I had forgotten that the good Dr. Su sent me a link to a dietary trial of ketogenic diets in kids with autism a few months ago. He reminded me of this himself when he quoted some comments I made in a recent blog post, but then "Paleo Guy" extraordinaire earned bonus margarita mixes for his machine by reminding me yet again and sending me a link to a complimentary paper that is an excellent review of ketosis in general.
I will get back to posting on sleep. It's just the continuing sleep deprivation I've been experiencing makes the reading of the sleep textbook a bit too painful. However, I'm committed to restoring good sleep hygiene habits and no more twitter at 3am. In addition, each little beastie now has an LED nightlight play toy thingie that switches off after 30 minutes. They get huggable freedom from fear of the dark, and we all get blessed nighttime blackness. Win win. We'll just ignore the shutting down of the melatonin with the 30 minutes of LED glow. It's better than leaving the hall light on all night.
Right. Dr. Su's paper. It is a study of 30 kids from Crete with autism who were placed on a ketogenic diet for 6 months in 1999. They went on a "John Radcliffe" version of a ketogenic diet, consisting of 30% medium chain triglyceride oil, 30% fresh cream, 11% saturated fat (oops! overshooting the USDA 2011 guidelines by a bit), 19% carbohydrates, and 10% protein along with vitamin and mineral supplements. The kids were placed on the diet in 4 week intervals, followed by 2 weeks of anything goes, so on and off. The kids' urine was tested with ketostix and their serum checked for beta hydroxybutyrate (a ketone) to measure the amount of ketosis. After 6 months, the diets were discontinued, and the kids were evaluated monthly for another 6 months.
At the beginning of the study, 2 of the 30 kids met criteria for mild autism, the rest were more severe. Interestingly enough the premise of the study was to presumably improve mitochondrial efficiency in the brain via ketosis (using ketone bodies as fuel rather than glucose). 11 years later a small study did in fact confirm that kids with autism often have problems with mitochondrial efficiency.
23 kids tolerated the diet beyond the initial 4 weeks, and of those, 5 more discontinued the diet due to lack of improvement during the first few cycles. Of the remaining 18 kids, two boys improved enough in symptoms to be taken out of the special school and placed in mainstream education. Overall the 18 ketogenic kids "presented with improvements in their social behavior and interactions, speech, cooperation, stereotypy, and... hyperactivity, which contributed significantly to their improvement in learning."
The kids who did not stay on the diet were the most severely affected by autism, and the ones who had the best response were ones most mildly affected. Another interesting fact from the study is that the kids maintained their improvements through the two week washout periods and in the 6 months after the study was over. None of the kids had any complications (such as poor weight gain or selenium deficiency) seen in other trials of ketogenic diets in kids with epilepsy.
Overall (using the original sample size of 30), 26.66% of the kids benefited significantly from the diet. The researchers also have a nice explanatory paragraph about the biochemistry of ketosis and how it favors the relaxing inhibitory neurotransmitter GABA over the excitatory, and in excess, neurotoxic glutamate:
"The increase of ketone bodies maintains the synaptosomal content of γ-aminobutyric acid (GABA) at a higher level, a phenomenon that may contribute to the beneficial effect of a ketogenic diet in children with epilepsy and perhaps children with autistic behavior. Other researchers, in an attempt to clarify the manner in which ketone bodies increase the synaptosomal content of GABA, showed that the metabolism of ketone bodies to acetyl coenyzme A results in a decrease of the pool of brain oxaloacetate, which is consumed in the citrate synthetase reaction. As less oxaloacetate is available for the aspartate aminotransferase reaction, thereby lowering the rate of glutamate transamination, more glutamate becomes accessible to the glutamate decarboxylase pathway, thus favoring the synthesis of GABA."
Couldn't have said it better myself!
Well, this wasn't a large study or a blinded study and there was no control, but for some kids, the improvement was exceptional, and ketosis didn't have to be strictly maintained. My personal preference is not to live in ketosis, but rather to dip in on occasion via 16 or 24 hour fasting and some very low carb breakfasts after overnight fasts. This study seems to suggest that dipping into ketosis can have benefit for brain energetics, though the kids went through a larger scale "dip" than I ever have.
And, once again, dietary therapies prove to be exceedingly beneficial for some, but won't do much of anything for others. It would be important for any parent of an autistic child to know that ahead of time before pinning one's hope on a ketogenic diet. On the other hand, autism is currently incurable, and a ketogenic diet seems like a nice weapon to have in the arsenal against this disease.
(Put in the links and fixed some of those bizarre sentence structures. I shouldn't be allowed to blog when sleep-deprived.)
Edited to add links to the rest of my posts on autism. I cover gluten-free diets, inflammation, mitochondria, vitamin D, theories about the pathology:
Diet and Autism1
Diet and Autism 2
Autism and Vitamin D
Autism 4 - Inflammation Speculation
Brain Efficiency, Pediatric Edition
Autism and Interpregnancy Interval
Monday, January 31, 2011
Friday, January 28, 2011
I Hate Homocysteine (Also It Is Elevated in Schizophrenia and Bipolar Disorder)
There are some biochemical reactions that are just gorgeous. Poetry. Glycolysis and the citric acid cycle, for example. I used to be able to draw out the whole process, and there was always something very pleasing about doing so. Enter glucose and oxygen and a few other things, and exit energy in the form of ATP, flying off the citric acid cycle like sparkling droplets of water off a spinning wheel.
The folate cycle, on the other hand, is ugly. It plays a starring role in Evolutionary Psychiatry, however, and I have to come to terms with it. There are a zillion components, an army of vitamins, and end-products going every which way - amino acids, neurotransmitters, membrane lipids, and whatever the heck homocysteine is. (seriously - my anchor article for this post calls homocysteine a "non-protein amino acid". What does that even mean?)
Homocysteine is a by-product of the folate cycle. It is supposed to be recycled back into methionine, but if you are low in certain B vitamins (or, like 10% of people, genetically deficient in certain enzymes that work to recycle homocysteine), you end up with too much of it hanging around. And when that happens, you happen to have a higher risk of all sorts of nasty things, such as heart disease, stroke, hip fractures, and dementia. Turns out that homocysteine likes to cleave the disulfide bridges in cysteine molecules. That doesn't sound so bad, but it affects things you might need, like collagen, for example, which plays a major part in holding bones together and keeping your arteries nice and elastic. High homocysteine *sometimes* goes hand in hand with high triglycerides, high blood pressure (from those stiff, inelastic arteries, one would presume), low HDL, high fasting glucose, and abdominal obesity. All those signs together (or three of them at least, anyway) make up the so-called metabolic syndrome which plagues our Western populations.
The good news is that abnormally high blood levels of homocysteine can rather easily be lowered by B vitamin supplementation. Almost any B vitamin will do the trick - B6, B12, folate, even betaine. That's rather exciting, one would think. Plausible biologic mechanism for a big, big problem. Cheap and simple fix. The bad news is that lowering homocysteine with B vitamin supplementation doesn't seem to make one whit of difference in cardiovascular disease, or at least it didn't in the 3700 Norwegian heart attack survivors who were followed for two years in the last decade (3) or seem help 5500 folks with known vascular disease or diabetes (4).
I don't really care about your hearts or bones. That's not true. I care. But your brains interest me a lot more. A new paper came out this month in Psychiatry Research from researchers in Croatia about high blood levels of homocysteine in patients with bipolar disorder and schizophrenia. And you will not be surprised to know that metabolic syndrome and obesity (and diabetes and heart disease) are more common in these patients than in the general population. While some of the medications used to treat these conditions cause obesity and impaired glucose tolerance, when you really parse the data, there appears to be an increased risk of metabolic syndrome just from having the illnesses, apart from any medication contribution.
(A rather unrelated aside - antipsychotic medications are well known for some pretty disturbing side effects. One of the scariest ones is called "neuroleptic malignant syndrome" where you get a high fever, stiffness, blood pressure spikes, and it can lead to kidney failure and death from muscle injury. One of the fastest treatments for NMS is electroshock therapy, believe it or not. What many people don't know is that schizophrenics institutionalized in the years prior to the invention of medication would suffer high fevers, stiffness, and death (it was called "malignant catatonia"). Now there is no question that the medicines cause NMS, but there is also an additional issue with the dopamine regulation in schizophrenia that could lead to autonomic dysfunction in a serious and fatal way. Just some food for thought.)
Right. Homocysteine. Not only does it degrade important things like bones and arteries, but it also might be able to antagonize the NMDA receptor in the brain (1), which could be a mechanism by which homocysteine itself could cause psychosis directly. It has been suggested that high homocysteine and low folate and B12 are independent risk factors for the development of schizophrenia and bipolar disorder (2).
The Croatians did a pretty simple study. They measured the fasting homocysteine and other signs of metabolic syndrome in patients admitted to their hospital ward with schizophrenia and bipolar disorder. They did not measure serum folate and B12, which is unfortunate, because that would be interesting to know. Oh well. The results? 34.2% of the sample of 60-odd patients had metabolic syndrome. And 67% of those with metabolic syndrome had high homocysteine. Only 23% of participants without high homocysteine had metabolic syndrome. In addition, high blood pressure also independently correlated with high homocysteine, which at least makes biologic sense.
One more little interesting tidbit from the paper - high homocysteine has also been found to be correlated with high omega 6 fatty acid levels in patients with major depression.
The take home? As I said in the Zombieland 2 post, I tend to connect high homocysteine levels with poor nutrition in general. Also, high homocysteine can be caused by a number of drugs and supplements, including niacin, metformin, insulin, corticosteroids, NSAIDs, and some anticonvulsants cause high homocysteine levels too. Chronic high intensity exercise and smoking are also related to high homocysteine. What do we do about it? Having all the B vitamin players on the team can help, so it can be properly recycled. The Norwegians were heart attack survivors - the damage had already been done. Maybe (comparable to omega 3s for mild cognitive impairment = possibly useful vs omega 3s and Alzheimers = a disappointment) homocysteine is something to keep low in the long term as a preventative strategy. Lowering homocysteine did seem to reduce stroke incidence by 25% in the HOPE2 trial. But who knows? We'll have to wait for more studies.
The brain is on the front lines, and metabolic syndrome (or the inflammation behind it) has psychiatric components as well. It is all linked in ways that we only barely understand.
The folate cycle, on the other hand, is ugly. It plays a starring role in Evolutionary Psychiatry, however, and I have to come to terms with it. There are a zillion components, an army of vitamins, and end-products going every which way - amino acids, neurotransmitters, membrane lipids, and whatever the heck homocysteine is. (seriously - my anchor article for this post calls homocysteine a "non-protein amino acid". What does that even mean?)
 |
| Image from Wikipedia |
Homocysteine is a by-product of the folate cycle. It is supposed to be recycled back into methionine, but if you are low in certain B vitamins (or, like 10% of people, genetically deficient in certain enzymes that work to recycle homocysteine), you end up with too much of it hanging around. And when that happens, you happen to have a higher risk of all sorts of nasty things, such as heart disease, stroke, hip fractures, and dementia. Turns out that homocysteine likes to cleave the disulfide bridges in cysteine molecules. That doesn't sound so bad, but it affects things you might need, like collagen, for example, which plays a major part in holding bones together and keeping your arteries nice and elastic. High homocysteine *sometimes* goes hand in hand with high triglycerides, high blood pressure (from those stiff, inelastic arteries, one would presume), low HDL, high fasting glucose, and abdominal obesity. All those signs together (or three of them at least, anyway) make up the so-called metabolic syndrome which plagues our Western populations.
The good news is that abnormally high blood levels of homocysteine can rather easily be lowered by B vitamin supplementation. Almost any B vitamin will do the trick - B6, B12, folate, even betaine. That's rather exciting, one would think. Plausible biologic mechanism for a big, big problem. Cheap and simple fix. The bad news is that lowering homocysteine with B vitamin supplementation doesn't seem to make one whit of difference in cardiovascular disease, or at least it didn't in the 3700 Norwegian heart attack survivors who were followed for two years in the last decade (3) or seem help 5500 folks with known vascular disease or diabetes (4).
I don't really care about your hearts or bones. That's not true. I care. But your brains interest me a lot more. A new paper came out this month in Psychiatry Research from researchers in Croatia about high blood levels of homocysteine in patients with bipolar disorder and schizophrenia. And you will not be surprised to know that metabolic syndrome and obesity (and diabetes and heart disease) are more common in these patients than in the general population. While some of the medications used to treat these conditions cause obesity and impaired glucose tolerance, when you really parse the data, there appears to be an increased risk of metabolic syndrome just from having the illnesses, apart from any medication contribution.
(A rather unrelated aside - antipsychotic medications are well known for some pretty disturbing side effects. One of the scariest ones is called "neuroleptic malignant syndrome" where you get a high fever, stiffness, blood pressure spikes, and it can lead to kidney failure and death from muscle injury. One of the fastest treatments for NMS is electroshock therapy, believe it or not. What many people don't know is that schizophrenics institutionalized in the years prior to the invention of medication would suffer high fevers, stiffness, and death (it was called "malignant catatonia"). Now there is no question that the medicines cause NMS, but there is also an additional issue with the dopamine regulation in schizophrenia that could lead to autonomic dysfunction in a serious and fatal way. Just some food for thought.)
Right. Homocysteine. Not only does it degrade important things like bones and arteries, but it also might be able to antagonize the NMDA receptor in the brain (1), which could be a mechanism by which homocysteine itself could cause psychosis directly. It has been suggested that high homocysteine and low folate and B12 are independent risk factors for the development of schizophrenia and bipolar disorder (2).
The Croatians did a pretty simple study. They measured the fasting homocysteine and other signs of metabolic syndrome in patients admitted to their hospital ward with schizophrenia and bipolar disorder. They did not measure serum folate and B12, which is unfortunate, because that would be interesting to know. Oh well. The results? 34.2% of the sample of 60-odd patients had metabolic syndrome. And 67% of those with metabolic syndrome had high homocysteine. Only 23% of participants without high homocysteine had metabolic syndrome. In addition, high blood pressure also independently correlated with high homocysteine, which at least makes biologic sense.
One more little interesting tidbit from the paper - high homocysteine has also been found to be correlated with high omega 6 fatty acid levels in patients with major depression.
The take home? As I said in the Zombieland 2 post, I tend to connect high homocysteine levels with poor nutrition in general. Also, high homocysteine can be caused by a number of drugs and supplements, including niacin, metformin, insulin, corticosteroids, NSAIDs, and some anticonvulsants cause high homocysteine levels too. Chronic high intensity exercise and smoking are also related to high homocysteine. What do we do about it? Having all the B vitamin players on the team can help, so it can be properly recycled. The Norwegians were heart attack survivors - the damage had already been done. Maybe (comparable to omega 3s for mild cognitive impairment = possibly useful vs omega 3s and Alzheimers = a disappointment) homocysteine is something to keep low in the long term as a preventative strategy. Lowering homocysteine did seem to reduce stroke incidence by 25% in the HOPE2 trial. But who knows? We'll have to wait for more studies.
The brain is on the front lines, and metabolic syndrome (or the inflammation behind it) has psychiatric components as well. It is all linked in ways that we only barely understand.
Thursday, January 27, 2011
Dietary Fat Intake and Depression Risk
More sleep coming soon, but a paper came out yesterday that ought to be blogged about (open access, too from PLoS One):
Dietary Fat Intake and the Risk of Depression: The SUN Project
The paper begins mild-mannered: "Emerging evidence relates some nutritional factors to depression risk. However, there is a scarcity of longitudinal assessments on this relationship."
The researchers followed a group of Spanish university graduates, initially depression-free, for an open enrollment period of 1999-2010. 12,059 ultimately signed up. At baseline they filled out a food frequency questionnaire to estimate the amount of saturated fat, polyunsaturated fats, trans fats, monounsaturated fats eaten, and the use of "culinary fats" (olive oil, seed oils, butter, and margarine). During the follow up period (of median 6 years), 657 new cases of depression were identified (via a new diagnosis of depression by a physician or initiating the use of antidepressant drugs). As is typical, confounders were accounted for, including adherence to a Mediterranean Diet (legumes, fruits, vegetables, fish, cereals, and low in meat and dairy products), which has already been shown to correlate with decreased depression (1). Turns out there was a reasonably strong (and dose-dependent) correlation between trans fat usage and depression - the less trans fat the Spaniards ate, the less likely they were to become depressed, and those in the highest quintile of trans fat intake had a 48% increased risk of developing depression compared to those who ate no trans fats. There was also a weaker inverse correlation with the amount of MUFA and PUFA eaten (meaning these types of fats may be protective against depression.)
In Europe, suicide rates and mental disorders are higher in Northern Europe, and the lowest in the Southern Mediterranean countries. I can think of a number of possible reasons for this trend (sunlight, relaxed lifestyle, vitamin D *cough*), but the overall food choices differ mainly with respect to olive oil and pulses. Very little is known about the specific types of fat and risk for depression, except with respect to the omega 3s. And even those studies are tricky - often, the omega3 capsule is compared to a placebo capsule of olive oil, and in some trials, both the fish oil group and the olive oil (control) group improve. It could be that both fish oil and olive oil improve mood, or that the increased fat content in general improved mood, as there is some evidence that low fat diets adversely affect mood (2)(3).
Now the discussion and speculation - always the most interesting part. The commonly accepted mechanism now for depression is one of inflammation leading to a decrease in BDNF, which is a nerve fertilizer necessary for axonal growth, nerve survival, and synaptic plasticity and function. Some of this awesome nerve fertilizer is made in the endothelium (possibly through a nitric oxide mechanism). Now cardiovascular disease, which correlates with depression, is also likely mediated through inflammation and endothelial dysfunction. Trans fats are thought to cause inflammation and endothelial dysfunction, so it would make a lot of sense if they trash your brain along with your coronary arteries.
Here's a rather scary analysis (though also makes me question the conclusions of the whole study) - the people studied overall actually ate a lot of whole foods and a very low amount of trans fats, and most of it came from whole fat dairy (I'm assuming, then, they are talking about CLA, which as far as I know is a very good fat associated with reductions in diabetes and obesity (both of which individually correlate with depression also, of course) though it is in truth a natural trans fat). In this study sample, in the highest quintile, trans fat made up only 0.4% of calories. In America, trans fat intake is up to 2.5% of calories, and the main sources are artificial foods (such as processed snack foods and margarine.)
Olive oil, on the other hand, is thought to have antioxidant and anti-inflammatory effects, and various metabolites of olive oil can improve sleep and improve the binding of serotonin to its receptors. The folks in the study overall (being a Mediterranean population) ate a ton of olive oil and very little butter, margarine, or seed oil. (These researchers are big olive oil fans.)
So what can we glean from this study? Not that much - the strength of the design was a large population, but a huge weakness is that the diet was measured only once, at the beginning of the study, through a food questionnaire. It was felt that the use of college graduates would help the validation, as they might be more likely to give accurate information about diet. However, it seems that most of this highly educated cohort ate very similar diets, which means the whole effort may have been something of a wash. I'm always skeptical of the ability of epidemiologists to adjust for confounding variables.
But it does make sense biologically that olive oil and PUFA intake (since they weren't using seed oils, I'm guessing a lot of the PUFA was in fish) would correlate with a happier brain, while the inflammatory trans fats would trash the endothelium and BDNF. So maybe we hang our hats on that a little.
Dietary Fat Intake and the Risk of Depression: The SUN Project
The paper begins mild-mannered: "Emerging evidence relates some nutritional factors to depression risk. However, there is a scarcity of longitudinal assessments on this relationship."
The researchers followed a group of Spanish university graduates, initially depression-free, for an open enrollment period of 1999-2010. 12,059 ultimately signed up. At baseline they filled out a food frequency questionnaire to estimate the amount of saturated fat, polyunsaturated fats, trans fats, monounsaturated fats eaten, and the use of "culinary fats" (olive oil, seed oils, butter, and margarine). During the follow up period (of median 6 years), 657 new cases of depression were identified (via a new diagnosis of depression by a physician or initiating the use of antidepressant drugs). As is typical, confounders were accounted for, including adherence to a Mediterranean Diet (legumes, fruits, vegetables, fish, cereals, and low in meat and dairy products), which has already been shown to correlate with decreased depression (1). Turns out there was a reasonably strong (and dose-dependent) correlation between trans fat usage and depression - the less trans fat the Spaniards ate, the less likely they were to become depressed, and those in the highest quintile of trans fat intake had a 48% increased risk of developing depression compared to those who ate no trans fats. There was also a weaker inverse correlation with the amount of MUFA and PUFA eaten (meaning these types of fats may be protective against depression.)
In Europe, suicide rates and mental disorders are higher in Northern Europe, and the lowest in the Southern Mediterranean countries. I can think of a number of possible reasons for this trend (sunlight, relaxed lifestyle, vitamin D *cough*), but the overall food choices differ mainly with respect to olive oil and pulses. Very little is known about the specific types of fat and risk for depression, except with respect to the omega 3s. And even those studies are tricky - often, the omega3 capsule is compared to a placebo capsule of olive oil, and in some trials, both the fish oil group and the olive oil (control) group improve. It could be that both fish oil and olive oil improve mood, or that the increased fat content in general improved mood, as there is some evidence that low fat diets adversely affect mood (2)(3).
Now the discussion and speculation - always the most interesting part. The commonly accepted mechanism now for depression is one of inflammation leading to a decrease in BDNF, which is a nerve fertilizer necessary for axonal growth, nerve survival, and synaptic plasticity and function. Some of this awesome nerve fertilizer is made in the endothelium (possibly through a nitric oxide mechanism). Now cardiovascular disease, which correlates with depression, is also likely mediated through inflammation and endothelial dysfunction. Trans fats are thought to cause inflammation and endothelial dysfunction, so it would make a lot of sense if they trash your brain along with your coronary arteries.
Here's a rather scary analysis (though also makes me question the conclusions of the whole study) - the people studied overall actually ate a lot of whole foods and a very low amount of trans fats, and most of it came from whole fat dairy (I'm assuming, then, they are talking about CLA, which as far as I know is a very good fat associated with reductions in diabetes and obesity (both of which individually correlate with depression also, of course) though it is in truth a natural trans fat). In this study sample, in the highest quintile, trans fat made up only 0.4% of calories. In America, trans fat intake is up to 2.5% of calories, and the main sources are artificial foods (such as processed snack foods and margarine.)
Olive oil, on the other hand, is thought to have antioxidant and anti-inflammatory effects, and various metabolites of olive oil can improve sleep and improve the binding of serotonin to its receptors. The folks in the study overall (being a Mediterranean population) ate a ton of olive oil and very little butter, margarine, or seed oil. (These researchers are big olive oil fans.)
So what can we glean from this study? Not that much - the strength of the design was a large population, but a huge weakness is that the diet was measured only once, at the beginning of the study, through a food questionnaire. It was felt that the use of college graduates would help the validation, as they might be more likely to give accurate information about diet. However, it seems that most of this highly educated cohort ate very similar diets, which means the whole effort may have been something of a wash. I'm always skeptical of the ability of epidemiologists to adjust for confounding variables.
But it does make sense biologically that olive oil and PUFA intake (since they weren't using seed oils, I'm guessing a lot of the PUFA was in fish) would correlate with a happier brain, while the inflammatory trans fats would trash the endothelium and BDNF. So maybe we hang our hats on that a little.
Tuesday, January 25, 2011
Appetite, Sleep, and Mood - The Connection
Whew. Between making up for my holiday vacation and the snow days (we might get yet another storm, up to 18 inches, tomorrow, and there is still 2&1/2 feet on the ground!!), work has been incredibly busy. At the same time, my children have decided to run sleep deprivation experiments on me. The problem with being sleep-deprived is that when you try to read rather clunky textbooks on the basic and clinical science of sleep and mental illness, you tend to nod off rather quickly. (the reference for this post is the aforementioned clunky textbook)
That's a rather verbose introduction to the fact that I need a perky song or two to blog by today. Let's start with Ra Ra Riot's Boy. (right click in new tab if you want to keep reading).
So - appetite, sleep, and mood. We psychiatrist types ask about such things all the time, because we know they are inexorably related. In fact, problematic appetite, sleep and energy levels have a clinical nickname - "neurovegetative symptoms." Well, that's not much of a nickname. We call it "neuroveg" for short. We also call ending a relationship with a patient "termination." And emotions "affects." We aren't particularly fun people, really. (Kidding! Sort of.)
So let's talk neurotransmitters. Wakefulness in general is supported by several excitatory neurotransmitter pathways, among them acetylcholine and norepinephrine. These brain chemicals send wakey wakey signals to the forebrain, and when this happens, our brain EEG signals go from large sleepy floppy slow wave sleep to the brisk jagged beta waves of being awake. If we lack acetylcholine and norepinephrine signals to the forebrain, we get all drowsy and fall into non-REM sleep (all our restorative sleep). If you are into the whole neurochemistry/electricity thing, the excitatory neurotransmitters lead to rapid firing and depolarization of the wakeful brain neurons. The lack of that signal leads to a relative hyperpolarization and long, slow lazy signal of the sleeping brain.
To get into even more nitty gritty, remember that the basic energy currency of the cells is ATP. That's short for adenosine triphosphate. In order to lend power to chemical reactions, the ATP gives up its three phosphates one by one until it becomes plain old adenosine again. And in the brain, the more adenosine, the more difficult it becomes to send signal to the wakey wakey neurons. That makes sense - you've spent your energy reserves and have a bunch of waste adenosine around? Chill out, cool down, and rest, so the nighttime healing and restoration of reserves can commence.
(Time for another song? I really like this one by The Black Keys. It's overplayed but, some songs are never really overplayed.)
To recap - the neurotransmitter monoamines, norepinephrine and acetylcholine, promote wakefulness. Non-REM sleep (stage 1-4) is the opposite of wakefulness, and lack of monoamine input leads to progressively more slow wave sleep. BUT, remember that during polysomography, it is difficult to tell the difference between someone waking up and someone in REM sleep. The EEG waves of REM sleep are impossible to tell from being awake - only the rapid eye movements and the paralyzing of our major large muscle groups can let the sleep researcher know that the subject is in REM sleep and hasn't woken up.
Turns out REM sleep neurons turn on when there is almost NO input from the monoamines, while sleepy-inducing neurotransmitters like GABA (GABA receptors are activated by GABA (duh), benzos like valium, alcohol, and sleep medicines like lunesta or ambien.) seem to activate both non-REM and REM sleep.
So - in major depressive disorder, we seem to have a lack of monoamines in the right places at the right time in the brain. GABA is more or less okay. Therefore, you get a classic sleep hypnogram for major depression - lots of REM sleep that starts way too early in the night, lots of wakefulness, and almost no restorative slow wave sleep. All clinically effective medicinal treatments for major depressive disorder will improve your hypnogram by increasing the amount of time it takes you to get to REM sleep 10 DAYS EARLIER than you notice any improvement in mood.
(If your depressive disorder has a lot of anxiety symptoms too, your GABA is probably lacking, so then the sleep gets really messed up.)
Now, let's bring in appetite. The Nurses' Health Study and some other studies show that chronic short duration of sleep and chronic long duration of sleep are associated with type II diabetes. Laboratory subjects who are studied in sleep restriction and sleep deprivation have impaired glucose tolerance and increased appetite. In the majority of serious psychiatric disorders, disruption of the circadian rhythm and sleep occurs, and major psychiatric disorders are also associated with an increase in appetite and risk of diabetes. Some of this increase is medication-driven, but there also appears to be an increase in risk of diabetes and weight gain independent of medications.
The center of appetite and mental problems appears to be the hormone orexin. As we learned earlier, orexin is a hormone that makes you hungry. Serotonin seems to suppress orexin. Folks with schizophrenia and atypical depression seem to be pretty low on serotonin, and they will be hungrier and have more central obesity than folks without those disorders.
Putting it all together, disturbances in the sleep-wake cycle reported in psychosis and in atypical depression seem to disrupt the feedback mechanisms of energy and metabolism in a way that decreases glucose tolerance and reduces sleep efficiency and effectiveness. All the usual neurotransmitter suspects are implicated.
Another song? Sure, why not. How about The Cave by Mumford and Sons.
Or if you want a nice modern classical romantic song, try this little piece from the newest Pride and Prejudice movie. Good date movie - not too many tears.
That's a rather verbose introduction to the fact that I need a perky song or two to blog by today. Let's start with Ra Ra Riot's Boy. (right click in new tab if you want to keep reading).
So - appetite, sleep, and mood. We psychiatrist types ask about such things all the time, because we know they are inexorably related. In fact, problematic appetite, sleep and energy levels have a clinical nickname - "neurovegetative symptoms." Well, that's not much of a nickname. We call it "neuroveg" for short. We also call ending a relationship with a patient "termination." And emotions "affects." We aren't particularly fun people, really. (Kidding! Sort of.)
So let's talk neurotransmitters. Wakefulness in general is supported by several excitatory neurotransmitter pathways, among them acetylcholine and norepinephrine. These brain chemicals send wakey wakey signals to the forebrain, and when this happens, our brain EEG signals go from large sleepy floppy slow wave sleep to the brisk jagged beta waves of being awake. If we lack acetylcholine and norepinephrine signals to the forebrain, we get all drowsy and fall into non-REM sleep (all our restorative sleep). If you are into the whole neurochemistry/electricity thing, the excitatory neurotransmitters lead to rapid firing and depolarization of the wakeful brain neurons. The lack of that signal leads to a relative hyperpolarization and long, slow lazy signal of the sleeping brain.
To get into even more nitty gritty, remember that the basic energy currency of the cells is ATP. That's short for adenosine triphosphate. In order to lend power to chemical reactions, the ATP gives up its three phosphates one by one until it becomes plain old adenosine again. And in the brain, the more adenosine, the more difficult it becomes to send signal to the wakey wakey neurons. That makes sense - you've spent your energy reserves and have a bunch of waste adenosine around? Chill out, cool down, and rest, so the nighttime healing and restoration of reserves can commence.
(Time for another song? I really like this one by The Black Keys. It's overplayed but, some songs are never really overplayed.)
To recap - the neurotransmitter monoamines, norepinephrine and acetylcholine, promote wakefulness. Non-REM sleep (stage 1-4) is the opposite of wakefulness, and lack of monoamine input leads to progressively more slow wave sleep. BUT, remember that during polysomography, it is difficult to tell the difference between someone waking up and someone in REM sleep. The EEG waves of REM sleep are impossible to tell from being awake - only the rapid eye movements and the paralyzing of our major large muscle groups can let the sleep researcher know that the subject is in REM sleep and hasn't woken up.
Turns out REM sleep neurons turn on when there is almost NO input from the monoamines, while sleepy-inducing neurotransmitters like GABA (GABA receptors are activated by GABA (duh), benzos like valium, alcohol, and sleep medicines like lunesta or ambien.) seem to activate both non-REM and REM sleep.
So - in major depressive disorder, we seem to have a lack of monoamines in the right places at the right time in the brain. GABA is more or less okay. Therefore, you get a classic sleep hypnogram for major depression - lots of REM sleep that starts way too early in the night, lots of wakefulness, and almost no restorative slow wave sleep. All clinically effective medicinal treatments for major depressive disorder will improve your hypnogram by increasing the amount of time it takes you to get to REM sleep 10 DAYS EARLIER than you notice any improvement in mood.
(If your depressive disorder has a lot of anxiety symptoms too, your GABA is probably lacking, so then the sleep gets really messed up.)
Now, let's bring in appetite. The Nurses' Health Study and some other studies show that chronic short duration of sleep and chronic long duration of sleep are associated with type II diabetes. Laboratory subjects who are studied in sleep restriction and sleep deprivation have impaired glucose tolerance and increased appetite. In the majority of serious psychiatric disorders, disruption of the circadian rhythm and sleep occurs, and major psychiatric disorders are also associated with an increase in appetite and risk of diabetes. Some of this increase is medication-driven, but there also appears to be an increase in risk of diabetes and weight gain independent of medications.
The center of appetite and mental problems appears to be the hormone orexin. As we learned earlier, orexin is a hormone that makes you hungry. Serotonin seems to suppress orexin. Folks with schizophrenia and atypical depression seem to be pretty low on serotonin, and they will be hungrier and have more central obesity than folks without those disorders.
Putting it all together, disturbances in the sleep-wake cycle reported in psychosis and in atypical depression seem to disrupt the feedback mechanisms of energy and metabolism in a way that decreases glucose tolerance and reduces sleep efficiency and effectiveness. All the usual neurotransmitter suspects are implicated.
Another song? Sure, why not. How about The Cave by Mumford and Sons.
Or if you want a nice modern classical romantic song, try this little piece from the newest Pride and Prejudice movie. Good date movie - not too many tears.
Saturday, January 22, 2011
Chronotherapeutics for Affective Disorders
Little update 3/2/11 - Just found this website with research updates on chronotherapuetics which may be of interest: http://www.chronotherapeutics.org/Index.html
(end little update)
I'm going to spend some more time discussing some nitty gritty, genetics, and biochemistry related to mood disorders (especially), treatments for mood disorders, and circadian rhythm abnormalities. Bet you can't wait! In the mean time, however, I came upon some neat articles (1)(2) about the process of chronotherapeutics. That is, using light therapy, dark therapy, sleep deprivation and sleep phase delay or advance to treat mood disorders, such as depression and bipolar disorder. A little warning - these methods are powerful, quick, and affect the same neurotransmitter systems as psychiatric medications (more on that in a different post), and it is not a good idea to experiment with these all on your lonesome. Let me give you a worst case scenario - you try to treat depression with light therapy or sleep deprivation. Turns out you are bipolar. You get manic, spend $30,000 on a new stereo system, sleep with your boss, and antagonize your friends and relatives, and end up in a hospital after singing opera naked on your rooftop (this is an invented but not entirely unreasonable scenario). So... best to let some loved ones know if you attempt these methods, and if you already have a psychiatric diagnosis, don't attempt these methods without the blessing and observation of your therapist or doctor. In addition, if the methods aren't done quite right, you can very quickly relapse (within 1-2 days).
Most of you will be familiar with the concept of light therapy. Sitting in front of special 10,000 lux light sources on late autumn and winter mornings has been proven to be an effective treatment for seasonal affective disorder, major depressive disorders, and even bipolar depression (if you are careful - injudicious use of light therapy can also bring on mania). The FDA approved lights (such as the ones from this company - this is just the company I typically recommend to patients, I have no relationship to them and receive no monetary or other benefit from them) all have a 30 day money back guarantee, also, which is nice, and some insurance companies will pay for them if you are lucky. The usual method is to sit in front of the lights in the morning for 15-30 minutes, glancing at the light every 30 seconds to a minute or so. You have to do it nearly every day, and it works best if you begin when the seasons change (late September here at 40 degrees north). Light therapy can nearly instantaneously improve seasonal depression, and I've heard tales of trucks of light therapy boxes driving around to small towns in Alaska and reducing the winter suicide rate along the way.
But let's get back to the basics of chronotherapeutics. In general, interventions that lead to sleep phase advance (waking up early and going to sleep early) have an antidepressant effect, and sleep phase delay (going to sleep later and waking up later) will have a depressant (or anti-manic) effect. Also, reinforcing the natural circadian rhythm will tend to help mental illness - at hospitals in Canada (3) and Italy (4), they noticed that patients in sunny or easterly facing rooms were discharged on average 2&1/2 to 3&1/2 days earlier than patients in rooms without much sunlight. (Even more interestingly, the differences were minimal in the winter, but extended to up to 7 days in the autumn). Not surprisingly, all of this has been discovered before by our intrepid ancestors. Classical texts and descriptions of psychiatric wards from 1794 showed that depressed patients were advised to spend time out of doors, and agitated patients were closed up in darkened rooms (5).
One old-fashioned and newly-fashionable method of treating all sorts of depression is sleep deprivation (SD). There is complete sleep-deprivation, which is self-explanatory, and partial sleep-deprivation,which generally involves waking people up for the second half of the night. The only known contraindication to sleep deprivation is epilepsy (I've spent some time on the long-term seizure monitoring units in neurology, and we've been known to elicit seizures for diagnosis via EEG by sleep deprivation (basically, sending the medical students and residents - who were up anyway - to keep the patient awake at all hours) and use of a judicious amount of red wine). SD's efficacy has been reported in major depression, bipolar disorder, depression in schizophrenia and in Parkinson's disease, and post-partum depression. Patients who respond best to sleep deprivation are the same patients who respond best to antidepressant medications - those with a diurnal pattern of mood (typically more depressed in the morning and feeling pretty good by afternoon), low IL-6 levels, and an abnormal dexamethasone suppression test. Light therapy has similarly proved therapeutic (nearly instantly) with depression associated with ADHD, Parkinson's, Alzheimer's, pregnancy, post-natal, and regular depressive disorders.
As with every other method (such as therapy and antidepressants) (except shock therapy, which is up to 90% effective), light therapy and sleep deprivation is at least modestly helpful in 60-70% of cases. However, and interestingly, people with bipolar depression seem more likely to respond to sleep deprivation or light therapy than to standard antidepressant medications, suggesting to me (and truth be told I've read other papers with other evidence for this theory) that genetic issues with the circadian rhythm system is the primary problem leading to the vulnerability to bipolar disorder.Due to the tricky nature of bipolar depression and the risk of switching to mania with antidepressant drugs, some of the most robust data has been shown for chronotherapeutics (sleep deprivation, phase advance, or light therapy) for this condition, and mood stabilizers (which work upon the circadian rhythm proteins) can enhance and continue the initial benefits brought about via chronotherapeutics. The medicine remains useful, as once chronotherapeutics are discontinued (one can't be sleep-deprived forever, for example), the depression can return within a hours of a normal night's sleep. In fact, only 5-10% of the studied bipolar depressed patients remain with a normal mood through chronotherapeutics alone. Repeating the intervention doesn't always help, as people tend to become tolerant to the treatment.
One way of ameliorating the tolerance to chronotherapeutic techniques is to combine them. For example, there is a severely depressed patient with known bipolar disorder in the hospital. Start with a few days of sleep deprivation, then begin phase advance treatment (going to bed early, waking up early) and morning light therapy to retain the benefits over time. Perhaps add in some mood stabilizers to enhance the effect (again, I will go into more specifics as to how mood stabilizers and antidepressants affect, directly, the circadian rhythm system in another post - but to give you a preliminary taste, both serum and PET, SPECT, and fmri data has shown that antidepressants and sleep deprivation/phase delay/light therapy affect the same neurotransmitter system in similar areas of the brain), and we have a recipe for nearly immediate reversal of severe bipolar depression with maintenance of normal mood for the foreseeable future.
An interesting part of the discussion of chronotherapeutics is that the techniques (other than the physical lights of light therapy) cannot be patented. Therefore there is less (short-term) economic motivation for future study (as is the case with most evolutionary medicine ideas). However, in countries with socialized medicine, far-sighted bureaucrats might see the writing on the wall - cheap interventions (such as sticking all the depressed patients in easterly-facing rooms in the autumn) decreasing hospital times saves real taxpayer money very quickly. Days in the hospital equals thousands of dollars. It is that simple.
So if you are depressed, seek light and wakefulness (an old timey depression remedy was to wake up at 3am once a month for those known to be vulnerable to the condition), and if you are manic, seek darkness and low stimuli. Under close supervision, of course.
(end little update)
I'm going to spend some more time discussing some nitty gritty, genetics, and biochemistry related to mood disorders (especially), treatments for mood disorders, and circadian rhythm abnormalities. Bet you can't wait! In the mean time, however, I came upon some neat articles (1)(2) about the process of chronotherapeutics. That is, using light therapy, dark therapy, sleep deprivation and sleep phase delay or advance to treat mood disorders, such as depression and bipolar disorder. A little warning - these methods are powerful, quick, and affect the same neurotransmitter systems as psychiatric medications (more on that in a different post), and it is not a good idea to experiment with these all on your lonesome. Let me give you a worst case scenario - you try to treat depression with light therapy or sleep deprivation. Turns out you are bipolar. You get manic, spend $30,000 on a new stereo system, sleep with your boss, and antagonize your friends and relatives, and end up in a hospital after singing opera naked on your rooftop (this is an invented but not entirely unreasonable scenario). So... best to let some loved ones know if you attempt these methods, and if you already have a psychiatric diagnosis, don't attempt these methods without the blessing and observation of your therapist or doctor. In addition, if the methods aren't done quite right, you can very quickly relapse (within 1-2 days).
Most of you will be familiar with the concept of light therapy. Sitting in front of special 10,000 lux light sources on late autumn and winter mornings has been proven to be an effective treatment for seasonal affective disorder, major depressive disorders, and even bipolar depression (if you are careful - injudicious use of light therapy can also bring on mania). The FDA approved lights (such as the ones from this company - this is just the company I typically recommend to patients, I have no relationship to them and receive no monetary or other benefit from them) all have a 30 day money back guarantee, also, which is nice, and some insurance companies will pay for them if you are lucky. The usual method is to sit in front of the lights in the morning for 15-30 minutes, glancing at the light every 30 seconds to a minute or so. You have to do it nearly every day, and it works best if you begin when the seasons change (late September here at 40 degrees north). Light therapy can nearly instantaneously improve seasonal depression, and I've heard tales of trucks of light therapy boxes driving around to small towns in Alaska and reducing the winter suicide rate along the way.
But let's get back to the basics of chronotherapeutics. In general, interventions that lead to sleep phase advance (waking up early and going to sleep early) have an antidepressant effect, and sleep phase delay (going to sleep later and waking up later) will have a depressant (or anti-manic) effect. Also, reinforcing the natural circadian rhythm will tend to help mental illness - at hospitals in Canada (3) and Italy (4), they noticed that patients in sunny or easterly facing rooms were discharged on average 2&1/2 to 3&1/2 days earlier than patients in rooms without much sunlight. (Even more interestingly, the differences were minimal in the winter, but extended to up to 7 days in the autumn). Not surprisingly, all of this has been discovered before by our intrepid ancestors. Classical texts and descriptions of psychiatric wards from 1794 showed that depressed patients were advised to spend time out of doors, and agitated patients were closed up in darkened rooms (5).
One old-fashioned and newly-fashionable method of treating all sorts of depression is sleep deprivation (SD). There is complete sleep-deprivation, which is self-explanatory, and partial sleep-deprivation,which generally involves waking people up for the second half of the night. The only known contraindication to sleep deprivation is epilepsy (I've spent some time on the long-term seizure monitoring units in neurology, and we've been known to elicit seizures for diagnosis via EEG by sleep deprivation (basically, sending the medical students and residents - who were up anyway - to keep the patient awake at all hours) and use of a judicious amount of red wine). SD's efficacy has been reported in major depression, bipolar disorder, depression in schizophrenia and in Parkinson's disease, and post-partum depression. Patients who respond best to sleep deprivation are the same patients who respond best to antidepressant medications - those with a diurnal pattern of mood (typically more depressed in the morning and feeling pretty good by afternoon), low IL-6 levels, and an abnormal dexamethasone suppression test. Light therapy has similarly proved therapeutic (nearly instantly) with depression associated with ADHD, Parkinson's, Alzheimer's, pregnancy, post-natal, and regular depressive disorders.
As with every other method (such as therapy and antidepressants) (except shock therapy, which is up to 90% effective), light therapy and sleep deprivation is at least modestly helpful in 60-70% of cases. However, and interestingly, people with bipolar depression seem more likely to respond to sleep deprivation or light therapy than to standard antidepressant medications, suggesting to me (and truth be told I've read other papers with other evidence for this theory) that genetic issues with the circadian rhythm system is the primary problem leading to the vulnerability to bipolar disorder.Due to the tricky nature of bipolar depression and the risk of switching to mania with antidepressant drugs, some of the most robust data has been shown for chronotherapeutics (sleep deprivation, phase advance, or light therapy) for this condition, and mood stabilizers (which work upon the circadian rhythm proteins) can enhance and continue the initial benefits brought about via chronotherapeutics. The medicine remains useful, as once chronotherapeutics are discontinued (one can't be sleep-deprived forever, for example), the depression can return within a hours of a normal night's sleep. In fact, only 5-10% of the studied bipolar depressed patients remain with a normal mood through chronotherapeutics alone. Repeating the intervention doesn't always help, as people tend to become tolerant to the treatment.
One way of ameliorating the tolerance to chronotherapeutic techniques is to combine them. For example, there is a severely depressed patient with known bipolar disorder in the hospital. Start with a few days of sleep deprivation, then begin phase advance treatment (going to bed early, waking up early) and morning light therapy to retain the benefits over time. Perhaps add in some mood stabilizers to enhance the effect (again, I will go into more specifics as to how mood stabilizers and antidepressants affect, directly, the circadian rhythm system in another post - but to give you a preliminary taste, both serum and PET, SPECT, and fmri data has shown that antidepressants and sleep deprivation/phase delay/light therapy affect the same neurotransmitter system in similar areas of the brain), and we have a recipe for nearly immediate reversal of severe bipolar depression with maintenance of normal mood for the foreseeable future.
An interesting part of the discussion of chronotherapeutics is that the techniques (other than the physical lights of light therapy) cannot be patented. Therefore there is less (short-term) economic motivation for future study (as is the case with most evolutionary medicine ideas). However, in countries with socialized medicine, far-sighted bureaucrats might see the writing on the wall - cheap interventions (such as sticking all the depressed patients in easterly-facing rooms in the autumn) decreasing hospital times saves real taxpayer money very quickly. Days in the hospital equals thousands of dollars. It is that simple.
So if you are depressed, seek light and wakefulness (an old timey depression remedy was to wake up at 3am once a month for those known to be vulnerable to the condition), and if you are manic, seek darkness and low stimuli. Under close supervision, of course.
Friday, January 21, 2011
Sleep Architecture
At the risk of recreating a wikipedia article, we need to lay some groundwork here and discuss the structure of normal sleep. Of course it is never as simple as that - normal sleep architecture changes throughout the life cycle. However, the basics are similar for everyone except perhaps preemies.
Sleep is defined using EEG readings (where you have a bunch of leads taped to your head, and the electrical output of the brain is measured on a polysomnography - which also includes muscle measurements and eye movement measurements to be completely accurate.) In general, all stages of non-REM sleep are characterized by a slowing and deepening of the waveforms as we get deeper and deeper into sleep. When we are awake but zoning out, or meditating, we have a type of waveform detected on the EEG called an "alpha wave." When the alpha waves start to become theta waves, we've progressed to stage 1 sleep. In general, someone who has been awakened from stage 1 sleep will not think he or she was actually sleeping. (Think Dad nodding in his chair on Sunday afternoon, and when you bug him, he blinks and goes back to watching the game as if nothing happened).
A few minutes into stage I, if all goes well, you go to stage 2, and then after another few minutes into stage 3 and 4. These last two stages are characterized by "delta waves" and are commonly referred to as "slow wave sleep" and represent the deep, refreshing sleep. After about an hour or a little more (total for 1-4), normal adults will transition to REM sleep, where eyes move rapidly and large muscle groups are paralyzed. This stage is when a lot of dreaming occurs (though dreaming also happens during slow wave sleep). REM sleep waves are somewhere in between stage I and wakefulness - in fact, the sleep scientists rely on the muscle readings and eye movement readings to distinguish between someone who has woken up, and someone who is in REM sleep.
Once the REM cycle is finished, one drops down through stage 1-4 again. The cycle repeats itself every 90 minutes or so (for newborns, every 45 minutes) throughout the night, though the last couple of cycles one spends more time in REM sleep and less time in slow wave sleep.
A couple of important things - the first cycle or two are the ones where we spend the most time in the deep, refreshing slow wave sleep, so it is vital that these cycles are of good quality. In classic Major Depressive Disorder, for example, patients will often never reach full slow wave sleep throughout the night, thus the common complaint of insomnia, feeling constant fatigue, irritability, or being too easily awakened. These same patients typically aren't hungry and lose weight. In "atypical" depression, seasonal affective disorder, or bipolar disorder, some patients will actually spend too much time in slow wave sleep. They also feel lethargic, and will be hungry and tend to gain weight.
Alcohol consumed close to bedtime will tend to decrease sleep latency (that is, the amount of time from being awake to being asleep when we go down for the night), increases the length of time to get to REM sleep, and increases slow wave sleep for the first half of the night. However, the second half of the night, there will be more wakefulness, more REM sleep, and less slow wave sleep. Alcohol is the most common go-to substance that chronic insomniacs use to get some shut-eye, and overall it decreases the quality and efficiency of sleep.
All told, sleep problems and fatigue arise from a complicated array of too much or too little in a number of neurochemical systems. There are natural chemicals promoting wakefulness, and chemicals promoting sedation as part of the circadian rhythm, and issues with any of these can lead to complaints of poor sleep, insomnia, or fatigue. I hope to get to more of the details in future posts!
Sleep is defined using EEG readings (where you have a bunch of leads taped to your head, and the electrical output of the brain is measured on a polysomnography - which also includes muscle measurements and eye movement measurements to be completely accurate.) In general, all stages of non-REM sleep are characterized by a slowing and deepening of the waveforms as we get deeper and deeper into sleep. When we are awake but zoning out, or meditating, we have a type of waveform detected on the EEG called an "alpha wave." When the alpha waves start to become theta waves, we've progressed to stage 1 sleep. In general, someone who has been awakened from stage 1 sleep will not think he or she was actually sleeping. (Think Dad nodding in his chair on Sunday afternoon, and when you bug him, he blinks and goes back to watching the game as if nothing happened).
 |
| EEG tracing of stage 1 sleep with mostly theta waves and some alpha |
A few minutes into stage I, if all goes well, you go to stage 2, and then after another few minutes into stage 3 and 4. These last two stages are characterized by "delta waves" and are commonly referred to as "slow wave sleep" and represent the deep, refreshing sleep. After about an hour or a little more (total for 1-4), normal adults will transition to REM sleep, where eyes move rapidly and large muscle groups are paralyzed. This stage is when a lot of dreaming occurs (though dreaming also happens during slow wave sleep). REM sleep waves are somewhere in between stage I and wakefulness - in fact, the sleep scientists rely on the muscle readings and eye movement readings to distinguish between someone who has woken up, and someone who is in REM sleep.
Once the REM cycle is finished, one drops down through stage 1-4 again. The cycle repeats itself every 90 minutes or so (for newborns, every 45 minutes) throughout the night, though the last couple of cycles one spends more time in REM sleep and less time in slow wave sleep.
 |
| Normal sleep architecture |
A couple of important things - the first cycle or two are the ones where we spend the most time in the deep, refreshing slow wave sleep, so it is vital that these cycles are of good quality. In classic Major Depressive Disorder, for example, patients will often never reach full slow wave sleep throughout the night, thus the common complaint of insomnia, feeling constant fatigue, irritability, or being too easily awakened. These same patients typically aren't hungry and lose weight. In "atypical" depression, seasonal affective disorder, or bipolar disorder, some patients will actually spend too much time in slow wave sleep. They also feel lethargic, and will be hungry and tend to gain weight.
Alcohol consumed close to bedtime will tend to decrease sleep latency (that is, the amount of time from being awake to being asleep when we go down for the night), increases the length of time to get to REM sleep, and increases slow wave sleep for the first half of the night. However, the second half of the night, there will be more wakefulness, more REM sleep, and less slow wave sleep. Alcohol is the most common go-to substance that chronic insomniacs use to get some shut-eye, and overall it decreases the quality and efficiency of sleep.
All told, sleep problems and fatigue arise from a complicated array of too much or too little in a number of neurochemical systems. There are natural chemicals promoting wakefulness, and chemicals promoting sedation as part of the circadian rhythm, and issues with any of these can lead to complaints of poor sleep, insomnia, or fatigue. I hope to get to more of the details in future posts!
Tuesday, January 18, 2011
Health guidance For Fasting
Fast at month of ramadhan, if is sighted from health viewpoint, have severally benefit. And medical science now have admitted benefit of fasts that gets to induce to health and body goodness and someone think. This article constitute translation article that I translates from Dr. Farouk Haffejee's writing that gets title: “Some health guidelines for fasting “, obviously after ask for permit to
HUSH HUSH HEALTHY LIFE
Life healthying to constitute everybody aim. A variety effort is done that its life lies on prima condition. And, apparently secret living healthy not lays in to outgrow it production or someone wages. To get us healthy life not necessarily waits until our production outgrow. Even little wages if we aptly intend to live healthy, therefore gets to be accomplished.
For men with big production,
For men with big production,
Monday, January 17, 2011
Circadian Rhythm, Psychiatric Symptoms, and Pineal Gland Tumor
Today's Green Journal had an interesting letter to the editor. "Ivan," a 19 y/o, had a history of a pineal gland tumor (the pineal gland secretes melatonin) that had been resected in 2001. In order to decrease building pressure in his brain, he had a second surgery for a VP shunt to drain his cerebrospinal fluid into his abdominal region. After the second surgery, he had insomnia, a disturbed sleep-wake cycle, and fragmented sleep. In June 2004 he began to exhibit paranoia and other classic signs of bipolar disorder. By 2007 he was on several psychiatric medications, and he was not able to continue school due to severe fatigue and bipolar symptoms. A sleep study showed an irregular sleep/wake cycle, and 24 hour urine measure of a melatonin metabolite showed barely detectable levels.
The patient was started on melatonin (a controlled release formulation), his sleep cycle stabilized, and his psychiatric medication was slowly withdrawn over the next several months. Repeat sleep studies showed normalized sleep. Since rapid release melatonin lasts 60-90 minutes, it was felt it was not a suitable replacement for the absent pineal gland - thus the controlled release formulation.
Interestingly enough, the patient discontinued his melatonin in 2009 and remained symptom free, with a stable sleep-wake cycle. The authors of the letter speculated that his bipolar symptoms arose from lack of restorative sleep, and with the help of exogenous melatonin, the patient was able to somehow use other signals to synchronize his sleep wake times, preventing relapse.
Lesson - sleep is exceedingly important (more on this fact in future posts). Also, all my first episode psychotic patients get an MRI and a full medical work-up.
The patient was started on melatonin (a controlled release formulation), his sleep cycle stabilized, and his psychiatric medication was slowly withdrawn over the next several months. Repeat sleep studies showed normalized sleep. Since rapid release melatonin lasts 60-90 minutes, it was felt it was not a suitable replacement for the absent pineal gland - thus the controlled release formulation.
Interestingly enough, the patient discontinued his melatonin in 2009 and remained symptom free, with a stable sleep-wake cycle. The authors of the letter speculated that his bipolar symptoms arose from lack of restorative sleep, and with the help of exogenous melatonin, the patient was able to somehow use other signals to synchronize his sleep wake times, preventing relapse.
Lesson - sleep is exceedingly important (more on this fact in future posts). Also, all my first episode psychotic patients get an MRI and a full medical work-up.
Sunday, January 16, 2011
The Neurobiology of Sleep
There is quite a bit going on, and I'm not always capable of doing it all with one hand behind my back, especially when sleep-deprived. One of my colleagues had a baby recently, and she asked us when our kids began sleeping through the night. Another colleague, mother of three, said "never." And to some extent it is true - sure, the newborn every 3-4 hour torture phase passes, but then you get teething, and then nightmares/fear of the dark, and beyond that I wouldn't know from personal experience, but let's just say I've got one teething and one afraid of the dark, and I am thoroughly sleep-deprived.
Which wouldn't bother me too much, except that I put on a couple of pounds (darn cortisol) and vanity is a failing of mine. From medical training I'm an old hand at sleep deprivation. Now there are actually laws against the amount of work I did back in the day. Not that I disagree with those laws as a rule - I happened to do my psych consultation service on some of the same floors where the medicine interns wore EEG leads post-call (meaning after being up all day and all night, and rounding on patients in the morning) as part of a study on resident work hours. Turns out they spent a good deal of those post-morning rounds in phase I sleep. Since I'm sure most of you don't care for sleepwalking doctors in charge of communicating vital information about your admission and hospital course, I imagine you are probably in favor of laws controlling medical residents' work hours. You might be surprised by the response within the medical community. They want residents to suffer - they think it makes better doctors. And working crazy hours does build confidence and experience faster than anything. However, I hope it is not terribly controversial to suggest that we not make new doctors at the expense of safety (too much).
Well, sleep! Which I am sorely missing. I'm not young anymore, after all. I have at hand a basic reference for the neurobiology of the circadian rhythms. It is from the supplements from the Journal of Clinical Psychiatry (which I normally throw away, as they are generally thinly-gilded advertisements for the pharmaceutical industry. And this supplement is no different- it came out in 2005, which was right about when Ambien CR and Rozerem were being marketed, and if you read the entire supplement you get statements about how cheap, long-used sleeping pills aren't FDA approved (of course they are not - they were generic long before the current FDA approval process, and who would bother to spend the several gazillion dollars needed for the current FDA approval process for generic medicines?) But, pharmaceutical advertising notwithstanding, the paper I'm referencing is rather too basic to be dangerous, and it is free (with free registration) for everyone, so let's call it egalitarian.
The Human Circadian System and Normal and Disordered Sleep
The neurobiology of sleep is nearly as simple as light and dark. We have, in our brains, right in the middle a bit above our eyes, a little area called the superchiasmatic nucleus. It is an area of about 10,000 neurons that runs our circadian rhythms. Without light stimulus, it tends to fire in a rhythmic pattern in a cycle of a bit more than 24 hours. Light stimulus will reign it in and keep it correlated with our natural light/dark cycles.
Light hits the retina of our eyeballs, which then sends a signal up through our optic nerve directly to the superchiasmatic nucleus. There a dimer of two proteins is made in response to the light - CLOCK+BMAL1 (let me suggest that the scientist who named the CLOCK protein was a tad more poetic than the namer of BMAL1). BMAL1/CLOCK starts the day running by binding the per/cry promoter regions in the nucleus, leading to the creation of the PER/CRY protein complex (there are in fact 2 pers and 3 crys, but let's just call it per/cry for simplicity's sake.)
From here, PERs and CRYs have to bond with other PERs and CRYs to form dimers, or else they are broken down very readily. The dimer of PER/CRY is then translocated from the nucleus to the cytoplasm for daytime cellular activity. All right! Throughout the night, when no new PERs or CRYs are made, the dimers already in the cytoplasm slowly degrade, until light comes again and more new ones are made. Thus the cycle of life and light and dark. That, in a nutshell, is the circadian rhythm.
Under conditions of sleep deprivation, our circadian clock will keep us from getting too far out of whack from light/dark cycles. We will readily sleep in the wee hours of the morning (and in fact major industrial accidents such as the Exxon Valdez crash and the Three Mile Island radiation leak happened at 3-4 am - at least according to my book on chaos and sleep), and yet even if sleep deprived and given ample opportunity, we have a hard time sleeping during the "forbidden zones" of 9am and 9pm.
And what of that famous pineal gland hormone, melatonin? It is secreted in response to dark, and light stimulus (such as checking the twitter feed on the ipad at 3am, or turning the hall light on to quell the 3 y/o's fear of the dark) will diminish melatonin secretion immediately. The human superchiasmatic nucleus (SCN) has a bunch of melatonin receptors (there are very few in the human brain outside this region). Melatonin signals the SCN to cool it and settle down for the night. Melatonin seems to sharpen the natural SCN response to light and dark. Without proper melatonin signaling, light and dark signals to sleep or wake up are attenuated, leading to night wakefulness and daytime sleepiness.
So what to do if you have insomnia? The first thing is to cut out any late night retina stimulators - like TV or internet. Music or low-light reading is probably okay. Our retinas were never designed for HDTV at midnight streaming so much signal straight into our brains (I'm reminded of when my oldest as a baby was awake at night, and my husband, trying to spare me, dutifully took her downstairs and began watching "Three Kings" with her at 2am - well, that Iraqi sun on the big screen TV at 2am did nothing for our baby's ability to sleep, and she was WIRED for several hours.) Do not turn on the lights for a midnight visit to the refrigerator or the restroom. I'm not entirely convinced that complete, black darkness is necessary given our ancestral propensity to sleep under the moon and stars, but as little light as possible is likely ideal.
Get rid of the clocks, too. I don't use an alarm and haven't for many years. If you need an alarm to wake up, you aren't getting nearly enough sleep in the first place.
There is an online resource called "CBTforInsomnia.com" that has an inexpensive program to help with insomnia (I have no connections to this resource and receive no money from promoting it).
Failing that, if you have a condition such as depression, anxiety, or bipolar disorder, sleep is exceedingly important. I'll focus more on these individual conditions in separate blog posts. In these cases I often feel it is prudent to prescribe sleep medicines (in fact, with an escalating mania, especially a psychotic mania, sleep medicines will nip it in the bud as quickly as anything else), but it is obviously not the ideal and is not a long term solution.
My own preferred sleep remedy is magnesium supplementation. I take magnesium oxide (low bioavailability, but easy to find at any drugstore) 250-500mg (depending on how many nights in a row I forget to take it), a lower dose of magnesium citrate, or a low dose of magnesium gel meant to spread on the skin, and I sleep well, right up until one of the children wakes me up. Maybe I should coat them with magnesium too.
Which wouldn't bother me too much, except that I put on a couple of pounds (darn cortisol) and vanity is a failing of mine. From medical training I'm an old hand at sleep deprivation. Now there are actually laws against the amount of work I did back in the day. Not that I disagree with those laws as a rule - I happened to do my psych consultation service on some of the same floors where the medicine interns wore EEG leads post-call (meaning after being up all day and all night, and rounding on patients in the morning) as part of a study on resident work hours. Turns out they spent a good deal of those post-morning rounds in phase I sleep. Since I'm sure most of you don't care for sleepwalking doctors in charge of communicating vital information about your admission and hospital course, I imagine you are probably in favor of laws controlling medical residents' work hours. You might be surprised by the response within the medical community. They want residents to suffer - they think it makes better doctors. And working crazy hours does build confidence and experience faster than anything. However, I hope it is not terribly controversial to suggest that we not make new doctors at the expense of safety (too much).
Well, sleep! Which I am sorely missing. I'm not young anymore, after all. I have at hand a basic reference for the neurobiology of the circadian rhythms. It is from the supplements from the Journal of Clinical Psychiatry (which I normally throw away, as they are generally thinly-gilded advertisements for the pharmaceutical industry. And this supplement is no different- it came out in 2005, which was right about when Ambien CR and Rozerem were being marketed, and if you read the entire supplement you get statements about how cheap, long-used sleeping pills aren't FDA approved (of course they are not - they were generic long before the current FDA approval process, and who would bother to spend the several gazillion dollars needed for the current FDA approval process for generic medicines?) But, pharmaceutical advertising notwithstanding, the paper I'm referencing is rather too basic to be dangerous, and it is free (with free registration) for everyone, so let's call it egalitarian.
The Human Circadian System and Normal and Disordered Sleep
The neurobiology of sleep is nearly as simple as light and dark. We have, in our brains, right in the middle a bit above our eyes, a little area called the superchiasmatic nucleus. It is an area of about 10,000 neurons that runs our circadian rhythms. Without light stimulus, it tends to fire in a rhythmic pattern in a cycle of a bit more than 24 hours. Light stimulus will reign it in and keep it correlated with our natural light/dark cycles.
Light hits the retina of our eyeballs, which then sends a signal up through our optic nerve directly to the superchiasmatic nucleus. There a dimer of two proteins is made in response to the light - CLOCK+BMAL1 (let me suggest that the scientist who named the CLOCK protein was a tad more poetic than the namer of BMAL1). BMAL1/CLOCK starts the day running by binding the per/cry promoter regions in the nucleus, leading to the creation of the PER/CRY protein complex (there are in fact 2 pers and 3 crys, but let's just call it per/cry for simplicity's sake.)
From here, PERs and CRYs have to bond with other PERs and CRYs to form dimers, or else they are broken down very readily. The dimer of PER/CRY is then translocated from the nucleus to the cytoplasm for daytime cellular activity. All right! Throughout the night, when no new PERs or CRYs are made, the dimers already in the cytoplasm slowly degrade, until light comes again and more new ones are made. Thus the cycle of life and light and dark. That, in a nutshell, is the circadian rhythm.
Under conditions of sleep deprivation, our circadian clock will keep us from getting too far out of whack from light/dark cycles. We will readily sleep in the wee hours of the morning (and in fact major industrial accidents such as the Exxon Valdez crash and the Three Mile Island radiation leak happened at 3-4 am - at least according to my book on chaos and sleep), and yet even if sleep deprived and given ample opportunity, we have a hard time sleeping during the "forbidden zones" of 9am and 9pm.
And what of that famous pineal gland hormone, melatonin? It is secreted in response to dark, and light stimulus (such as checking the twitter feed on the ipad at 3am, or turning the hall light on to quell the 3 y/o's fear of the dark) will diminish melatonin secretion immediately. The human superchiasmatic nucleus (SCN) has a bunch of melatonin receptors (there are very few in the human brain outside this region). Melatonin signals the SCN to cool it and settle down for the night. Melatonin seems to sharpen the natural SCN response to light and dark. Without proper melatonin signaling, light and dark signals to sleep or wake up are attenuated, leading to night wakefulness and daytime sleepiness.
So what to do if you have insomnia? The first thing is to cut out any late night retina stimulators - like TV or internet. Music or low-light reading is probably okay. Our retinas were never designed for HDTV at midnight streaming so much signal straight into our brains (I'm reminded of when my oldest as a baby was awake at night, and my husband, trying to spare me, dutifully took her downstairs and began watching "Three Kings" with her at 2am - well, that Iraqi sun on the big screen TV at 2am did nothing for our baby's ability to sleep, and she was WIRED for several hours.) Do not turn on the lights for a midnight visit to the refrigerator or the restroom. I'm not entirely convinced that complete, black darkness is necessary given our ancestral propensity to sleep under the moon and stars, but as little light as possible is likely ideal.
Get rid of the clocks, too. I don't use an alarm and haven't for many years. If you need an alarm to wake up, you aren't getting nearly enough sleep in the first place.
There is an online resource called "CBTforInsomnia.com" that has an inexpensive program to help with insomnia (I have no connections to this resource and receive no money from promoting it).
Failing that, if you have a condition such as depression, anxiety, or bipolar disorder, sleep is exceedingly important. I'll focus more on these individual conditions in separate blog posts. In these cases I often feel it is prudent to prescribe sleep medicines (in fact, with an escalating mania, especially a psychotic mania, sleep medicines will nip it in the bud as quickly as anything else), but it is obviously not the ideal and is not a long term solution.
My own preferred sleep remedy is magnesium supplementation. I take magnesium oxide (low bioavailability, but easy to find at any drugstore) 250-500mg (depending on how many nights in a row I forget to take it), a lower dose of magnesium citrate, or a low dose of magnesium gel meant to spread on the skin, and I sleep well, right up until one of the children wakes me up. Maybe I should coat them with magnesium too.
Saturday, January 15, 2011
5 Mistakes When Someone Had Done Bathroom
Since the first bath is considered as a useful therapy to relax the mind and cleanse the body if done correctly. But unfortunately some people just make mistakes when taking a bath. Anything?
Some other benefits of a bath is to help circulation, relieve stress, soothe sore leg muscles and ease inflammation joint pain.
As quoted from Sixwise.com, there are some mistakes made, thereby reducing or eliminating the benefits of bathing.
Here are some of the mistakes made by a person while showering, namely:
1. Clean the tub with toxic chemicals
Various cleaners are used to clean the tub containing hazardous materials are sometimes associated with cancer, reproductive problems and also damage the central nervous sisem. If the material is hazardous, then chances are there is residue left behind and mingled with the water bath.
2. Bathroom with shower, dirty filter
Use a shower bath can make the body become more relaxed, but only a few people who pay attention to cleanliness showernya filter. Researchers found about 80 percent of germs contained in the shower is sphingomonads or methylobacteria family. The bacteria can infect open wounds, attacks the immune system is weak, urinary tract infections and pneumonia.
3. Just use the shower gel alone
Generally shower gel on the market contain ingredients associated with the toxicity of the reproductive organs, allergies, disorders of the immune system, disrupt the nervous and other organ sisem.
4. Soak in chlorinated water
Bathing with water containing chlorine can be very dangerous, especially if the water is warm water. Because warm water will open pores of the skin and the water vapor will inhaled into the body. For that use filters or filters on showers and faucets are also used.
5. Bathing with hot water
Using a water bath that is too hot can be harmful to the skin, which causes skin blisters or dry. Therefore use warm water only, if you use the shower (shower), set temperature to prevent overheating.
Friday, January 14, 2011
Cyst, whether it?
Many women are afraid that if all of a sudden the doctor said "you've had the cyst. " Yes, why do women really did not expect him one of the diseases suffer from content that could interfere with pregnancy.
What is a cyst?
- cyst, including benign tumors such membrane-wrapped by the network.
- cystic shape and some are shaped like wine.
- cysts may contain air, viscous liquid, or pus.
- A collection of tumor cells were separated by normal tissue around it and can not be spread to other body parts. That is the reason why relatively easy benign tumor removed surgically and do not endanger the health of the sufferer.
Medicine alone can not ensure the origin of these cysts that cause disease, but predicted a cyst arising from the return of menstrual blood and stuck anywhere including the ovary wall. Therefore, no wonder if the existence of this disease will be difficult to be detected early in its development.
Cysts can be divided into two kinds, namely:1. Non-neoplastic cystsNon-neoplastic cysts are benign and usually will deflate by itself after two or three months.2. Neoplastic cysts.Kneoplastik cysts usually have surgery, but still depends on the size and nature, whether harmful or not.
Cysts are generally not accompanied by specific complaints or symptoms. Complaints will usually appear if the size of the cyst was enlarged and interfere with other organs located in the vicinity. If the patient is pressing the urinary tract, intestines, nerves, or major blood vessels around the pelvic cavity, then? will cause complaints of difficult urination and bowel movements, indigestion, tingling, or swelling in the feet.
Cyst is a benign tumor, but 20-30% of cysts can potentially become malignant. The situation was characterized by the occurrence of tumor enlargement in a short period, thus triggering the growth of cancer.
The most effective way to cope with cysts, namely:
1. By raising the cyst through surgery.
However, actions such treatment has yet to give a satisfactory result. Cyst removal surgery does not guarantee the cysts will not grow back later. During a woman is still producing eggs, the potential to grow cyst will still be there. However, with increasing knowledge and awareness of women at this time to check their reproductive organs is an appropriate first step to reduce the risk of cyst.
2. Overcoming cyst with Laparoscopy
Laparoscopy is a surgical technique or operations performed by making two or three small holes (diameter of 50-10 millimeters) around the abdomen of the patient. One hole in the navel is used to insert a device equipped with a camera to transfer images in the abdominal cavity to the screen, while two other holes for the other surgical equipment.
This technique is also called minimal surgery technique invansif (Minimal Invansive Surgery). However, this technique still has a risk for patients, especially because during the operation, the doctor who handles require space in the abdominal cavity so that it requires carbon dioxide (CO2) to develop the abdominal cavity, among others, risks that can occur when high pressure gas enters into in blood vessels.
Water: Single Important Nutrient
Water is said to be the lifeline for every living being. It is the most important nutrient for health. Water is such an essential fluids that helps to the vital functioning in the body. It helps to lubricate the joints, regulates temperature and provides essential minerals and fluids. Water helps you to get the blush on your skin. It has been recommended that
Thursday, January 13, 2011
Good Habits For Healthy Heart
Heart is a vital organ in our body and absolute to be maintained. Disorders that occur in highly lethal heart, therefore prevention is the most important thing being done to keep our heart from food consumption and exercise.
Holly Andersen, a researcher from the Ronald O Perelman Heart Institute in New York, explains some good habits that can be applied in everyday life for awake cardiac health. Starting from the trivial things such as walking up to find the vital numbers.
The following good practices in question.
1. Know the vital figures
Before there was a problem with the heart, it's good to know the important numbers that are indicators of heart health. Among these are blood pressure, pulse rate, levels of total fat, cholesterol and triglycerides.
2. Walk
The flurry of activity that is always solid and should not be a reason for not exercising. Every now and then leave a private vehicle and walked toward the nearest bus stop to ride public transportation to the office. Simply by walking for 20-30 minutes a day, the risk of premature death from heart attack can be reduced by 50 percent.
3. Laugh as often as possible
Even if to just walk away just still hard to take the time, try to laugh more often. Speaking of burning calories, laughed uproariously for 15 minutes can be synchronized with the aerobics for 30 minutes. Laughter also suppress the release of the stress hormone cortisol, so that more blood pressure under control.
4. Note the waist circumference
The mistake that often happens is that people are too worried about weight, whereas the risk factors of metabolic syndrome and heart problems more precisely associated with waist circumference. Central obesity or belly fat fatty liver indicate that causes cholesterol levels difficult to control.
5. Enough sleep
Staying up late into the night not only makes the body feel tired the next day. Lack of sleep also can increase stress and blood pressure so that it can give a bad impact on heart health. It seems trivial but adequate rest is an important requirement that must be met if you want to live long.