I am becoming increasingly convinced that ketone bodies play an important role in ADHD. Ketone bodies are an alternative fuel source for the brain that becomes critically important when glucose levels in the blood are low [12]. As has been said before, the brain is unable to utilize fatty acids as fuel. However, it can utilize ketone bodies, and thus their presence becomes a protective mechanism for the brain when glucose is in short supply.
Ketone bodies are produced by the liver as a by-product of fat metabolism. In the absence of fats in the diet, significantly fewer ketone bodies are produced; i.e., the body derives more ketone bodies from dietary fat than from internally synthesized fats [38]. Furthermore, and most significantly, certain specialized cells in the brain called astrocytes are also able to scavenge free fatty acids from the blood and manufacture ketone bodies from them. It is hypothesized that ketone bodies in the brain can also act as "cellular substrates, thereby preserving neuronal synaptic function and structural stability." ([12], abstract). I suspect that astrocytes may be able to accumulate stores of ketone bodies that can serve both as fuel for the brain in times of glucose deficiency, and to assure that important signals such as dopamine get transmitted across synaptic junctions. But insufficient dietary fats will significantly reduce the availability of this critical nutritional resource.
Saturday, November 21, 2009
8. Explaining the Gender Bias in ADHD
It is curious that the incidence of ADHD is much higher in boys than in girls. Some estimates claim that the ratio of boys to girls diagnosed with ADHD is as high as 10:1. In the context of a theory that ADHD is caused by fat insufficiency, what are the factors that might afford protection for girls?
First of all, the ratio of fat to muscle in girls is generally much higher than in boys. For the same body weight and size, a girl will have significantly more subcutaneous fat, as contrasted with a much higher muscle-to-fat ratio for a boy. This implies that the supply of bioavailable fats will be significantly higher for girls than for boys.
Secondly, and most importantly, the female hormone estrogen is a powerful weapon for increasing fat metabolism. Exactly how this is accomplished remains somewhat unclear, but it has been hypothesized that estrogen achieves this effect by stimulating an increase in both growth hormone and adrenaline. Growth hormone has been demonstrated to increase mobilization of fatty acids from fat tissue [30], and it is well known that adrenaline does this too [24]. Growth hormone also inhibits insulin production, and reduced insulin at the outset would greatly improve the odds of getting insulin levels sufficiently suppressed to allow fat mobilization.
Several investigators have studied gender differences in plasma free fatty acids in response to exercise, and have shown that females end up with significantly higher levels of fatty acids in the blood after an equivalent amount of exercise than do their male counterparts [2].
Thus, the extra fat cells, the enhanced mobilization of fat from these fat cells in general, and the enhanced effect of exercise on fat release all likely contribute to the significantly reduced likelihood of a girl succumbing to ADHD than a boy.
First of all, the ratio of fat to muscle in girls is generally much higher than in boys. For the same body weight and size, a girl will have significantly more subcutaneous fat, as contrasted with a much higher muscle-to-fat ratio for a boy. This implies that the supply of bioavailable fats will be significantly higher for girls than for boys.
Secondly, and most importantly, the female hormone estrogen is a powerful weapon for increasing fat metabolism. Exactly how this is accomplished remains somewhat unclear, but it has been hypothesized that estrogen achieves this effect by stimulating an increase in both growth hormone and adrenaline. Growth hormone has been demonstrated to increase mobilization of fatty acids from fat tissue [30], and it is well known that adrenaline does this too [24]. Growth hormone also inhibits insulin production, and reduced insulin at the outset would greatly improve the odds of getting insulin levels sufficiently suppressed to allow fat mobilization.
Several investigators have studied gender differences in plasma free fatty acids in response to exercise, and have shown that females end up with significantly higher levels of fatty acids in the blood after an equivalent amount of exercise than do their male counterparts [2].
Thus, the extra fat cells, the enhanced mobilization of fat from these fat cells in general, and the enhanced effect of exercise on fat release all likely contribute to the significantly reduced likelihood of a girl succumbing to ADHD than a boy.
9. Dopamine
Dopamine is an incredibly important hormone that is released from the substantia nigra in the midbrain and relayed to other parts of the brain through three principal neural pathways: the nigrostriatal pathway to the cerebellum to control body movement, the mesolimbic tract to the reward center and seat of emotion, and the mesocortical tract to the frontal lobes of the cerebral cortex that control high level planning and reasoning. These pathways are part of the white matter that is shrunken in size in the ADHD child's brain. With poor transmission speeds and an inability to maintain a strong signal, these poorly insulated pathways dissipate the message that the dopamine is trying to send.
A recent study by Dr. Nora Volkow compared the brains of 53 nonmedicated ADHD adults with those of 44 healthy non-ADHD adults over the period from 2001 to 2009, using positron emission tomography (PET) brain imaging [36]. The study focused on dopamine receptors, which propagate the signal to distant parts of the brain, and dopamine transporters, which recycle excess dopamine after the signal is transmitted. The study found that both receptors and transporters were reduced in number in the ADHD brains as compared with the normal controls. The receptor count is likely reduced as a consequence of the slow and inefficient transport across the networks. The transporters are reduced in turn in order to slow down the process that sends the dopamine back into storage. This allows the dopamine to stay in the synapse for a longer period of time. Ritalin achieves a similar effect, and this is believed to be the main reason why it is effective.
Research on rats has shown that dopamine release is severely impaired in the absence of insulin [9]. This may be an intentional design as protection against releasing dopamine when there is insufficient glucose to fuel the resulting brain activities. However,the ADHD child, who has an efficient glucose metabolism, must deplete the excess insulin before fats from fat stores can be released. Meanwhile, the dopamine supply is exhausted while trying to send signals over faulty networks, and the release of fats comes too late to be effective.
The brain needs fats as well as glucose for acquiring new knowledge - to reconfigure and reinforce the neural connections. The ADHD child is trapped in a catch-22, because, in order to get at the fat stores, the insulin levels must be low, but if the insulin levels are low, glucose is also likely low (since the insulin is so efficient) and, as well, the dopamine release will be suppressed. A child who consumes a low-fat diet and has very efficient glucose metabolism will likely never have, simultaneously, sufficient blood levels of dopamine, fats and glucose. As soon as the insulin levels are sufficiently low to allow the fats to be released, the glucose and dopamine are likely already depleted. With little fat in the dietary sources, and with impoverished and insulin-suppressed fat cells, it is difficult to imagine where the fat supply for the brain is going to come from.
A recent study by Dr. Nora Volkow compared the brains of 53 nonmedicated ADHD adults with those of 44 healthy non-ADHD adults over the period from 2001 to 2009, using positron emission tomography (PET) brain imaging [36]. The study focused on dopamine receptors, which propagate the signal to distant parts of the brain, and dopamine transporters, which recycle excess dopamine after the signal is transmitted. The study found that both receptors and transporters were reduced in number in the ADHD brains as compared with the normal controls. The receptor count is likely reduced as a consequence of the slow and inefficient transport across the networks. The transporters are reduced in turn in order to slow down the process that sends the dopamine back into storage. This allows the dopamine to stay in the synapse for a longer period of time. Ritalin achieves a similar effect, and this is believed to be the main reason why it is effective.
Research on rats has shown that dopamine release is severely impaired in the absence of insulin [9]. This may be an intentional design as protection against releasing dopamine when there is insufficient glucose to fuel the resulting brain activities. However,the ADHD child, who has an efficient glucose metabolism, must deplete the excess insulin before fats from fat stores can be released. Meanwhile, the dopamine supply is exhausted while trying to send signals over faulty networks, and the release of fats comes too late to be effective.
The brain needs fats as well as glucose for acquiring new knowledge - to reconfigure and reinforce the neural connections. The ADHD child is trapped in a catch-22, because, in order to get at the fat stores, the insulin levels must be low, but if the insulin levels are low, glucose is also likely low (since the insulin is so efficient) and, as well, the dopamine release will be suppressed. A child who consumes a low-fat diet and has very efficient glucose metabolism will likely never have, simultaneously, sufficient blood levels of dopamine, fats and glucose. As soon as the insulin levels are sufficiently low to allow the fats to be released, the glucose and dopamine are likely already depleted. With little fat in the dietary sources, and with impoverished and insulin-suppressed fat cells, it is difficult to imagine where the fat supply for the brain is going to come from.
10. Stunted Growth and Vitamin D and Calcium Deficiency
In my article on obesity, I argued that calcium deficiency plays an important role because calcium is necessary for the release of insulin from the pancreas and for the uptake of glucose by the muscles. Obesity is strongly associated with both calcium deficiency and insulin resistance, and I argue that the fat cells compensate by inserting themselves into the energy chain. They take upon themselves the task of converting glucose to fat, and they program the muscles to strongly prefer fat over glucose as an energy source. In the process, they hoard calcium and vitamin D, and cause measurable deficiencies in these important nutrients in the blood serum.
It is likely that some ADHD children may suffer from calcium deficiency as well, mainly as a consequence of vitamin D deficiency, a syndrome that is at epidemic proportions in the U.S (Vitamin D Deficiency Epidmemic). Probably the most significant nutritional role of vitamin D is its ability to promote both the absorption of calcium from the gut and the transport of calcium across membranes, a process that is extremely important in many aspects of metabolism and brain function. ADHD children tend to be stunted in growth, and their levels of growth hormone are abnormally low. Extending the length of a bone requires an enormous amount of calcium. Thus, by keeping the bones short, the calcium that would have gone into bone growth can be diverted to assure an adequate supply of insulin and an efficient glucose uptake mechanism in the muscle and fat cells.
It could be that ADHD children also sacrifice calcium levels in the brain in order to assure enough calcium for the efficient metabolism of glucose, which is extremely essential when the body is relying mainly on glucose as an energy source. Evidence that calcium channels in the brain are important for memory comes from the surprising result from a study involving 1,268 people who were being treated for high blood pressure (Calcium Blockers and Memory). The study found that people who take calcium blockers to lower blood pressure score less well on memory tests than people who use other medicines to lower blood pressure. Studies using Magnetic resonance Imaging (MRI) verified brain damage in the white matter of the brains of the people who used calcium blockers.
If ADHD children are deficient in calcium in their brains, they are also likely less able to utilize ketone bodies as an energy source in the brain. This conclusion comes indirectly from studies involving alzheimer's patients. It has been found that alzheimer's patients' brains are deficient in the ability to utilize glucose for fuel, and, as a result, regulatory control mechanisms have led to an increased supply of calcium in the brain, which plays an essential role in the metabolism of ketone bodies [13]. This allows them to efficiently use ketone bodies instead of glucose as a fuel source. The converse of this observation is that reduced calcium in the brain would interfere with ketone body metabolism, leaving the brain even more vulnerable to situations of reduced blood glucose levels.
Vitamin D itself plays an important role in brain function, in addition to its influence on calcium, as implied by the existence of a wide distribution of vitamin D receptors throughout the brain [20] (Vitamin D and the Brain) . Vitamin D also affects proteins in the brain that are directly involved in learning and memory, as well as motor control. It may be that, for some ADHD children, insufficient vitamin D is even the main cause of their symptoms.
It is likely that some ADHD children may suffer from calcium deficiency as well, mainly as a consequence of vitamin D deficiency, a syndrome that is at epidemic proportions in the U.S (Vitamin D Deficiency Epidmemic). Probably the most significant nutritional role of vitamin D is its ability to promote both the absorption of calcium from the gut and the transport of calcium across membranes, a process that is extremely important in many aspects of metabolism and brain function. ADHD children tend to be stunted in growth, and their levels of growth hormone are abnormally low. Extending the length of a bone requires an enormous amount of calcium. Thus, by keeping the bones short, the calcium that would have gone into bone growth can be diverted to assure an adequate supply of insulin and an efficient glucose uptake mechanism in the muscle and fat cells.
It could be that ADHD children also sacrifice calcium levels in the brain in order to assure enough calcium for the efficient metabolism of glucose, which is extremely essential when the body is relying mainly on glucose as an energy source. Evidence that calcium channels in the brain are important for memory comes from the surprising result from a study involving 1,268 people who were being treated for high blood pressure (Calcium Blockers and Memory). The study found that people who take calcium blockers to lower blood pressure score less well on memory tests than people who use other medicines to lower blood pressure. Studies using Magnetic resonance Imaging (MRI) verified brain damage in the white matter of the brains of the people who used calcium blockers.
If ADHD children are deficient in calcium in their brains, they are also likely less able to utilize ketone bodies as an energy source in the brain. This conclusion comes indirectly from studies involving alzheimer's patients. It has been found that alzheimer's patients' brains are deficient in the ability to utilize glucose for fuel, and, as a result, regulatory control mechanisms have led to an increased supply of calcium in the brain, which plays an essential role in the metabolism of ketone bodies [13]. This allows them to efficiently use ketone bodies instead of glucose as a fuel source. The converse of this observation is that reduced calcium in the brain would interfere with ketone body metabolism, leaving the brain even more vulnerable to situations of reduced blood glucose levels.
Vitamin D itself plays an important role in brain function, in addition to its influence on calcium, as implied by the existence of a wide distribution of vitamin D receptors throughout the brain [20] (Vitamin D and the Brain) . Vitamin D also affects proteins in the brain that are directly involved in learning and memory, as well as motor control. It may be that, for some ADHD children, insufficient vitamin D is even the main cause of their symptoms.
11. ADHD and Anorexia
Fat cells are part of the endocrine system, and, as I've discussed before, they have the power to influence the degree to which muscle cells prefer glucose versus fats as an energy source. They exercise this control by releasing two signaling peptides: leptin and adiponectin. Adiponectin promotes glucose consumption by the muscles, and it also acts directly on the fat cells to encourage them to take up glucose and convert it to fat. Leptin, on the other hand, stimulates the muscles to prefer fat consumption over glucose consumption.
Statistically, children with ADHD have an abnormally efficient glucose metabolism rate, i.e., for the same amount of insulin, blood sugar levels drop more quickly after a meal than in other children. This observation suggests that their fat cells have arranged a set point of a high adiponectin to leptin ratio, such that the muscles prefer glucose over fats, and fat cells are predisposed to convert glucose to fat. The glucose levels drop more quickly because the muscles and fat cells are using more of it.
Anorexics, children who intentionally starve themselves, are known to have extremely efficient glucose metabolism (tend towards hypoglycemia) and also to have a high ratio of adiponectin to leptin concentrations [21]. This strategy maximizes availability of fatty acids to the heart and brain. It is curious that anorexia is much more common in girls, and ADHD is much more common in boys.
Researchers at Harvard Medical School suspected that there might be an association between anorexia and ADHD. To test this hypothesis, they compared girls with ADHD against a control group to see whether the ones with ADHD were predisposed towards anorexia (ADHD and Anorexia). The results showed that girls with ADHD were 3.6 times more likely than the control group to develop an eating disorder. I have come to believe that anorexia is a technique to combat ADHD that girls are able to adopt, whereas boys do not have enough fat cells to carry out the task of converting glucose to fat. Ritalin is well known to reduce appetite, and long term use can lead to an anorexia-like condition. It may well work, in part, because it achieves this ultra-thin state, thus conserving fats by minimizing the consumption of fat by cells that can get by on glucose.
Statistically, children with ADHD have an abnormally efficient glucose metabolism rate, i.e., for the same amount of insulin, blood sugar levels drop more quickly after a meal than in other children. This observation suggests that their fat cells have arranged a set point of a high adiponectin to leptin ratio, such that the muscles prefer glucose over fats, and fat cells are predisposed to convert glucose to fat. The glucose levels drop more quickly because the muscles and fat cells are using more of it.
Anorexics, children who intentionally starve themselves, are known to have extremely efficient glucose metabolism (tend towards hypoglycemia) and also to have a high ratio of adiponectin to leptin concentrations [21]. This strategy maximizes availability of fatty acids to the heart and brain. It is curious that anorexia is much more common in girls, and ADHD is much more common in boys.
Researchers at Harvard Medical School suspected that there might be an association between anorexia and ADHD. To test this hypothesis, they compared girls with ADHD against a control group to see whether the ones with ADHD were predisposed towards anorexia (ADHD and Anorexia). The results showed that girls with ADHD were 3.6 times more likely than the control group to develop an eating disorder. I have come to believe that anorexia is a technique to combat ADHD that girls are able to adopt, whereas boys do not have enough fat cells to carry out the task of converting glucose to fat. Ritalin is well known to reduce appetite, and long term use can lead to an anorexia-like condition. It may well work, in part, because it achieves this ultra-thin state, thus conserving fats by minimizing the consumption of fat by cells that can get by on glucose.
12. ADHD and Fatty Acid Deficiencies
The incidence of symptoms associated with deficiencies in fatty acids, such as dry hair and skin, excessive thirst and frequent urination, has been observed to be higher in ADHD children as compared with the general population [33]. It has been proposed by many researchers that ADHD children are deficient in essential fatty acids, and omega-3 fat supplements are often prescribed as part of their treatment program [29].
A study involving 96 boys from schools in Indiana, 53 of which had been diagnosed with ADHD, looked at the concentrations of fatty acids found in blood plasma [4]. It was determined that the ADHD children as a group had significantly lower amounts of essential fatty acids (omega-3 and omega-6 fats) in their blood than did the controls. Furthermore, among the ADHD group, the 21 subjects who also manifested many symptoms of essential fatty acid deficiency had further depleted serum levels than the other 32 subjects with ADHD.
A study involving 96 boys from schools in Indiana, 53 of which had been diagnosed with ADHD, looked at the concentrations of fatty acids found in blood plasma [4]. It was determined that the ADHD children as a group had significantly lower amounts of essential fatty acids (omega-3 and omega-6 fats) in their blood than did the controls. Furthermore, among the ADHD group, the 21 subjects who also manifested many symptoms of essential fatty acid deficiency had further depleted serum levels than the other 32 subjects with ADHD.
13. ADHD and Sleep Disorders
A recent study has shown that adolescents diagnosed with ADHD are significantly more likely to suffer from sleep disorders such as insomnia, sleep terrors, nightmares, and snoring, compared to controls. I suspect these problems during sleep stem from insufficent fats. The brain is unable to properly integrate the newly acquired knowledge and experiences of the day before into long term memory stores, due to the insufficient supply of fats to build the myelin sheaths surrounding newly constructed nerve fibers and reinforcements. These deficiencies in resources critical to the goals of sleeping may be the source of extreme restlessness, wakefulness, and night terrors.
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