The brain is essentially a post-mitotic organ. That is science-speak that can be loosely translated to mean each nerve cell (also called a neuron) is as old as the owner of the brain. Many of the other organs of the body produce individual cells on a continuous basis. For example, the lining cells of the intestinal tract are recycled about every 3 to 5 days. Because of this, 'aging' has a very different meaning to a cell that lives for a week than it does for cells that must survive for 80 or 90 years. Neurons live a long time and are exposed to numerous dents and dings every day. They must also contend with insults that don't individually affect cell function in any meaningful fashion, but when such 'sub-threshold' changes accumulate over time, they collectively conspire to produce alterations that very dramatically impair neuronal characteristics. One example of this type of insult is called oxidation. That is what happens when a nail rusts. The same process can affect living cells and tissues by chemically altering vital structural attributes subsequently producing detrimental functional implications. When nerve cell membranes are oxidized, they become stiffer. There are proteins imbedded within the membranes that act as 'receptors' for molecules that enable nerve cells to communicate. These molecules are called neurotransmitters and go by the familiar names serotonin (important in mood disorders), dopamine (the 'feel-good' transmitter), and norepinephrine (for focus and attention). There are many others, more than 50 all together, that serve a variety of uses. For them to do their job, they must attach to a receptor molecule that lives in the membrane. When this pair (neurotransmitter-receptor) is formed, it changes shape. A mental picture of this process might be a key in a lock. After being inserted, the key is turned which opens the lock. Some locks can become 'sticky' or even 'frozen.' When this occurs, the key may be inserted without unlocking the lock. A similar process can develop in neuronal membranes. When they are oxidized, they get stiff and receptors respond less actively when bound to a neurotransmitter. Since this process is the basis for nerve cell communication, when it is impaired brain function is compromised. This is one mechanism that is associated with aging and contributes to memory alterations, for example. Short-lived cells are not around long enough for the buildup of multiple oxidative changes to occur, which takes longer than the 5 days these cells live. 

Neurons must also contend with more catastrophic insults such as strokes, traumatic events, and hemorrhages. These tend to produce damage in a local, isolated region of the brain. They tend to kill cells at the center, leave cells at a distance alone, and produce an intermediate zone of cells that are alive but not functioning optimally.

If part of another organ, such as the liver, is lost, the remaining cells take over and cover for their lost compatriots because each cell in these organs does essentially the same thing. The brain is quite different in this regard. No two neurons are identical and different regions of the brain are wired differently and provide different functions. Given these constraints, how is it possible to 'recover' lost function, and how does the brain cope with chronic disease such as that which accumulates as we age? In other words, what is the brain's backup plan?  

Generally speaking, there are several processes involved. The sick nerve cells can be made healthier. Other functioning nerve cells can learn to compensate for their neighbors who have died, and new nerve cells can be formed. To understand how the brain addresses such problems, it is helpful to consider a simpler example. For this I will use a severed nerve in the hand whose job it is to provide sensation to a specific area of skin. When such a peripheral nerve is cut, several things happen. You lose sensation to a portion of the skin. The body detects this and initiates a response. New nerve cells start to grow out from the spinal cord and the surrounding nerves in the hand start to respond. The nerves supplying touch sensation to contiguous areas of skin realize the presence of the damaged nerve nearby and start to grow and expand into the 'denervated' numb spot. Various nerve growth factors and other chemicals and electrical signals orchestrate this complex process.

The brain reacts in a similar fashion. Neighboring neurons sense the nearby injury and send out branches that integrate into the network of nerves that were injured. Because of the high degree of connectivity between one brain cell and thousands of others, many widely separated regions of the brain are put on notice. They start to reconfigure, or rewire, their connections in ways designed to return functions that were lost or decreased. This process can be visualized on special brain scans called fMRI scans (for functional Magnetic Resonance Imaging). When we perform certain tasks, whether it is moving a finger or adding 3+5, it requires brain activity in specific regions of the brain. This activity is identified by the fMRI scan and is identified as an area of the brain that 'lights up.' Certain tasks cause a portion of the left frontal lobe to light up. When this portion of the brain gets sick or is injured, it lights up less vigorously. However, in time, when the same task is undertaken, something interesting is seen on the fMRI scan. Nearby areas 'turn on' as do brain regions at a distance from the damaged area. Sometimes they show up as mirror image regions on the other side of the brain, in this case the right frontal lobe. Other times they show up as bright spots on the same side of the brain but in the left parietal or left occipital lobe region. These represent signs that the brain is compensating for the loss of function at another area. Again, a host of growth factors, proteins and electrical signals coordinate the process.

What is important to know is that we have a degree of control over what is happening. By training our brains we can facilitate this entire process. In part, this helps explain why different types of therapy work to help stroke patients. Physical activity of various sorts, unrelated to the area involved, acts to enhance the recovery response. You would think the mechanism would be merely augmented blood flow to the brain, yet there are many other pathways that are switched on in the brain by physical exercise of all sorts. They make nerve cells more resistant to future insults, speed up nerve communication, and increase nerve to nerve contact points. Proper sleep is restorative to healthy brains and has additional benefits for sick brains. Stress causes neurons to shrivel up; something that is counterproductive to a healing brain. Stress reduction facilitates brain health and healing. Dietary approaches that lower insulin levels and are anti-inflammatory reinforce each of the above mechanisms and healing pathways. So, the brain can do a lot to heal itself, but the power to turbocharge the response is in your hands!  

During recent human evolutionary history (about 1.5 million years ago), the human brain increased in size by 33% in less than a million years.  For this extraordinary expansion to occur required exceptionally favorable circumstances.  By any measure, the modern human brain is large.  Brains generally increase in size as body size increases.  However, the human brain is about 3.5 times larger than that of chimpanzees which, as adults, have a lean body weight not very different from ours. 

This massive expansion is even more remarkable when the nutritional demands it places on the body are considered.  In adult humans the brain weighs 1400 grams, or approximately 2.3% of the body weight.  However, it consumes almost one quarter of the body's daily energy requirement.  In infants this disparity is even greater.  At birth, the brain weighs 400 grams and constitutes 11% of the body weight yet consumes almost three quarters of the energy intake!  Thus, any theory of human brain evolution must account for the environmental circumstances that would allow our ancestors to commit a large, disproportionate and continuous nutrient supply to the brain, especially early in life.

Most theories are plagued by the 'chicken or the egg' dilemma.  This refers to the fact that hunting, tool use and other more cerebral pursuits have been considered as being forces that drove this rapid brain expansion.  However, for these to exist in the first place, a large brain would have been a prerequisite.  So how did improvements in brain anatomy and wiring develop before a larger brain existed that would have facilitated the formulation of higher brain functions?  And how could this have happened over such a brief period of evolutionary time?  Moreover, the main period of brain expansion was during late fetal and early post-natal development.  At this stage a bigger brain would not have conferred any survival value.

Recent clues have suggested the role of a nutrient dense diet. This meant a diet higher in meat and fat with a lower plant content.  As a possible means of procuring such a diet, hunting would have exceeded the mental capacity at this stage of development and brain size.  A likely solution for attaining a high quality diet without the necessity for a sophisticated procurement system appears to be a shore-based diet.  This meant exploiting the abundant, sustained, and easily accessible food supply at the waters edge.  It probably involved harvesting bird eggs, mollusks, and crustaceans which were nutrient and energy rich.  This diet could have been easily harvested by humans of all ages, both genders and required no special skills or bodily strength.  

Because of the incessant demands for a nutrient and calorie dense diet, especially during the most rapid period of brain growth perinatally, during a time of absolute dependency, it was vital to prevent periods of nutrient deprivation.  This is of interest in light of the fact that although the brains of newborn humans and chimps are similar in size, human infants have about one pound of body fat.  Body fat is almost nonexistent in chimp newborns.  This fat store provided calories that could last for three weeks and thus constituted a formidable buffer against environmental variability.  Fat deposition in the human fetus accounts for 90% of the weight gain leading up to delivery.  This represents an exceptional metabolic commitment and suggests that it somehow  facilitates the survival of the infant.

From a caloric perspective, the brain is able to utilize glucose but can't tap into fat or protein sources to any degree.  It does posses the metabolic machinery to generate energy from ketone bodies, which are compounds that occur due to partial fat combustion.  These are efficiently burned in the brain and can provide 30% of its caloric demands during the newborn period.  Ketones are also a source of carbon for the synthesis of brain lipids and cholesterol that comprise a large fraction of neuronal cell membranes.  Neurons work by being active electrically.  Most cells manifesting high electrical activity (such as neurons, photoreceptor cells and cardiac cells) have a high concentration of DHA (docosahexanoic acid-a long chain omega 3 fatty acid that provides membrane flexibility and function).  The DHA concentration in the fat stores at birth is higher than it is at any other time.  A shore-based diet provides a continuous supply of this vital nutrient for the synthesis and recycling of neuronal membranes and synaptic connections.

These dietary demands are vital at birth, but are no less important for the aging brain.  High energy requirements and the demand for a nutrient dense diet with abundant long-chain omega 3 fatty acids are critical for optimal brain function and act to slow brain aging.  The efficiency with which the brain metabolizes glucose declines as we age.  If energetic demands are to be successfully met as we age, ketone bodies are an ideal fuel source because they generate energy with lower oxygen use and are delivered to the brain via a different transporter than glucose uses.  For these reasons current dietary choices should more closely mirror the shore-based diet responsible for the rapid evolution of the flexible thinking machine we call our brain. 

No, this is not a blog entry about sinusitis, rhinitis or epistaxis (how doctors refer to a bloody nose). It involves an evolutionary discussion of nasal function, anatomy, and connections with prevalent modern day health problems.

In human physiology, the chemical senses (smell and taste) play minor roles compared to vision, hearing and touch.  However, it is well-known that a number of odors can involuntarily elicit access to memories, thought to be forgotten.  Likewise, intense memories can sometimes produce specific olfactory (smell related) experiences.  Olfaction also has a significant impact on human social behavior and mood.

The olfactory system provides for the detection of volatile chemical substances. The receptor cells are located in the mucosal surface of the nose.  They reside high in the nasal cavity where it comes into intimate contact with the base of the brain cavity (located behind the bridge of the nose). This is where receptor neurons (called bipolar olfactory receptor neurons) reside.  They are able to detect the roughly 5,000 odors humans are able to differentiate.  Once stimulated, these neurons transmit an impulse to a relay station (the olfactory bulb) located within the brain cavity. From here the impulse is transmitted directly to the cerebral cortex - that thin layer of nerves that comprises the gray matter overlying the brain.  It forms a series of hills and valleys and is what you first observe when you look at the surface of the brain. The primary destinations of the nerve cells that originate in the olfactory bulb are the entorhinal cortex and the amygdala. The entorhinal cortex is where much of the processing occurs that creates mental awareness of a specific odor.  The amygdala is part of the limbic system, an ancient anatomic region that contributes to memory function and visceral responses including fear, anxiety and stress. It is no accident these are described as being visceral, because, as you can see from their anatomic connection with the nose (a key participant in detecting and processing the aroma of freshly cooked food) they are linked with the digestive tract.  The intimate relationship of the 'nose brain' with memory, learning, and emotional traits is also intriguing.

Specific odorants (volatile chemicals that contact the olfactory receptor neurons which generate an electrical signal that is transmitted to the brain) are stimuli our nose detects and our brain uses to create a mental image it associates with that chemical. This mental picture the brain creates is what is referred to as an odor.  Think of a bottle of chemicals used to clean paint brushes.  That is the odorant.  When we smell it, the mental image of 'turpentine' is generated.  This is the odor, or smell we perceive.  Using a visual analogy, the wooden platform with four legs used for writing is perceived as a desk. Since odors are mental constructs, they may be subject to additional mental processing and may even be perceived differently dependent on subsequent personal experiences.

Chemical senses, including smell, play an important role in the animal kingdom.  They have been used as a method of communication with other members of the species, for detection of food, for identification of potential environmental dangers such as larger animals on the prowl or rancid potentially toxic food, and for reception of biological signals pertinent to mating and reproductive processes.  Olfactory signals differ from typical visual or auditory stimuli in that they are frequently transient, but are often extraordinarily complex.  For example, the aroma of coffee is made up of more than 800 volatile components.  It is also difficult to 'label' smells and as a result they are often described by the situation in which they are encountered such as "this smells like Christmas."

Olfactory signals also provide discriminatory functions in social interactions by allowing for the identification of individuals.  For example, mothers are able to identify their newborn babies by odor after only a brief exposure (less than an hour).

These examples serve to underscore the intimate connectivity between odors, nasal function, and the brain.  The anatomical infrastructure is primitive and the link to survival benefits for the organism suggests a long-standing important nexus between the olfactory system and and vital aspects of human physiology. 

If we fast forward to modern times, the current epidemics we are confronted with include obesity (and the closely associated disorders diabetes and cardiovascular disease) and various states of mental decline including Alzheimer's disease (AD).  These conditions don't exist in isolation.  Obesity increases the risk of developing AD two or three-fold.  There have also been links established between impaired olfactory function and AD.  This is not surprising given the close proximity, intimate connectively, and anatomic overlap between the nose brain and the vital memory center called the hippocampus.  In fact, the earliest neuropathological findings identified in the brains of patients with AD occur in the nose brain (entorhinal cortex).  From here, they spread throughout the brain. Convergent data reveal that AD patients show impaired olfactory performance, specifically in tasks of odor identification.  Recently, an association was found between decreased olfaction and diminished left hippocampal volume in persons with probable AD.  Loss of the sense of smell (not related to sinus and other local diseases) has been identified as a predictor for later cognitive decline in non-demented elderly retirees.  There are starting to be early hints that obesity might also be associated with altered olfactory function.  A study documented modified olfaction in obese children aged 10 to 16 years.  Clearly, more studies are required to investigate this correlation.  Hence, there are links between impairments of olfactory function and both AD and the obese state.

Thus it appears there is a link between obesity, AD and the nose brain.  The question might be asked, what is its substrate.  Clues to this exist.  Numerous investigators have identified decreased insulin signaling in the brains of patients with AD.  This has been documented in animal models of AD.  In addition, when insulin levels in the brain are evaluated, they are lower in AD than in age equivalent normals.  AD patients are frequently found to be insulin resistant.  This means their bodies don't react normally to the hormonal effects of insulin.  Insulin is the hormone that regulates and controls blood sugar levels.  With a diminished response to insulin, blood sugar levels rise and higher insulin levels are needed to bring them back to normal.  As insulin levels rise in the bloodstream, they fall in the brain.  One reason for this is that insulin in the blood can't be as effectively transported to the brain because of modifications in the blood-brain-barrier (BBB).  Animals with lowered brain insulin develop mental decline and memory loss.  In short, they become demented.

The same findings exist in obese, non demented persons.  That is, they have lower brain insulin levels.  One effect of brain insulin is that it decreases appetite.  This makes the connection seem potentially causal.  It would be interesting to find out whether deviations in olfaction constitute a common feature of states of insulin deficiency in the brain associated with obesity and AD.  This is not far fetched because there are high levels of insulin receptors in the nose brain.

Whether this is true, or not, the nose-brain connection may provide a therapeutic route for treatment.  Over the years spontaneous passage from the nose to the brain has been documented for viruses, heavy metals and bioactive peptides such as CCK (cholecystokinin).  More recently, investigators have documented the passage of nasally applied insulin (the same hormone used to regulate blood sugar) across the nasal mucosa into the brain.  In addition, they have shown enhanced focus, memory, and performance of daily activities in patients with early AD who had been studied after intra-nasal application of insulin. 

These astounding observations should serve as an incentive to pursue additional research in the nose-brain connection including its potential as a therapeutic conduit for some of the common health concerns afflicting many persons today.

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!

The prognosis for most patients with malignant brain tumors is poor.  Surgical resection followed by radiation therapy is the standard therapy.  Chemotherapy is often used in an adjuvant fashion.  Of potential interest in this area are several papers that have appeared in the medical literature over the past 10-15 years evaluating potential dietary approaches to these devastating, and frequently poorly responsive, neoplasms.  Interestingly, they didn't seem to make the radar screen of most oncologists and other physicians treating these patients.  Recently there has been renewed interest in the possible beneficial effects of a nutritional program to assist in the treatment of various cancers. 

The basis for such an approach arises from the metabolic inflexibility shown by brain tumor cells.  Having arisen from the same basic cell type, brain tumor cells share many common traits with normal brain cells.  However one of the key differences, and one that is shared by many other types of cancer cells, is that as they make the normal to cancerous transition they lose some of the properties of the normal brain cells.  In the case at hand, we will contrast how normal and cancer cells produce the large amount of energy that allows them to proliferate.  Brain cells depend almost exclusively on glucose they receive from the blood stream as the ultimate fuel source they generate their energy from.  Somewhere during their evolutionary history they learned a neat trick.  Famine and starvation were common occurrences and were usually associated with a fall in glucose availability.  This was because the body can only store enough glucose (mostly in the liver) to last about 24 hours.  After this reserve is exhausted, protein is broken down and converted to glucose to provide a continuing fuel supply for the brain cells.  It is not surprising that if this continues unabated our lean tissues including the heart and muscles would eventually start to malfunction.  In order to prevent this from occurring, we tap into our fat stores.  Yet, the brain can't burn fat so how does this help?  The fats in the blood are transported to the liver where they are partially burned.  The remaining partially burned fats are called ketone bodies, or ketones.  They are released into the blood and carried to the brain where they may be used as an alternative fuel source by the brain cells.  This preserves our lean tissue and gives the brain an additional source of energy.

Thus, normal brain cells can burn a mixture of glucose and ketone bodies and are very happy to do so.  They actually feel no difference because the energy is all they require whatever the source.  Stick with me, this is where it gets interesting.  Brain cancer cells usually lose the sophisticated metabolic machinery required to burn both glucose and ketones.  They still depend solely on glucose.  When they are faced with less glucose and more ketone bodies, they can only use the former.  Hence they react as if they were being starved.  When this happens, they can't produce the energy required to sustain their rapid growth rate, at least this is what should happen theoretically.  But does it really occur this way.  That is what several fascinating studies suggest.

In an article published in the Journal of the American College of Nutrition (1995;14:202-208) the impact of a diet that decreased serum glucose levels and increased ketone levels in two patients with advanced malignant astrocytomas (brain tumors) was studied.  To determine the effect on the metabolic rate of the tumors a special type of scanning technique was used.  It is called positron emission tomography, or PET.  Since tumors can't burn ketones, their metabolic rate is determined by how much glucose they burn.  That is precisely what PET scans measure.  After only one week on the diet these patients had their PET scans.  Amazingly, the metabolic rate of the tumors was cut by 20%.  This was the end of the study. 

What we really want to know is what effect this type of diet will have on the growth of the tumor.  This information can only be provided by controlled clinical trials.  To make sure they are comparing apples with apples, scientists need to perform the experiment in identical animals with identical tumor types.  When this was done they observed a 35-65% decrease in tumor growth and a marked increase in function and survival.  If confirmed in humans, this would be extraordinary indeed.      

The type of diet used was a calorically-restricted ketogenic diet.  One version of the diet was enhanced by the provision of MCT oil (medium chain triglyceride) which is rapidly converted to ketones in the body.  For information in how the diet was configured you can see the published results in the Journal of the American Dietetic Association (1995;95:693-697).    

I recently received an email questioning whether mental illness might in whole or in part be related to diet and nutrition.  It is clear to me that the two are intimately related.  Around the turn of the prior century the mental asylums of the southern United States were filled with patients suffering from dementia, melancholy, psychosis and a host of related ailments.  The disease responsible for this malady became known as pellagra.  The prevailing view of the medical profession at this time was that such an epidemic could only be caused by an infectious agent.  It took the knowledge and willpower of Dr. Joseph Goldberger to convince his colleagues that pestilence was not the cause.  He proved that the deficiency of a single nutrient from the diet, niacin (nicotinic acid) in this case, was the causative factor.  To change the mindset of the medical establishment he and his associates held 'filth fests' where they, acting as human guinea pigs, injected themselves with blood and ingested the excreta from patients severely afflicted with pellagra.  Other than for squeamishness in several of the study participants, no symptoms of disease developed over the ensuing six months.  This served to dispel any further investigations into the 'germ' theory of pellagra (niacin, or nicotinic acid, deficiency disease).  Nicotinic acid therapy produced miraculous results.  In spite of this discovery, it still took five years to cure the large number of patients suffering from the disorder.  Part of the problem was the persistence of poor dietary habits.  Poor nutrition remains a major health problem today.

Because of sporadic food fortification, pellagra has become a relic of the past.  However, the broad role of nutrition, and more specifically the impact of prolonged, less severe, dietary deficiencies appears to be playing an increasing role in the production of an array of illnesses.  Mental diseases are no exception.  This is being recognized in the clinic and in the laboratory.  Based on such insights physicians have started recommending dietary interventions alone, or in addition to pharmaceutical treatments to help their patients.  A Harvard-based psychiatrist, Dr. Andrew Stohl, thought one reason responsible for the increase in depressive disorders he was seeing was related to changes in the essential fatty acid content in the modern diet.  There are two essential fats required by the body.  They are the groups of omega 3 and omega 6 fatty acids.  We are consuming much more omega 6 fatty acids than required, and much less omega 3 fat.  Not only is the absolute amount of each class of fats important, their  ratio is also key.  Today we are experiencing an absolute deficiency of the omega 3 fats and a dramatic increase in the omega 6/omega 3 ratio in our diet.  When persistent, these alterations produce inflammation and cause changes in cellular attributes of neuronal function. 

To test his theory, he studied the response to essential fatty acid (EFA) therapy in a group of depressed patients.  Using pharmacological doses of the omega 3 EFAs (meaning about 5-10 times the amount required on a daily basis), he noted a marked improvement in their depressive symptoms.  Additional studies documented improvement in patients with Bipolar Disorder.  He also observed that in a number of his patients he was able to lower the dosage of medication when he incorporated omega 3 EFAs to the treatment regimen.  Obviously this is something that should not be considered without the input of your personal physician.  It does show the power of nutrition to beneficially impact brain function specifically in the arena of mood disorders.

When provided in amounts in excess of the RDI, other nutrients such as folic acid have been shown to beneficially impact depressive symptomatology.  This suggests that they have functional utility beyond their established role in basic metabolic processes. 

Mental illness clearly also has a genetic component, but the clinical phenotype-meaning if, when, and how it expresses itself- is clearly modulated by nutritional factors.  This reasoning even applies in the realm of ADD/ADHD (attention-deficit disorder/attention-deficit-hyperactivity disorder) where symptomatic improvement has coincided with EFA therapy.  This suggests to me there are intimate links between brain function, diet and mental illness and one component in the prevention and/or treatment of these devastating conditions should involve dietary recommendations.

There are millions of Americans who require insulin for the medical treatment of diabetes.  Doctors who direct the therapy of these patients often recommend what is referred to as 'tight' glucose control.  Such a regimen necessitates multiple injections of insulin throughout the day designed to keep blood sugar levels within normal limits at all times.  The purpose of this approach is to minimize the chances of developing cardiovascular complications (such as heart attack and stroke) that are associated with poor blood sugar regulation.  This requires frequent blood sugar testing throughout the day, calculation of insulin doses based upon the blood sugar level, and frequent injections of insulin.  One of the most troubling complications of this type of therapy is hypoglycemia (low blood sugar).  These hypoglycemic episodes are directly related to the injection of an excess of insulin.  When this occurs, symptoms may develop that include tremulousness, jittery feelings, dysphoria, and slowed mentation.  In the presence of even lower glucose levels confusion, somnolence and coma may ensue.  These constitute medical emergencies.  Whether these episodes are mild, or more severe, they are not good for the health of the brain.  Yet, for diabetics they are an unfortunate fact of life.  They may develop slowly, or more rapidly.  With a gradual onset the patients are trained to eat or drink something containing a rapidly digestible source of glucose to counteract the falling sugar level.  This frequently is sufficient to mitigate symptoms of hypoglycemia, but may generate an associated surge, or overshoot, of blood sugar-an undesirable result.  Such is the life of a person grappling with diabetes.  

Anything that would alleviate the occasionally serious signs and symptoms arising from these episodes would be helpful for a large segment of the population and would save many neurons.  A clever study, published in the medical journal Diabetes (1994;43:1311-1317), provided clues to this dilemma.  The brain usually depends almost exclusively on glucose to supply its substantial energy requirements.  During hypoglycemia associated with prolonged fasting or strenuous exercise, circulating ketone body levels increase many-fold.  Ketone bodies (acetoacetate and beta hydroxybutyrate) are products of partial fat metabolism which are generated in the liver and are secreted into the circulation.  They constitute a fuel source that is easily burned by the brain and is able to provide the energy the falling blood glucose can't.  This study was designed to investigate whether ketones would provide similar protection under insulin-induced hypoglycemia.  The experimental conditions were chosen to model what happens when diabetics become hypoglycemic due to injection of too much insulin.

Infusion of precise amounts of insulin was performed in two groups of subjects, one who had shortly before received an infusion of ketone bodies, and one group who had received a placebo (inactive infusion containing no ketone bodies).  Blood samples were then drawn and cognitive function testing was performed. 

Compared to the group that received insulin plus placebo (no ketones), the group that had insulin plus ketone bodies had reduced signs and symptoms of hypoglycemia.  They remained asymptomatic until blood glucose levels fell to the 40 mg/dl range compared to the production of symptoms in the more typical 50 mg/dl range of blood sugar in the other group.  These remarkable findings suggest that ketones help protect neurons from severe hypoglycemia.  While such therapy may not be useful in all circumstances, it is expected to expand the safety margin of tight glucose control in a large number of diabetic patients. 

Ketone body therapy is not currently available.  However,  when taken as a supplement to the diet MCT oil (medium chain triglyceride) is rapidly turned into ketone bodies which would be expected to produce the same beneficial effect.

The primary fuel sources the body uses to generate energy are fat and glucose.  We are only able to store enough glucose to last for 24 hours.  Well before that, we start breaking down protein and turning it into glucose.  This is done to keep the brain humming along because it is not able to burn fat.  If we don't eat for longer time intervals then what happens?  We have an almost unlimited capacity for storing fat, so why not tap into that?  That makes sense and is exactly what happens.  The only problem, at least for the brain, is where does the glucose come from that it requires since fat can't be turned into glucose in any meaningful amount.  Protein is the ultimate raw material used by the body to produce glucose for the brain.  In essence, the body is cannibalizing muscle to turn it into glucose for brain food.  Obviously, if this continues we would lose skeletal muscle, heart muscle and the protein in organs like liver and kidney.  Several ingenious metabolic changes emerged during our evolutionary past to address this quandary. 

As fat is utilized during a fast, it goes through a process in the liver where in the partially metabolized state it may be turned into ketone bodies which include acetoacetate and hydroxybutyrate.  These are released into the circulation where many organs may use them as an alternative fuel source.  The brain is one such organ.  This change in fuel use by the brain may take place immediately, but to fully make the transition takes a week or two.  When fully engaged, ketones may produce almost half of the energy the brain requires (the remainder still coming from glucose).  The key concept in being able to conserve lean tissue such as protein during a fast is to decrease the dependence of the brain on glucose.  Provision of ketone bodies achieves this goal. 

This metabolic conversion has other benefits as well.  In addition to providing an alternative fuel for energy generation for neurons, the metabolism of ketone bodies has a subtle impact upon neurotransmitter levels in the brain.  As you may recall, neurotransmitters are the chemicals secreted by one neuron that bind to a neighboring neuron thus allowing them to communicate with each other.  There are neurotransmitters that excite, or stimulate neurons, and others that relax or calm down neurons.  They act in a yin-yang fashion to keep brain activity in the 'just right' zone.  Glutamate is the excitatory transmitter and GABA (gamma amino butyric acid) is the inhibitory, or relaxing transmitter.  The switch to ketones shifts this balance to a more relaxing mode.  It is believed that this neurotransmitter modulation is one of the reasons a ketogenic diet is so effective in controlling pediatric epilepsy.  It also is able to neutralize the stimulation generated by excessive calcium influx into neurons that occurs as we age.  As intracellular calcium builds up in nerve cells it damages them.   By shifting the GABA/Glutamate balance, this is minimized.  Another unexpected benefit provided by the use of ketone bodies is an increase in the energy charge of neurons.  What this means is that nerve cells have more energy to take advantage of.

In a prior article, I mentioned that one of the earliest findings detected in the brain of a person at risk for the development of Alzheimer's disease is a decrease in their brain's ability to efficiently use glucose.  Ketone bodies are able to compensate for this.  By administering a formulation containing MCT oil (medium chain triglycerides are turned into ketones) to subjects with Alzheimer's disease, researchers were able to improve mental functioning.  These findings were reported in the medical journal Neurobiology of Aging (2004;25:311-314).  This observation illustrates the power of ketones to beneficially impact brain function.  What we all must remember is that dietary changes can generate ketones as effectively as MCT oil.

If you have children you may recall the tale of Goldilocks and the three bears.  They were Momma Bear, Poppa Bear and Baby Bear.  The take home lesson from the story, at least regarding porridge, was that the best temperature was not too hot, not too cold, but just right.  Neurons have similar needs when it comes to glucose and insulin levels.  I refer to this "just right" concept as the "Goldilocks Principle."  The major fuel the brain burns is sugar, or more precisely glucose.  The body can make glucose and we can consume it, or foods containing it, in our diet.  White bread is an example of a food source of glucose.  The starch in the white bread is a large molecule composed of long strands of single glucose molecules linked together side to side.  These links, or chemical bonds, holding the glucose together must be broken apart during the digestive process.  When this occurs, the glucose is able to be absorbed.  Not only is it absorbed, it is rapidly absorbed.  More rapidly than the body can use it.  This allows it to build up in the blood stream.  As a matter of fact, if you are aware of the glycemic index of food (a quantitative scale that categorizes the impact various foods have on the blood sugar level), white bread sets the upper standard at 100.  To put this in perspective, white table sugar comes in at about 60.

When the blood sugar skyrockets upward, it sends a signal to the pancreas, an organ in the back of the abdomen behind the stomach, to release insulin into the circulation.  One of the functions of insulin is to allow the body to clear glucose from the bloodstream thus preventing the buildup of high blood sugar levels.  Other foods that contribute to this blood sugar surge are refined carbohydrates such as cakes, cookies, desserts, and soda.  These are staples in the average diet of most Americans.  When consumed throughout the day, this type of diet produces a roller coaster effect on blood glucose and insulin levels.  High, then low, then high, then low and so on cyclically over and over throughout the day.  From the brain's perspective it is exposed to blood sugar levels of 150, then 60, then 140, then 65, and so on.  The reason for the very low, sometimes too low, sugar levels, is that after insulin clears most of the glucose from the blood it is  itself cleared more slowly and thus 'hangs around' for awhile.  This allows it to drive down blood sugar levels below normal.  You might have experienced this a couple of hours after a meal when you felt jittery, dizzy, or mentally woozy.  Welcome to the world of hypoglycemia (blood sugar that is too low).  Since the most potent stimulus for appetite is a low, or falling, blood sugar level you feel quite hungry.  If refined carbs are eaten, they initiate the cycle again.  This is the typical dietary roller coaster based upon an inability to feel satisfied and not hungry for prolonged intervals.  You have just eaten and are hungry again.  If you have been here before, you now know why.

These recurrent surges of glucose are bad for the brain.  Since the brain isn't able to store glucose in any meaningful amount, it depends on a stable, continuous supply.  When we become hypoglycemic, neurons are not able to maintain the high energy levels they depend on for optimal functioning.  When glucose and insulin  levels are elevated two things happen.  To protect themselves from these extremes, neurons tend to become 'resistant' to the action of insulin, and insulin levels in the brain fall.  This is exactly what is observed in the brains of patients suffering from Alzheimer's disease, and to a lesser extent, in persons with failing memories.  To prevent this, our goal should be to maintain a persistent and stable blood glucose and insulin level.  This is determined by dietary means.  It requires the avoidance of refined carbohydrates including fructose and HFCS (high fructose corn syrup, or all corn syrup, for that matter) and trans fats (partially hydrogenated oils, usually corn oil, safflower oil, or cottonseed oil).  Good foods for the brain include those with lean protein and essential omega 3 fatty acids such as eggs, cold water fish, walnuts, and flax and pumpkin seeds.  Non-starchy fruits and veggies such as berries of all types, avocados, olives, spinach, colorful bell peppers and so forth are also at the top of the list.  In addition, I love spices of all sorts.  They contain wonderful nutrients and literally no calories and include turmeric, sage, ginger, rosemary, and cinnamon to name a few.  It is necessary to avoid excessive calories.  A lean body is usually the home of a happy brain.  If you build your diet based upon these guidelines, you will be doing your brain (and body) a big favor!

Any student of the brain and its anatomy is abundantly aware of the seemingly impossible terminology used to identify each of its hills and valleys-hypothalamus, subiculum, insula, fornix, putamen, and others too numerous to list.  Two that are of interest for this discussion are the cuneus and the hippocampus.  They are not visible from the surface of the brain, but are tucked safely along its inner surface.  Although they are separated geographically, they both participate in a vital mental function-memory.  These discrete regions communicate with each other via a deep band of fibers (the long processes called axons that connect nerve cells).  Because we use our memory constantly there is never a moment when these nerve cells are inactive.  As a matter of fact, the brain constitutes 2% of the body weight and consumes 20% of the energy so, on average, it requires 10X the energy  the remainder of the body gets by on. 

Glucose is the primary fuel used by nerve cells to produce all this energy.  When we notice ourselves becoming hypoglycemic, we sense that our brain is not functioning on all cylinders and experience "brain fog."  That is because the brain doesn't really store an appreciable amount of glucose and thus requires a stable continuous supply to get the job done.  There are even brain scans that are able to generate pictures demonstrating how much sugar each area of the brain is consuming.  This type of scan is called a PET scan (for Positron Emission Tomography).  Because of its high metabolic rate, the brain consumes a lot of glucose and this can be seen on a PET scan.  Some of you might be aware of the application of PET scans in cancer diagnosis.  This is useful because most tumors also burn glucose at a rapid rate and hence are easily identified on PET scans.  As chemotherapy  attacks the cancer cells, subsequent scans show less glucose being used by the tumors and correlate with less metabolic activity and subsequent shrinkage.

Similar findings can be identified on PET scans as we age.  When nerve cells become less efficient at burning glucose, they appear less bright on the scan.  This correlates with lower glucose metabolism and impaired function.  This is typically identified in the brains of persons with Alzheimer's disease.  Initially it develops in localized regions and then as time passes it progresses to involve more and more of the surface of the brain.  Often the first symptoms noticed have to do with a declining memory.  For this reason it is no surprise that PET scans show a fall in glucose metabolism in the areas comprising the cuneus and hippocampus.  This radiologic finding is one method used to confirm the diagnosis of Alzheimer's disease.

An illuminating paper on this topic was published in the Proceedings of the National Academy of Sciences (Volume 101, Number 1, pages 284-289) wherein the researchers used this imaging technique to study the brains of mentally normal, healthy middle-aged persons ranging in age from 20-39 years.  The common factor shared by each of the subjects was the possession of one copy of a certain gene (or more precisely, allele) called the APO E epsilon 4 allele.   This is a risk factor for the development of Alzheimer's disease.

When the brains of these subjects were scanned, the results were remarkable.  As a group, they had a lower glucose metabolic rate in the identical regions that are identified early on during the course of Alzheimer's disease, although not as severe.  Since this usually is seen in people who are in their mid-seventies, it was surprising to find the same, albeit milder, findings in asymptomatic subjects who were more than 40 years younger.   As far as I am aware, this is the earliest abnormality able to predict the subsequent development of Alzheimer's.

As such, it provides evidence that the development of the disorder starts early in life and progresses slowly over decades.  It also gives us a protracted window of time to be proactive in slowing down or even preventing it.  Just as heart disease has risk factors that are able to be modified, so does memory loss and neurodegeneration.  In this instance, impaired ability of the brain to use glucose is the risk factor.  This has been referred to as Type III diabetes by various neuroscientists and researchers in the arena of brain health.  The similarities between Type II diabetes (usually referred to as adult-onset diabetes) and the brain condition referred to as Type III diabetes are remarkable.  They are both metabolic disorders having to do with abnormalities of glucose metabolism, which is something we have a great deal of control over.  I will discuss what this means and why it is important in the next article.

Today is September 4, 2007.  It coincides with the publication of my first book:  The Brain Trust Program.  You can read more about it at  www.DrMccleary.com.  This is also my initial blog entry.  I hope to have many more to share.

I would like to introduce myself.  My name is Larry McCleary.  I am a pediatric neurosurgeon and was acting Chief of Pediatric Neurosurgery at The Children's Hospital in Denver for a number of years.  I did my training at New York University-Bellevue Medical Center in NYC.  I had the pleasure of training with one of the premier pediatric neurosurgeons in the world, Dr. Fred Epstein.  I have retired from that position and now live in Incline Village, Nevada.  While I was doing brain surgery in children I published a number of professional articles in medical journals.  Since that time I have changed my focus from caring for children with sick brains to writing and developing and testing unique nutritional supplement formulations for a variety of conditions.  This path was a logical step that evolved from the fact that I love to read medical literature and dispense it in an understandable format such as the book that was just published, use it to design unique nutritional formulations, or speak about it to reporters, interviewers or general audiences.  As a practicing physician it was my goal to provide optimal care to my patients.  Now I strive to do the same by supplying readers with current insights, beneficial information, and novel nutritional products.

I am also the Doctor for the Shining Stars Foundation.  It is a non-profit organization in Colorado whose mission statement is to provide programs to help children with cancer and other life threatening diseases.  We have had children from all four corners of the country participate.  The web site is www.ShiningStarsFoundation.org.  We are currently in the process of writing a book that chronicles the lives and showcases the spirit of these brave children.  There is also a documentary film being produced that is based on interviews of the kids being conducted by other children going through similar situations.  The kids have said to us again and again that the most powerful tool to help them get through the cancer experience is communication with their peers.  The film is designed to make their experiences available for other children around the world who are fighting a similar battle.

I wish to welcome you to an ongoing discussion of a number of topics I find fascinating and that I hope will strike your fancy as well.  They will involve brain health and other aspects of diet, nutrition, metabolism, science and nutritional supplementation.

Thanks for joining the ride!

Larry McCleary, M D.