulent type of fruit that appears on today's grocery shelves.  It would have been small, tough, and shriveled.  Nothing resembling what is eaten today.  The major difference is that the current varietals are aptly described as tasting sweet, for good reasons.  They are large and starchy; full of sugar. The typical apple contains approximately 1.5 grams of glucose, 6 grams of fructose (fruit sugar), and 3 grams of sucrose (read table sugar).  

 As our gene pool evolved over the past several million years, one of the major influences shaping genetic alterations is the diet.  Of note is the observation that, aside from the past 10,000-20,000 years, we have been exposed to food that included essentially no rapidly absorbed carbohydrates (other than for seasonal honey-like substances).  The rapid absorption of the glucose in starchy foods such as potatoes and bread has been studied along with the related rapid rise in blood insulin levels (associated with the Glycemic Index concept).  Books have been written discussing the Glycemic Index and what it implies.  However, in my opinion, equal emphasis has not been given to the impact that fruit sugar, or fructose, as it is otherwise called, has upon our health.  As an example, the GI (Glycemic Index) of white bread is 100.  That represents the exaggerated rate of rise in blood glucose, and with it the tightly correlated rise in blood insulin levels.  If you consume the same number of carbohydrates in the form of table sugar (or sucrose, which consists of a molecule of glucose and fructose linked together), the GI is only about 60, roughly two-thirds as high as the white bread.  This makes it seem like eating sugar is healthy because its GI is much lower than that of bread.  This couldn't be further from the truth.... for reasons other than those reflected by their glycemic index.

Sugars, such as glucose and fructose, have the uncanny ability to bind to functional proteins, fats and DNA particles.  When this occurs, they dramatically degrade the vital activity of these molecules.  This forms the basis for a commonly requested lab test called HBA1c that measures the average blood sugar level for the past couple of months.  This is a test that represents adequacy of blood sugar regulation over a long period of time and is important in diabetic control.  It reflects the innate ability of these sugars to bind to the hemoglobin protein that is naturally present in the bloodstream.

What is important to note is that the propensity of fructose to bind to these important biological molecules is ten-fold greater than that of glucose even though glucose has a much higher GI.  This is a shortcoming of the GI.  There are many reasons why this distinction is important, but the one I am most concerned about is the relationship between binding of these sugars to delicate proteins in the body and the correlation with brain atrophy.  Brain atrophy may be viewed as brain shrinkage, which is not a good thing to have going on in your brain.  Clinical investigations have documented the close correlation between brain atrophy and level of HbA1c in the blood-a proxy for the degree of binding of these sugars to functional compounds in the body.  One study even found it to be the most significant indicator of brain atrophy. 

The take home message is to avoid foods that contain high amounts of fructose, or fruit sugar.  In this context it is not necessarily the apple I am referring to, but HFCS (high-fructose corn syrup) and table sugar (sucrose).  Numerous foods contain 20 to 40 or more grams of these ingredients.  Be careful to read labels because they even sneak into ketchup and other condiments.   

Athletes who compete at the highest level are able to do so because they train the muscles they depend on to maintain their competitive edge.  For example, basketball players are required to get high off the court to lob a pass or perform a jump shot over the outstretched arms of an opponent.  The extensor muscles in the leg such as the quadriceps and gastronemius/soleus groups are the ones that must perform. The same principle applies for each sport.  To maximize performance, attention must focus on the appropriate muscle groups.  Brain training follows similar rules .... to a degree.

When the brain performs a task, we see no external movement or activity associated with the neurons that were firing during a particular thought process.  To visualize what parts of the brain were activated, scientists use very sophisticated types of brain scanning devices.  The two most popular are PET scanning, for Positron Emission Tomography, and functional MRI scanning, which is a type of magnetic scan.  When a subject is required to perform a mental function such as an arithmetic calculation in one of these machines, specific regions of the brain 'light up.'  This is a reflection of the increased metabolic activity in the requisite areas of the brain necessary for the particular function required.  If the muscles of an athlete were imaged in a scanner while exercising, we would see analogous findings.

The optimal training for an athlete mandates a training regimen designed to work out specific muscle groups under competitive conditions.  The optimal training regimen for the brain is somewhat different.  The cognitive demands of modern day life necessitate a flexible thinking machine, not a robot that performs one thing well time and time again.  This observation mandates quite a different training approach.  What seems to work best is a program that turns on, activates, or lights up, large regions of the cerebral cortex-the surface of the brain which is the part of the brain most densely packed with nerve-to-nerve connections.

Going back to the lab for a moment, when asked to perform a unique task that has not been done before, it is common to see large areas of the brain turned on when visualized via a functional MRI scan.  This is not unexpected.  What is surprising, however, is when that same task is performed a second time or a third time, there is much less response on the scan.  Much smaller areas light up.  An athlete excels by repetitive training and the enhanced ability to maximally fire certain muscles.  The brain seems to 'learn' how to do something in a way that the second time around it functions better and faster with less work.  However, to get to this point it needs to start out performing a unique task.  Hence, it seems like novel situations are what the brain was built to handle and what it should be trained for and with.

What is the take home message from all of this science-speak?  It is that 'the brain loves novelty.'  Translated into modern living circumstances this means if you want to train your brain most effectively you should choose tasks that are out of the ordinary for your daily circumstances.  Simple examples include such basic chores as using the computer mouse with your left hand if you are right-handed, walking on an irregular surface with bare feet, going backwards up the stairs, or in a non-physical example, approaching a common problem in a unique way.  All of these are brain-training exercises.  What is worth noting is that as you activate, or engage, large regions of the brain for one task, these same regions may be required for the performance of other, possibly more complex and unrelated, demands.  Yet, you have trained them and thus enhanced their connectivity with neighboring neurons with these seemingly simple training tools. 

So, each day it would be a good idea to try and activate your brain in new, novel and different ways in challenging circumstances.  It will also be fun and exciting.  Enjoy your new brain workouts!

I was reading the reviews of Gary Taubes' new book Good Calories, Bad Calories on the Amazon.com website and was amused to see that for the most part the reviewers gave him either 1 Star or 5 Stars.  He was either loved or hated.  There must be many good reasons for such a polarized reception to what he had to say but my impression was that the line in the sand was drawn based on his discussion of the "fat vs carbohydrate" hypothesis.

Much of the literature studying the impact of various subcategories of macronutrients (such as saturated fat, trans fat, starch, and rapidly absorbed or refined carbohydrates) on vascular disease has been limited by the tools available for evaluating their propensity to modulate specific lipid parameters or other biological endpoints.  Variances in these variables are then related to heart attack rates, strokes, Alzheimer's disease or other cardiovascular endpoints.  As technology advances, the tools become available to more intimately dissect and measure physiologic indicators that will ultimately be found to reliably predict desired clinical outcomes of interest.  Until appropriate tools are available, scientists must often rely on inadequate metabolic measurements and opine about their prognostic implications.

In his review of the science behind the 'fat' hypothesis of heart disease, Mr. Taubes starts with the parameter of choice at the time, that being TC (Total Cholesterol).  He describes how it was quantitated in thousands of persons in numerous large studies designed to prove that TC was a predictor of future heart disease in broad population groups (as opposed to those subjects with familial hyperlipidemia).  Since the distribution of TC was almost superimposable between the groups with and without heart disease, it clearly was a poor discriminator between the two.

Following TC as the preferred indicator was LDL cholesterol (a. k. a.-the 'bad' cholesterol).  This was a bit better.  The latest, and hopefully most discriminating parameter thus far is the subclass determination of LDL cholesterol as measured by gradient gel electrophoresis.  This is a blood test that identifies the component particles that are the purported 'bad actors' in the heart disease saga-the small, dense LDL particles located in subfraction IVb.  Levels above 10% appear to identify those individuals who are at greatest risk of undergoing invasive cardiac surgeries such as angioplasty, stenting, and bypass procedures. 

This parameter is directly related to serum triglyceride levels and inversely related to HDL cholesterol (the 'good' cholesterol) levels.  The small, dense LDL particles are those that studies have shown are the most likely to damage blood vessels.  Because they vary as the HDL and TG levels do, they are intimately related to the action of insulin and insulin and blood sugar levels.  They are also linked to inflammatory mediators such as CRP (C-reactive protein), an indicator of inflammation throughout the body and a well-established predictor of future cardiac events.

Hopefully as measurement of LDL subclasses become more commonplace, discourses on heart disease will become less divisive.