Monday, November 18, 2013

Preserving Brain Function: Principles, Pitfalls, and Practical Conclusions


I recently had the opportunity to attend a physician-only-lecture at a hospital about the use of ketogenic diets for the treatment of epilepsy in children.  If you at least casually follow the discourse on this dietary approach on the interwebz, especially with regard to the interest of effecting cures, you’d probably think that not only should all children with epilepsy be placed on a ketogenic diet, but that failing to do so amounts to nothing less than egregious malpractice; another failure of the medical profession to employ the best treatments available because of the inherent evils of pharmaceutical companies and of patent medicine.

The truth is, although there are a myriad of proposed mechanisms as far as how ketogenic diets work (review articles have been rapidly accumulating in many different medical publications) no one can really say one way or the other, and to suggest otherwise points to an utter lack of thoroughness in reading of the literature on the topic, a bias in the interpretation of said literature, or both.

I say this in part by way of criticism and disgust, and in part because I know how complex neuropsychobiology and neuropharmacology (and related disciplines) are and have always been owing mainly, in my estimation, to the lack of experimental methods sophisticated enough to draw definitive conclusions; in particular, the inability to convert correlational data derived from such experimentation to proof of cause and effect.  What is clear, however, is that there is an energy deficiency in various neurological disorders including epilepsy; that is to say, a deficiency of glucose and oxygen, the primary substrates by which cells of the nervous system generate energy, which is evidenced by a respiratory quotient[*] that stabilizes at 1.0 therein.

Therefore, the most parsimonious explanation for why ketogenic diets work, when they do, is that the ketone bodies so generated are supplying neurons (and glial cells) with energy, which would normally be provided by glucose, thereby preventing these cells from literally succumbing to the demands placed on them, by all the stressors they have to deal with on a moment to moment basis.  Why then do children with epilepsy develop energy deficiency problems?  Or stated another way, why do they lose the ability to generate energy by way of the oxidative metabolism of glucose, in which carbon dioxide, rather than lactic acid, is produced?  This is a question too complex and speculative to have a discussion on for this audience and for the space I’ve allotted myself here.  Just know for now that this mismatch, between energy reserves and energy demands, represents the essence of the problem.

I’m fully aware of the fact that my post thus far, five paragraphs in, lacks a thesis of any kind whatsoever.  Annoying, I know.  I also know readers in particular appreciate a neat list of recommendations based on a solid foundation of evidence that should have been presented in the body of the article.

But rather than do that, because of the speculative nature of the subject matter, I want to finish up this post by doing two things.  The first is to describe, in the simplest way possible, the way in which the brain should work, especially with regard to energy and stress. The second is to have a general discussion of a few, in my estimation, means to preserve and optimize this system, based on the preceding theoretical discussion. 

By endeavoring to focus on mechanisms (which is the best we could do at this point if we wish to avoid overstating any point) you should see why the focus on particular foods (e.g. the sweet potato) or painting ourselves into a corner by restricting our diets to only those foods that have been deemed “evolutionarily-approved” (whatever that exactly means), is not only utterly silly, but also arbitrary and fatally flawed.


Energy problems should be expected to manifest in the brain first and most notably because the brain, per unit weight, is the most voracious consumer of energy, namely glucose, of all the organs in the body. (The brain represents merely 2 percent of the body’s total weight yet accounts for 15 percent of the body’s total energy expenditure.) So when a deficiency of energy does occur, the brain and associated structures, which coordinate processes as diverse as memory, learning, mood, and behavior, are impacted quite notably.

One reason as to why the ketogenic diet may ‘work’ is that ketone bodies have a sedative effect in the brain, like the neurotransmitters gamma-aminobutyric acid (GABA) and gamma-hydroxybutyric acid (GHB), thereby protectively reducing the energy demands so as to prevent cells from literally overworking themselves to the point of malfunction and death.

What first got me thinking about the similarities between GABA, GHB, and ketone bodies was an internship I had at one of the major poison control centers in the U.S., where it was drilled into the interns by the medical director that valproic acid (brand name Depakene), a drug used for seizures and structurally similar to both GABA and ketone bodies, would when taken in excess cause ammonia to accumulate to toxic levels in the blood (for which carnitine would be given as an antidote.) Suffice it to say here, the fact that the toxic accumulation of ammonia is a side effect of valproic acid reinforces the idea that the ketone bodies and valproic acid are acting in the ways that GABA normally would in the brain.

In the brain, under normal circumstances GABA derives from glucose by way of the highly prevalent brain amino acid glutamate.  In the absence or improper use of glucose, valproic acid, or ketone bodies – those compounds that are structurally similar to GABA – are probably ‘filling in’ for the glucose-derived GABA that, for whatever reason, is missing.[†] The synthesis of GABA is intimately tied to the oxidative metabolism of glucose, which entails the use of enzymes found exclusively in the brain.

In all, valproic acid mimics the effects of GABA, and the ketone bodies are probably acting in a similar yet more basic way, owing to their structural similarity.[‡] The not-so-rigid dichotomy between the excitatory and the inhibitory systems in the brain is thusly shifted to favor the latter system, whereby the flow of electrical signals through various brain pathways defensively becomes depressed.  Lowering the energy charge in the cell (i.e. depleting ATP) has a similar effect, activating the enzymes that synthesize GABA from glucose and depleting brain dopamine (evidenced by elevated dopamine turnover rates when GABA is introduced exogenously in relatively large amounts).  These enzymes are dependent on vitamin B6, a deficiency of which predisposes to seizures in children and adults. 

In healthy and young people, this system should kick in in the face of prolonged or excessive stress, which rapidly depletes energy stores in the brain.  Healthy and young people should also be more resilient to ‘running out’ of energy, owing partly to the efficiency by which the glucocorticoid system operates in their bodies since the glucocorticoids, in excess, interfere with the storage of glucose in brain cells.[§]  The turnover of GABA is many times higher than that of other neurotransmitters, such as acetylcholine and dopamine, suggesting that the brain has many homeostatic mechanisms in place to maintain GABA concentrations within a certain physiological range under a wide range of external conditions.


1. To me, like the use of synthetic glucocorticoid products, ketogenic diets, as of now, is nothing more than a last-ditch effort when all other means fail.  Merely a symptomatic solution, there are probably long-term consequences associated with having this system chronically active and in overdrive.  I’ve heard mentioned offhand by a Paleo blogger that high fat diets relieve anxiety in rats by way of GABA, apparently without reading the study that was linked to support this claim.  Some of the beneficial effects of these diets can be attributed to the surge in glucose brought about by the stress hormones, temporarily relieving the energy stress caused by the deficiency of glucose, so as to prevent the irreversible degradation of brain structural material that would otherwise supply that energy, as well as GABA.  At the same time, owing to their purported sedative and inhibitory effects in the brain, the ketone bodies themselves are neuroprotective.  However, the ketone bodies incidentally block the oxidative metabolism of glucose.

2. Vitamin B6 is a cofactor (tightly bound) of two enzymes: one involved in the synthesis of glucose-derived glutamate and one that makes GABA from glutamate.  A deficiency of vitamin B6 decreases its concentrations in the cells that make GABA, favoring the inactive state of the two vitamin B6-dependent enzymes involved in making GABA.  In point of fact, a diet deficient in vitamin B6 in children and adults can lead to seizures that respond dramatically to treatments that include the vitamin.[**]

3. The amino acids taurine and glycine have similar receptor interaction patterns as GABA.  As such, taurine and glycine induce 'inhibitory' effects in the regions of the brain where they are active.  Animal studies show that chronically low intake of these amino acids, or their precursors, could lead to irreversible degenerative changes in the brain, eyes, and spinal cord.

4. The rationale behind the use of pharmaceutical anti-depressants (i.e. stimulants) stems largely from experiments in which correlations are made between levels of certain neurotransmitters in the brain (or their metabolites in the blood and urine) and the ability of animals to which stressors are imposed, to cope and to avoid developing conditioned helplessness, where the animals simply give up and fail to perform effective avoidance responses to subsequent stressors.

Whether these measured neurotransmitters are, in fact, the cause of depression – a condition that is already poorly defined – is uncertain, as, if you recall, the wherewithal currently available to study these relationships lack the requisite sophistication.

However, as I’ve stated before, animals permitted to develop effective means to cope with stressors have lower levels of anxiety, which, in turn, make then more effective at coping with stressors.  GABA, and probably the ketone bodies and valproic acid, helps individuals cope more effectively with various stressors, in part by reducing anxiety, without adding to the energy stress like the anti-depressants, which now bear the black box warning, the most serious of all warnings, alerting clinicians and patients of an increased risk of suicidal thoughts and behaviors in children and young adults.  Cortisol levels are also lower in animals with effective coping mechanisms.  To put things in more concrete terms, the ability to turn fears and worries into plans and actions soften all of the energy problems described above and help to preserve brain functioning. 

5. The rapidity with which learning is acquired I think reflects how efficiently the systems in the brain and the body ‘work’ to maintain energy availability and the delicate balance among dopamine, serotonin, cortisol, noradrenalin and GABA.

The distinction, however, between learning and simple arousal and stimulation should be made and recognized, especially when interpreting experiments designed to study the ins and outs of learning.  Suffice it to say here, reducing anxiety and employing effective coping techniques facilitates the acquisition of the biochemical and physical changes in the brain that are thought to signify learning.  Learning implies adaptability to changes in the environment, the capacity for which, according to Han Selye and others, determines our susceptibility to disease, aging, and death.

6. Maintaining steady blood glucose levels helps to prevent the drastic changes in glucose availability to the brain, of which merely transient interruptions can cause harm.  I’ve found through my own experimentation that small, mixed meals spaced out equally throughout the day are superior to large, intermittent meals.

Dear reader,

From hereon out, I’ll be writing for Matt Stone’s site, 180degreehealth, somewhat regularly as a site author, so some of my future articles will be posted there, not here.  I’ll be sure to let you know each time one of my posts go live over there.

Happy Thanksgiving,


[*] A respiratory quotient of 1.0 indicates pure glucose use in relation to protein and fat.
[†] Glucose can be converted to GABA, but ketone bodies and fatty acids can’t.
[‡] Because I was asked once already (email), and because its’ probably on the minds of readers now, I’ll mention here so as to dodge answering the same question that as a supplement, GABA is probably useless, as GABA, being highly charged, is unlikely to cross into the brain from the blood, and very little GABA is found outside the central nervous system.
[§] The primary glucocorticoid secreted by the adrenal cortices is hydrocortisone, or cortisol.
[**] Since there are many other vitamin B6-dependent enzymes in the brain, we can’t say for sure that the improvements seen upon the addition of vitamin B6 are due to effects on the GABA system only.