The term "neurodevelopmental disorders" encompasses a large group of neurological disorders that become evident during periods of brain maturation. They frequently share complex neurological features including various learning disabilities and complex behavioral features. These disorders become evident in early childhood and tend to persist into the adult lifespan. Included in this constellation of disabilities are autism, ADD (attention deficit disorder) and pervasive developmental disorder. It is believed they are caused by genetic mutations and environmental factors.

Alterations in the configuration, wiring and connectivity of the developing brain are key contributors. There are specific periods during brain formation where certain influences can produce significant functional alterations that might be insignificant if they first occurred in adults.

Fetal and perinatal programming experiments in animals have documented persistent abnormalities in glucocorticoid receptors and signaling in offspring related to variations in maternal care that engender the perception of stress in the offspring. This alters stress responsivity -- changes that persist into adulthood. Many of the mutations that cause developmental disorders disrupt genes that are also expressed in the adult brain. This insight is significant because in addition to the developmental affects they cause in the brains of young children, it is possible that altered function of these genes may produce additional effects in adulthood (additive to those changes in brain wiring produced during the formative years).

This very possibility has been investigated in animal models of human neurodevelopmental disorders. Results suggest that persistent expression of the genes that caused the disorder to manifest initially during childhood may contribute to cognitive or behavioral problems in adults. These studies support the concept that treating the disrupted molecular mechanisms in adults might result in functional improvement. It has even been speculated that biochemical improvement of the underlying genetic defects may produce metabolic changes that allow adult neuroplasticity mechanisms to compensate for certain of the characteristic developmental problems.

The animal studies have investigated models of neurofibromatosis, a disorder in which neurological symptoms including attentional issues, deficits in executive function and learning disabilities are produced. One of the effects of the NF (neurofibromatosis) gene is to interfere with specific cellular signaling pathways. This results in the activation of Ras-signaling pathways.

There are pharmacological interventions that can reduce the isoprenylation of Ras, thereby tending to normalize this vital signaling pathway. HMG-CoA reductase inhibition with the drug lovastatin (a cholesterol-lowering drug) is one such intervention. Notably, short pharmaceutical treatment of animals with NF using lovastatin reduces the cognitive impairments in these animals while having no effects on control animals. When tested in humans, a 12 week treatment with simvastatin improved performance on a neuropsychological test. Moreover, the treatment protocol had the most robust beneficial effect on patients with the worst baseline status.

Similar benefits using this molecular approach have been observed in animal models of other neurodevelopmental disorders including Down's syndrome, Rubenstein-Taybi syndrome (another genetic disorder that is characterized by intellectual disorders, and specific physical features such as broad thumbs and and toes), Tuberous sclerosis, Fragile X syndrome (associated with learning disabilities, autism, ADD (attention deficit disorder) and epilepsy) and Rett syndrome.

The obvious conceptual epiphany in this approach is the ability to improve functional indicators in adults with neurodevelopmental disorders long after the brain has matured. Many of these disorders are common and disabling. They also have limited treatment options.

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).    

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.