Exercise and Intermittent Fasting Are Good For The Brain

In a recent NIH video-cast called "CC Grand Rounds" (first half of the video) Mark Mattson shared some insights he gained from basic research. Mainly that exercise is good for the brain, sedentary behavior is bad for the brain. And secondly, intermittent fasting has similar beneficial qualities for the brain. Both are "stressors" that seem to have beneficial advantages – something the Paleo Diet community has been harping about for ages (because that's what life has been in evolutionary times: you needed to move to get food, and sometimes you ended up without food for a day or two).

Does this have implications for ME/CFS patients? Well, if there is a level of low intensity exercise you can manage as patient – say going once or twice a day downstairs, rest, and then up again – then you should do it.

Obviously don't do exercise if you are crashed/relapsed. And if you crash/relapse after exercise, you are doing too much. Or the activity level of the exercise is too high.

If going once a day to the bathroom is about the exercise that you can do as an ME/CFS patient: than don't do more, but try to do it.

And if your exercise consists of (slightly) wiggling your arms and feet for 10 seconds while lying in bed, then rest half an hour, and then do 10 more second, then well, do that – but try to do at least that.

Find a low intensity level of exercise which you can maintain without crash/relapse!

And if you do something as an ME/CFS patient, do pace yourself (e.g. rest often enough).

And should you try intermittent fasting? I surely will give it a try. One thing I found helpful was that with a Paleo Diet (and no cereal grains), my hunger became much more manageable. One remark Mark Mattson made is that intermittent fasting may be hard to start, but after two or three weeks people get used to it. I'll see.

Wolfgang Lutz on Anxiety

(Adapted from a comment of mine at the blog Ad Libitum)

A consistent theme I notice (which for me started with my personal experience) when I read in blogs/forums about personal nutrition experience is that people with anxiety problems, who go Paleo/Atkins/Lutz/VLC/whatever diet, is that they get rid of their anxiety problems after a change in nutrition.

People talk a lot about nutrition in the context of obesity and diabetes and cardiovascular disease and what not – the elephant in the room is to which mental/psychological problems/diseases does nutrition contribute, and by how much?

E.g. Wolfgang Lutz mentioned in the german edition of his book that he got rid of anxiety. However it is only one short paragraph and it is hidden in the back of the book. As this passage is only in the german edition of Wolfgang Lutz's book, I think it is important to translate the passage into english.

It is a bit difficult to translate, as he uses an older idiom for his psychological ailments, which tends to be a bit ornate and flowery. In addition there were (due to the pre-scientific nature of psychology) a few changes in meaning of words, both in german and in english, and I am not really intimate with the history of each term  – how do you translate "seelisch" in the context of that short passage? As emotional, psychological, mental? What were the "Komplexe" that plagued him? I have a vague idea what he meant, but unfortunately he choose not to elaborate on that topic and did not deliver a more precise description (I guess the social stigma of not being able to handle your psychological problems…).

So take my translation with some grains of salt.

… I was [before my change in nutrition] in a constant state of emotional agitation and imbalance, which might have not been visible by others though. Somehow I was always plagued by complexes, anxious about something, expected bad news, and had the feeling to be constantly driven/pushed.

[After the change in nutrition] … Generally, my mood was much more balanced, and I could enjoy my life more than before; the feeling of inner arousal was gone. Only now I could recognize that palpitations in dangerous situations were gone – such as in traffic – and that I no longer broke out in sweat so easily. Making decisions was now much easier for me, which especially benefited the time I spent on radiology and giving dictations. Suddenly I had time for my hobbies, which I had to abandon because I had no energy left to spare for them.

Wolfgang Lutz – "Leben ohne Brot" ("Life without bread"), page 247

He makes good observation about obesity ("male" obesity pattern vs. "female" obesity pattern), he fails to record his (and his patients!) improvement on the "psychological front" in more detail however. Getting rid of anxiety and increasing energy was – at least for me – by far me more important than getting rid of a few (or even many) pounds. Was this "mental energy" he couldn't spare for his hobbies, or was this full blown fatigue (or even CFS?) that dragged him down? We'll never know.

Here is the passage in the german original, for all you kraut-speaking schweinhunde :-)

… Schließlich befand ich mich [vor der Kostumstellung], gemessen an heutigen Maßstäben, in einem ständigen seelischen Erregungszustand und Ungleichgewicht, was allerdings nach außen vielleicht nicht so sehr in Erscheinung trat. Ich war immer irgendwie geplagt von Komplexen, hatte vor irgendetwas Angst, erwartete eine unangenehme Nachricht, und hatte das Gefühl ständig angetrieben zu sein.

[Nach der Kostumstellung] … Überhaupt war meine Stimmung viel ausgeglichener, und ich konnte mein Leben nun mehr als früher genießen; das Gefühl der inneren Erregung war verschwunden. Jetzt erst merkte ich, dass ich in gefährlichen Situation, z.B. im Straßenverkehr, kein Herzklopfen mehr bekam und dass ich nicht mehr so leicht schwitzte. Ich konnte mich viel schneller entschließen als vorher, was sich besonders in einer Verkürzung der Durchleuchtungs- und Diktatzeiten äußerte. Plötzlich hatte ich wieder Zeit für meine alten Hobbies, die ich vorher eines nach dem anderen aufgegeben hatte, weil ich hierfür keine Energien mehr erübrigen konnte.

Wolfgang Lutz – "Leben ohne Brot", Seite 247

Where is the Evolution in Medicine?

The sequencing of the human genotype promised a lot, but it delivers only slowly and in small doses. Maybe gene expression studies will change that, but I won't hold my breath. I heard the gut microbiome is the latest rage and it will solve all our problems (it may be important, but not that important).

Meanwhile medicine seems to be wholly incapable to tackle massive problems like obesity, diabetes and cardiovascular disease. In diseases like MS progress seems glacial, despite the resources dedicated to its research.

What I am relatively hopeful however is that an better understanding of the evolutionary context of our nutrition (aka "The Paleo Diet" and somesuch) will be a game changer in medicine – and surely bring us a much needed improvement for our health.

So it brings me pleasure that I found a new blog from that area, Ad Libitum, of which I post just this one snippet:

You know, the first time I read Good Calories, Bad Calories, it struck me that there was a missing chapter right after the dementia chapter. There should have been one on psychiatric illness. It is no coincidence that our epidemic of metabolic derangement has coincided with a huge explosion of anxiety and depression, especially of the atypical kind. My bet is that whatever is making us fat is making us miserable too. Processed carbs? Hyperinsulinaemia? I don’t know. Whatever it is, it’s killing us in multiple ways.

Nutritional Causes for "Somatoform Disorders"?

This came in via dxrevisionwatch.com

… Finally, even though the investigated groups did not differ in their health habits, a tendency to always live and eat healthy had a specific and adverse effect on physical impairment in somatoform patients. This result is rather counterintuitive, but may be explained with an increased selective attention to bodily processes in general and somatosensory amplification [30,52]. Therefore, the respectable attempt to improve one's health may contribute to a vicious cycle of symptom perpetuation. …

Hmm, a person eats "healthy" – cereal grains instead of meat, seed oils instead of saturated fat, and lot's of dairy to top it off – and their "somatoform" impairment gets worse?

Truly a paradox.

If you accept that "healthy" food is healthy, that is.

If you have reason to believe that "healthy" food is actually bad for health and can cause disease – because most of the "healthy" food is evolutionary novel – this paradox goes away. And one can suspect that "somatoform disorders" are actually bodily diseases caused or at least perpetuated by unwise nutritional choices…

Of course these psycho*s will ignore any of this and continue to believe in their psychosomatic/somatoform woo.

Needed Nutritional Intervention Studies

I was thinking that we need some nutritional studies with regards to pathogenic effects of evolutionary novel foods, and whether a evolutionary "correct" diet (aka "the" Paleolithic Diet or "Paleo" for short) can alleviate health problems.

Patients should receive nutritional intervention in the form of counseling and be assigned to one of two groups:

• The control group should receive counseling based on the consensus view on optimal nutrition. As the "gold standard" with regards to nutrition seem to be the advise from the U.S. Department of Agriculture(!) (USDA), from the American Heart Association (AHA) and from the American Diabetes Association (ADA), the control group should receive counseling based on their advise.
• The treatment group ("Paleo") should receive counseling based on the avoidance of foods containing evolutionary novel ingredients (more or less an "Elimination Diet" based on evolutionary plausibilty):
  1. Avoidance of cereal grains and soy
  2. Avoidance of dairy
  3. Avoidance of seed oils
  Pre-intervention levels of those four ingredients should be recorded. Calorie-countring should not be recommended, macro-nutritient ratios should not be prescribed, the diet should neither be low-carb, nor low-fat, nor low-meat – so the health effects of these four evolutionary novel food ingredients can be investigated. However, some minimum recommendations of what foods to primarily eat should be made.

Diseases should include the "Diseases of Affluence", but not be limited to them:

• Obesity (doh!)
• Type 2 Diabetes
• Asthma
• Hypertension
• Gout
• Acne*, Dermatitis, Psoriasis, etc.
• Allergies (Hay Fever and the like)
• Cardiovascular Diseases
• Depression
• Anxiety
• Other neurological/psychological/mental/etc. health problems (e.g. Bipolar Disorder)
• Multiple Sclerosis (MS), cf. Terry Wahls
• ME/CFS

A pilot study for each disease should include at least 10 patients from that chosen disease.

The dietary advise should be followed for 3 months, possibly with an extension to 6 and 12 months.

Objective markers for each disease (e.g. weight for obesity) should be recorded as the primary disease makers by the investigators before the study, at 1 month, and after that at each 3-month-point. Surrogate markers should be recorded in addition, but not for the primary measurement of outcomes.

Patients should have a simple food and symptom diary. If possible, the patient should be encouraged to record disease makers, both objective (e.g. daily activity level with an odometer, daily weight) and subjective (e.g. perceived fatigue).

After a patient stops a diet (either at the end of study, or patient drops out), she/he should be (if possible) followed for another month with regards the aforementioned disease markers and symptoms.

If positive health effects from an Paleo Diet are found for one disease, follow-up studies could be further refined with an focus on individual components (e.g. only dairy, or dairy from pasteurized* milk).

There is a lot do and many pitfalls to avoid before such studies would get off the ground…

* As I traced my acne back to dairy from pasteurized milk (and to a lesser extent to eggs), studies finding an positive effect of avoidance of dairy could further look into the difference between raw-milk dairy and pasteurized-milk dairy.

Another Nail In The Coffin for the "Calories In = Calories Out" Theory

Dr. Briffa:

…

In this study, sedentary overweight and obese adults were randomised to one of three exercise groups for a period of 8 months.

1. aerobic exercise (treadmill, cross trainer machine, stationary bicycle) for a total of 12 miles a week at 65-80 per cent maximal intensity.
2. resistance training on 3 days per week designed to burn the same number of calories as the aerobic exercise of group 1.
3. both aerobic exercise and resistance training combined (group 1 exercise plus group 2 exercise)

The results revealed that both groups 1 and 3 lost weight and fat, and group 3 lost no more weight and fat than group 3 (despite doing twice as much exercise). Group 2 did not lose weight. All this led the authors to conclude that aerobic exercise is superior for weight loss. But what I (and perhaps other people) really want to know is just how effective the aerobic exercise was in terms of weight loss.

It turns out that individuals in group 1 lost a total of 1.66 kg (about 3.5 lbs) of fat. Remember, though, this is over an 8-month period, so the pounds were not exactly dropping off. Now, let’s factor in the amount of exercise the amount of exercise required to achieve this weight loss result…

Individuals exercised for a total of about 2 hours a week which means that the total amount of exercise over the study period came to about 70 hours. For each hour of exercise individuals lost about 1 ounce (or about 30 grams) in weight.

…

Case-Studies: Ketogenic Diet cures Bipolar Disorder

Ketogenic Diets and Bipolar Disorder: New Case Studies

One woman described her irritability going away and a sense of calm. Also "having my head screwed on straight--well, it's definitely worth giving up pie." She said her symptoms seemed better with a ketone level of 15mg/dl vs 5 mg/dl in the urine. The other woman noted that if she remained gluten-free, she felt much better, even though she had never been diagnosed with celiac disease.

Neither woman had any adverse consequences and they remained stable on the diet for 2-3 years at the time the paper was published.

So Bipolar "Disorder" seems to have nutritional causes (and mainly cereal grains and/or gluten, it seems). Hmmm, I wonder whether the psych* business will will take notice of that – it would kind of undermine their biases and their business after all, now wouldn't it?

Nice to see Emily Deans having a go at that:

Final note as I was in a bit of a hurry when I wrote the post at first… I did want to say there is a *lot* about these case study diets that could be therapeutic. No processed food, no sugar, lots of nutrients, lots of omega 3, low in gluten or gluten-free, likely low in histamine. The tracking of the ketones and one women's experience that the 15mg/dl ketone level felt more calming to her along with the sensible biologic mechanism makes the ketosis part plausible, but it is important to note these other possible factors.

"Blood test accurately distinguishes depressed patients from healthy controls"

Update: Some criticism below.

The initial assessment of a blood test to help diagnose major depressive disorder indicates it may become a useful clinical tool. In a paper published in the journal Molecular Psychiatry, a team including Massachusetts General Hospital (MGH) researchers reports that a test analyzing levels of nine biomarkers accurately distinguished patients diagnosed with depression from control participants without significant false-positive results.

“Traditionally, diagnosis of major depression and other mental disorders has been made based on patients’ reported symptoms, but the accuracy of that process varies a great deal, often depending on the experience and resources of the clinician conducting the assessment,” says George Papakostas, MD, of the MGH Department of Psychiatry, lead and corresponding author of the report. “Adding an objective biological test could improve diagnostic accuracy and may also help us track individual patients’ response to treatment.”

(via ProHealth)

Molecular Psychiatry? While I think this is genuinely credible scientific inquest of the biomedical variety, this somehow sounds like a joke to me: What do you get when you cross a profession that thinks childhood traumata can explain everything (if I may exaggerate a bit), with a profession that sees the world on a molecular level? People working on opposite ends, ignoring the "middle" and bound to be oblivious of the environmental factors that can cause disease. They should maybe throw in a genetic epidemiologist for good measure.

Human bodies are hierarchically organized, as with all living beings a reflection of their evolutionary history. The biochemical level, the genetic level, the cellular level (with its sub-divisions!), the level of the organs, plus how they evolved to "solve" problems in the context of the ever-changing environment. Unfortunately I can't find Rolf Löther's introduction into biology now to give a good quote from him here. He was using a quote along the lines that if you focus on one single hierarchic element (say, the molecular level), you will learn nothing if you not take the entire living being with its many hierarchical elements in account. And an living being makes only sense in its (evolutionary) environment, just like a boats makes only sense in water or a cars makes only sense in the context of some kind of way they selected for. And molecular biology seems like the attempt to find out what is wrong with the suspension of a four door sedan (is it the rate of the suspension? The damping?), while one is driving with 80 mph on a dirt track, instead of a paved road.

Still, I think they are on the right track (on a molecular level, harhar). Maybe I do them injustice, but alas, I doubt they will find out how environmental factors, like say our (neolithic, western) nutrition, can play into depression.

Without further prose from me, here is the abstract:

Assessment of a multi-assay, serum-based biological diagnostic test for major depressive disorder: a Pilot and Replication Study

G I Papakostas1, R C Shelton2, G Kinrys3, M E Henry4, B R Bakow1, S H Lipkin1, B Pi5, L Thurmond5 and J A Bilello5

1 Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
2 Vanderbilt University, Nashville, TN, USA
3 Cambridge Health Alliance and Harvard Medical School, Cambridge, MA, USA
4 Saint Elizabeth's Medical Center, Brighton, MA, USA
5 Ridge Diagnostics, Research Triangle Park, NC, USA
Correspondence: Dr GI Papakostas, Massachusetts General Hospital, Harvard Medical School, One Bowdoin Square, 6th Floor, Boston, MA 02114, USA.

Received 21 April 2011; Revised 14 July 2011; Accepted 7 November 2011; Published online 13 December 2011.

Abstract
Despite decades of intensive research, the development of a diagnostic test for major depressive disorder (MDD) had proven to be a formidable and elusive task, with all individual marker-based approaches yielding insufficient sensitivity and specificity for clinical use.

In the present work, we examined the diagnostic performance of a multi-assay, serum-based test in two independent samples of patients with MDD.

Serum levels of nine biomarkers (alpha1 antitrypsin, apolipoprotein CIII, brain-derived neurotrophic factor, cortisol, epidermal growth factor, myeloperoxidase, prolactin, resistin and soluble tumor necrosis factor alpha receptor type II) in peripheral blood were measured in two samples of MDD patients, and one of the non-depressed control subjects.

Biomarkers measured were agreed upon a priori, and were selected on the basis of previous exploratory analyses in separate patient/control samples.

Individual assay values were combined mathematically to yield an MDDScore.

A ‘positive’ test, (consistent with the presence of MDD) was defined as an MDDScore of 50 or greater.

For the Pilot Study, 36 MDD patients were recruited along with 43 non-depressed subjects. In this sample, the test demonstrated a sensitivity and specificity of 91.7% and 81.3%, respectively, in differentiating between the two groups.

The Replication Study involved 34 MDD subjects, and yielded nearly identical sensitivity and specificity (91.1% and 81%, respectively).

The results of the present study suggest that this test can differentiate MDD subjects from non-depressed controls with adequate sensitivity and specificity.

Further research is needed to confirm the performance of the test across various age and ethnic groups, and in different clinical settings.

So these were the markers they used:

• Alpha1 antitrypsin
• Apolipoprotein CIII
• Brain-derived neurotrophic factor
• Cortisol
• Epidermal growth factor
• Myeloperoxidase
• Prolactin
• Resistin
• Soluble tumor necrosis factor alpha receptor type II 

Update:

…
Although there were two depressed patient groups (n=36 and 34), there was only one set of controls (n=43); both patient samples were compared to it. This means the second, "replication", test was not fully independent of the first one. If the first finding was a fluke caused by the control group having weird results by chance, for instance, then the second study would just repeat the fluke.


The patients were significantly older, and with a higher BMI, than the controls. They did control for these variables, which is good, but this raises the question of whether these folks differed in other ways, that they didn't measure, and hence couldn't control for.

In both samples, the patients had a very significantly higher MDDScore than the controls (p less than 0.0001, both times). But in both cases, the difference in levels of EGF (epidermal growth factor) was almost as strong: p=0.0003 and p less than 0.0001, respectively. Other metabolites weren't far behind. Testing for EGF would almost certainly be cheaper than getting an MDDScore.

Finally, all these data demonstrate is that the test can distinguish between people with MDD and entirely healthy people. But how often are doctors going to need to do that? More likely, they'll want to distinguish depression from other things that are often confused with it, such as: bipolar disorder, anxiety disorders, chronic fatigue syndrome, bereavement, "stress", and all manner of physical illnesses e.g. thyroid problems. …

I think there is something wrong here

There is definitely something wrong here – and it looks like the CDC is not able to handle it. Bonus points for recording it, though.

Bill Lands on Omega-3 fatty acids

A shorter excerpt on YouTube and the original at the NIH (action starts around minute 12).

Bill Lands hits all the right talking points, but by Darwin, he does an awful presentation…

It's the environment, stupid!

Critics, on the other hand, have argued all along that both twin studies and family studies are unable to disentangle the potential roles of genes and environment. They have pointed out for decades that the validity of equal environment assumption (EEA) of the twin method is not supported by the evidence, and that the much more similar environments experienced by reared-together monozygotic (MZ) versus reared-together dizygotic (DZ) twin pairs confound the results of the twin method. Therefore, both family studies and twin studies prove nothing about genetics and their results can be completely explained by non-genetic factors. Most behavioral geneticists agree with this assessment as it relates to family studies, but continue to maintain that twin studies provide conclusive evidence that genes play an important role. Critics have also pointed to the massive methodological problems and untenable assumptions found in psychological and psychiatric adoption studies, as well as the major problems and environmental confounds in studies of purportedly reared-apart twins

And:

In study after study, applying GWAs to every common (non-infectious) physical disease and mental disorder, the results have been remarkably consistent: only genes with very minor effects have been uncovered (summarised in Manolio et al 2009; Dermitzakis and Clark 2009). In other words, the genetic variation confidently expected by medical geneticists to explain common diseases, cannot be found.

There are, nevertheless, certain exceptions to this blanket statement. One group are the single gene, mostly rare, genetic disorders whose discovery predated GWA studies2. These include cystic fibrosis, sickle cell anaemia and Huntington’s disease. … With these exceptions duly noted, however, we can reiterate that according to the best available data, genetic predispositions (i.e. causes) have a negligible role in heart disease, cancer, stroke, autoimmune diseases, obesity, autism, Parkinson’s disease, depression, schizophrenia and many other common mental and physical illnesses that are the major killers in Western countries.
…
This dearth of disease-causing genes is without question a scientific discovery of tremendous significance. It is comparable in stature to the discovery of vaccination, of antibiotics, or of the nature of infectious diseases, because it tells us that most disease, most of the time, is essentially environmental in origin.

Firstly, in my view, common diseases can not have its origin in genetic problems. And secondly, who says that common diseases (chronic, with presumably gradual onset and/or gradual build-up, like e.g. type 2 diabetes) can't have a infectious origin? I think nutrition is far more likley to be the culprit, but hey.

In a rare public sign of the struggle to come to terms with this genetically impoverished world-view, the authors of a brief review in Science magazine, Andrew Clark of Cornell University and Emmanouil Dermitzakis of the University of Geneva Medical School, Switzerland have been alone in stating the case even partly straightforwardly. According to them, the GWA studies tell us that “the magnitude of genetic effects is uniformly very small” and therefore “common variants provide little help in predicting risk” (Dermitzakis and Clark 2009). Consequently, the likelihood that personalised genomics will ever predict the occurrence of common diseases is “bleak”. This aim, they believe, will have to be abandoned altogether.

The first conclusion to be drawn from these quotes is that such directness implies that if the GWA findings are not finding their way to the front page the reason is not ambiguity in the results themselves. From a scientific perspective the GWA results, though negative, are robust and clear.

Most human geneticists view the GWA results somewhat differently, however. An invited workshop, convened by Collins and others, discussed the then-accumulating results in February 2009. The most visible outcome of this workshop was a lengthy review published in Nature and titled: “Finding the Missing Heritability of Complex Diseases.” (Manolio et al. 2009).

For a review paper that does not lay out any new concepts or directions, 27 senior scientists as coauthors might be considered overkill. “Finding the Missing Heritability”, however, should be understood not so much as a scientific contribution but as an effort to conceal the gaping hole in the science of medical genetics.

In their Science article, which was published almost simultaneously, Dermitzakis and Clark paused only briefly to consider whether so many genes could have been overlooked. Apparently, they thought it an unlikely possibility. Manolio et al., however, frame this as the central issue. According to them, since heritability measurements suggest that genes for disease must exist, they must be hiding under some as-yet-unturned genetic rock. They list several possible hiding places: there may be very many genes with exceedingly small effects; genes for disease may be highly represented by rare variants with large effects; disease genes may have complex genetic architectures; or they may exist as gene Copy Number Variants (CNVs). Since Manolio et al. presented their list, the scientific literature has seen further suggestions for where disease genes might be hiding. These include in mitochondrial DNA, epigenetics and in statistical anomalies (e.g. Eichler et al. 2010; Petronis 2010).

It is sad to see scientists working in the field genetics have so little grasp of evolution that they fail to see the evolutionary interdependence of genes and environment...