He who has learned, unlearns with difficulty.
—ancient Greek proverb
The more laws, the more offenders.
—ancient Latin proverb
Even a hare will insult a dead lion.
—ancient Latin proverb
Small favors conciliate, but great gifts make enemies.
—ancient Latin proverb
(Source of proverbs: There’s a Saying for That: PROVERBS from Around the World,edited by Bob Blaisdell, Dover Publications, 2013)
We have found additional reports in the literature, as far back as 2003,1,2 that warn of increased Alzheimer pathology in anticholinergic (antimuscarinic) drugs prescribed to treat “overactive bladder” in the elderly. These drugs do not have black box warnings about these disastrous potential side effects.
Although mildly effective in treating motor symptoms in Parkinson’s disease, but more often prescribed in these patients for bladder dysfunction, the use of antimuscarinic drugs has been shown to be associated with impaired neuropsychiatric and cognitive function. Clinical evidence suggests that M1 mAChR [M1 muscarinic acetylcholinergic receptor] antagonism may account for these unwanted side effects, as M1 AChR antagonists such as benztropine, orphenadrine, and trihexyphenidyl (Artane®) have been shown to increase amyloid plaque and neurofibrillary tangle densities similar to that found with Alzheimer’s disease pathology.
A 2003 paper1 reported on the autopsy findings for 120 neuropathologically confirmed Parkinson’s disease (PD) cases. The PD cases were divided into three subgroups depending on how long they had been using antimuscarinic drugs for movement or bladder control. “None” indicated no use of such drugs, short term use was less than 2 years, long term greater than 2 years. They also had two subgroups according to the use for 1–10 years of tricyclic antidepressants (also antimuscarinics).
As we indicated in the first part of this article (see it in the May 2015 Life Enhancementmagazine), one way to test for anticholinergic effects is whether or not a drug causes dry mouth. Tricyclic antidepressants do that. Not all drugs that cause dry mouth, however, are anticholinergics, so if you do experience dry mouth, you will need to check a reference to find out whether what you are taking has anticholinergic effects.
The results1 showed that there were no differences in Alzheimer pathology between the short-term use or no use (“None”) of antimuscarinics. However, plaques were more than twofold higher in the group chronically treated long term with antimuscarinics, tangles were twofold higher in the long-term treated as compared to the group exposed to no antimuscarinics. In the group treated with tricyclic antidepressants, plaques and tangles were more than twofold higher in the treated as compared to the untreated group though this did not reach significance and the authors note that depression itself may promote Alzheimer pathology. The authors conclude that their data are consistent with the possibility that prolonged use of antimuscarinic drugs “accelerates beta amyloidosis and senile plaque formation in the aging brain in subjects with PD.”
The commentary2 that discussed the above paper mentioned several anticholinergic medications used in the treatment of movement disorders (trihexyphenidyl, benztropine), urinary incontinence (tolterodine, oxybutynin) and dizziness (meclizine). The commentary notes that “[a]bundant evidence now implicates amyloidogenesis as a critical event in AD pathogenesis.” The authors then refer to evidence that muscarinic cholinergic stimulation can reduce amyloid beta formation in vitro and in vivo in animal studies, thus suggesting the way that antimuscarinics could be deleterious in AD. “The significance of these findings for the millions of healthy elderly patients taking anticholinergic drugs remains to be clarified.” They suggest that physicians prescribe these drugs cautiously and with frequent review and assessment of their benefits. We think that a strong warning should be required. When using a drug to treat a non-life threatening condition (urinary bladder incontinence), the acceptable potential downside should certainly itself be non-life threatening. That does not appear to be the case with anticholinergics for the treatment of urinary incontinence and we ourselves would avoid them entirely for this purpose.
We were amazed to see that, in the May 2015 Nature Neuroscience, a paper was published (Wan et al. Neural encoding of opposing strategy values in anterior and posterior cingulate cortex. pp. 752–9; commentary on pp. 616–7) that goes a very long way in supporting the notion that the brain is made up of discrete areas that, in decision-making, come to a decision by a consensus process, with competition between the differing areas as to what the areas would prefer as a decision. In other words, the idea that our personalities are not homogeneous, there really may be different characters inside our heads, and there is a continuous process of negotiation going on between these characters to produce a single decision that includes “everybody” in the decision-making process. What was nuts yesterday could be scientifically respectable today!
The way the authors of the commentary put it: “This result speaks to the idea that decisions may be realized via a distributed consensus, a viewpoint that argues that no single brain area is critical in decision-making, but that decisions instead emerge via competitions occurring in many brain regions.”
The process called “automatic writing,” which, since William James’A early writings on the subject (1885–1899), was used to describe how an author of fiction could write a story and just let the words flow effortlessly—it seems as if the text writes itself—without consciously interceding in the process would be entirely consistent with this viewpoint of distributed consciousness. The flow is where you allow the different brain areas to interact, watching them while they do this rather than directing them via central control. You might have to be a fiction writer to have had the experience of writing this way, with characters seeming to emerge spontaneously from the subconscious.
This dissociation of the consciousness into mutually exclusive parts is evidently a phenomenon destined, when understood, to cast a light into the abysses of Psychology.
Getting to the actual experiments described in Nature Neuroscience: The researchers used a Japanese game called shogi in which the players make decisions concerning moves that have either an offensive or a defensive purpose. The game is well suited to this, it is said, because the moves are so clear as to whether they are defensive or offensive. So while the players are making these decisions/moves, they are followed by fMRI to identify, which parts of the brain are interacting. The result was that they found very specific areas worked together when you made a defensive decision and very specific other areas worked together when you made an offensive decision. Posterior cingulate cortex reflected the subjective value of offensive strategies, while rostral anterior cingulate cortex activated as a function of the subjective value of the defensive strategy. These two regions interacted with the dorsolateral prefrontal cortex, which is said to be implicated in cognitive control. The commentary’s authors put it this way: “... the functional connectivity results of Wan et al1–2 suggest that, in addition to distributed competition, changes in connectivity could be crucial for understanding how flexible choices could be implemented.”
This is a revolutionary view of human consciousness that appears now to have emerged from science fiction to reach the pages of a highly respectable scientific journal.
Whoops. It may come as a shock to some people but genetically modified (GM) crops are not just created by humans, but also occur naturally. A news report in the 23 April 2015 Nature (pg. 410) reports on the discovery of a sweet potato cultivar that had apparently been infected by Agrobacterium bacteria in the past. These bacteria infect plants and transfer DNA into their host’s genome, which is how the genes ended up in the sweet potato. (In fact, modern genetic engineering commonly uses these bacteria as vehicles to transfer genes into plants they want to genetically modify.) The original paper on this subject was published in the Proceedings of The National Academy of Sciences,2 in which the authors concluded, “This finding could influence the public’s current perception that transgenic crops are ‘unnatural.’”
SEE BELOW IN THIS SECTION ON CHOLINE:
THE VAGUS NERVE, WITH ITS MAJOR NEUROTRANSMITTER BEING ACETYLCHOLINE,
WHEN ACTIVATED IN WOMEN CAN PRODUCE O R G A S M!
Are You One of the 92% of the Population
That Does Not Consume the Adequate Intake of
Choline Recommended by the Institute of Medicine?
CHOLINE is an Essential Nutrient But Much More
An article in a food industry trade journal (Hutt. "Choline: the Silent Deficiency," Prepared Foods, Jan. 2015) warns that Choline is the “Silent Deficiency” and cites Institute of Medicine data from 2007 to 2010 showing that 92% of Americans are not getting the recommended AI (adequate intake) of choline, 550 mg/day for men and 425 mg/day for women (more is recommended in the case of pregnant and lactating women). The article points out the opportunity for the food industry to “do well by doing good” (our words, not the article’s) by fortifying foods with choline. As they explain, the FDA allows a claim of a “good” source of choline for a product containing 75 mg of choline chloride or 137.5 mg of choline bitartrate per serving. To be permitted to say your product is an “excellent” source of choline, the FDA requires that the product contains twice this much per serving. The article goes on from there to discuss a number of health benefits from taking choline, typically (as in most trade publications) providing no references to the scientific literature on choline! Incredibly, the article claims that choline sales are not reported by companies that track the supplement market other than Nielsen/SPINS, which reported the combined sales of choline and inositol in 2012, with these sales in natural/mass channels reported to reach an unbelievably tiny $428,000. What gives? How can a nutrient as important as choline and ingested at such an officially estimated meager level by most Americans have escaped notice?
Chances are that you are not getting enough choline in your diet and, unless you take a choline supplement, you are not ingesting the AI recommended by the Institute of Medicine, an amount that (on the basis of the scientific literature) is on the low side of what would be optimal. Here are a few of the important health benefits provided by choline, some of which you have undoubtedly read about but others you are likely to have never heard of. You should know about these if you are not yet taking a choline supplement.
NOTE TO OUR READERS: In order to keep this newsletter from expanding beyond the bounds of a reader’s reasonable time to spare, we have not included much of what we had written up on beneficial effects of choline. More on that in a later newsletter!
CHOLINE FOR MEMORY AND LEARNING
One of the oldest known and studied effects of the cholinergic nervous system is its relation to learning and memory, with one early influential paper from 1974.1 A later paper2 showed that acetylcholine in the forebrain regulates adult hippocampal neurogenesis and learning. A recent paper3 reported that in a community-based population of nondemented individuals, participants in the Framingham Offspring Cohort (744 women and 647 men aged 36–83), higher concurrent dietary choline intake was related to better cognitive performance.
A MAJOR REGULATOR OF INFLAMMATION
INFLAMMATION, A RECOGNIZED CAUSE OF
CANCER, CARDIOVASCULAR DISEASE, AGE-
ASSOCIATED DISEASES, AND
An early (2007) review paper1 on the cholinergic antiinflammatory pathway quoted Claude Bernard who thought that health was due to equilibrium in the “milieu interieur” by a “continuous and delicate compensation, established with the most sensitive of balances” (“Lessons on the phenomena of life common to animals and vegetables”). This early view foresaw in a simple sketch the new understanding of health that we have today and in which the cholinergic antiinflammatory pathway plays a major role in maintaining that “balance” of which Claude Bernard wrote.
The review1 then discussed the emergence of the “cytokine theory of disease” in which defensive molecules, the inflammatory cytokines, produced by the immune system can cause the signs, symptoms, and damaging after effects of disease. The cholinergic antiinflammatory pathway is important in preventing the damage that can be caused by massive releases of these cytokines in response to various diseases. In one example, a major cytokine, TNF-alpha (tumor necrosis factor alpha) is released in response to gram-negative bacteria but excessive amounts of that release can cause septic shock. With the problem of antibiotic resistance increasingly making it difficult to treat septic shock, this condition has a high mortality rate.
The Vagus Nerve
An early discovery was that the vagus nerve served as a conduit for signals from the cholinergic nervous system to modulate the production of inflammatory cytokines. For example, the review1 notes that, “an accidental discovery revealed that intracerebral administration of a molecule that inhibited TNF production also increased efferent vagus nerve activity and inhibited inflammation outside the CNS.” The mechanism responsible for this effect was found to be acetylcholine, the major vagus nerve neurotransmitter. Acetylcholine signals the inhibition of cytokine synthesis via the vagus nerve.
Keep in mind that this was an early review on a research area about to explode, and it continues to expand at a dramatic pace today. The review points to scientific evidence suggesting that signaling via the vagus nerve can affect many aspects of human health, noting specifically that sudden death, increased morbidity and mortality following cardiac surgery in hostile or depressed patients, and increased death rates in patients with sepsis or organ failure have been linked (as of the date this paper was published and supported by new evidence since then) to decreased vagus nerve activity. These are just three examples out of many medical conditions in which deficient vagus nerve activity plays an important role.
One of those mysteries that remains unexplained is noted at the end of the review, where it is mentioned that clinical antiinflammatory responses may be linked to the fat induced stimulation of the cholinergic antiinflammatory pathway as in the case of rats, using fish oil, soy oil, olive oil or other fats. And, now (to the review, “now” is 2007), the review says, a major source of systemic TNF during lethal challenges is the spleen, the source of Galen’s black bile. The review finishes by asking: How did the ancient Greeks know? (It may have simply been that the ancients noticed that when people had this black gunk emerging from the spleen, they were unlikely to survive.)
Choline Attenuates Immune Inflammation in Patients with Asthma
A 2010 paper2 reported that, in a randomized study, 76 asthma patients were treated with 1500 mg of choline chloride twice daily + pharmacotherapy or with pharmacotherapy alone (pharmacotherapy was inhaled steroids and long-acting beta adrenergic agonist), with short acting beta adrenergic agonist given as needed. There was a significant decrease in symptom/drug use score of patients receiving choline from baseline, but no significant change in the symptom/drug use score from baseline in the standard pharmacotherapy alone group patients. Choline was also reported to significantly decrease peripheral eosinophil counts and Th2 response (the immune system activity that occurs during active disease) such as lower IL-4 levels and reduced TNF-alpha levels in the choline treated patients.
These results indicate activation of the cholinergic antiinflammatory pathway by treatment with choline in human asthma patients.
In an early study (2008)3 in the runup of research following the discovery of the cholinergic antiinflammatory pathway, a cross sectional survey of 1514 men and 1528 women with no history of cardiovascular disease was carried out (the ATTICA Study). Compared with the lowest tertile of choline intake (<250 mg/d), participants who consumed >310 mg/d had, on average, 22% lower concentrations of C-reactive protein [with high levels linked to poor cardiovascular health], a commonly used measure of inflammation, 26% lower concentration of IL-6 (an inflammatory cytokine), and 6% lower concentration of tumor necrosis factor alpha, another inflammatory cytokine. (Similarly, those who consumed >360 mg/d of betaine had an average of 10% lower homocysteine levels, 19% lower C-reactive protein, and 12% lower concentrations of TNFalpha than did those who consumed <260 mg/day.)
This was an associational study, thus did not provide evidence for cause and effect. But it was an early study and much more was to come in later research to support these findings as having causal implications.
A 2014 paper4 reported that chronic stimulation of the vagus nerve improved left ventricular function in a canine model of chronic mitral valve regurgitation. As the authors explain, autonomic dysregulation, failure of the systems regulating (for example) respiration and heart function, is characterized by activation of the sympathetic nervous system (adrenergic) and declining activity of the vagus (cholinergic) nerve and is an important contributor to the progression of heart failure. “One of the key features of chronic heart failure (CHF) is the autonomic sympathetic/parasympathetic (adrenergic/cholinergic) imbalance, which is usually characterized by excessive sympathetic drive accompanied by parasympathetic withdrawal.” They further explain that the use of inhibitors of sympathetic activity (such as beta adrenergic receptor blockers) is one of the ways that has been used to treat this problem but, “[o]n the other hand, reversing the sympathetic/parasympathetic imbalance by enhancing parasympathetic activity through vagal nerve stimulation (VNS) becomes an obvious potential therapeutic approach.”
In this study, dogs had mitral valve regurgitation induced experimentally and were treated with electrodes that stimulated the vagus nerve. The results showed improved contractile function and significant improvement (that is, reduced expression) of inflammatory markers such as C-reactive protein.
New Study Reports Genetic Differences Between Ethnic and Racial Groups in Amount of Choline Required
The Institute of Medicine of the National Institute of Health defines the “adequate intake” (AI) for choline as 550 mg/day for men and 425 mg/day for women. Many Americans are said not to ingest the AI for choline, which can result in fatty liver, liver damage, muscle damage, and may promote eventual dementia. In this new paper,1 scientists report that genetic differences (identified as single nucleotide polymorphisms, SNPs) between ethnic and racial groups indicate that the amount of choline required will differ between these groups. Seventy-nine humans were fed a low choline diet and 200 SNPs in 10 genes related to choline metabolism examined to determine associations with organ dysfunction. Some people on low choline diets presented with muscle damage, others with liver damage.
As the researchers note, the setting of dietary recommendations has not (or has rarely) considered genetic diversity in the need for daily intake of nutrients. They suggest that the simplest and safest way to deal with this is to set dietary recommendations at a level high enough to meet the needs of those with the greatest requirements. That may indeed be the simplest and safest way, but what these researchers probably have not considered is that dietary programs (school lunches, food stamps, etc.) are based upon these dietary recommendations and setting the level high enough to meet the needs of those with the greatest requirements would be quite a bit more expensive for these government programs than setting it at a level that would meet the requirements of the average American. Moreover, when you think of the case of choline, the foods that can supply it (eggs, dairy, and fish, for example) tend to be on the expensive side or perhaps on the yucky side (liver).
Add to the genetic variation the decreasing ability of older persons to transport choline into the brain2 and it appears likely that a significant fraction of the populace may require a higher intake of choline than that recommended by the Institute of Medicine of the National Institute of Health, where experiments on nutrition are usually done on college students. A recent paper4 showed that a donor of peroxynitrite, a potent oxidant, as well as other oxidants, caused rapid dose-dependent inhibition of the sodium-coupled high-affinity choline transporters, suggesting one possible mechanism for the decreased choline transport in older persons.
It has also been reported that choline acetyltransferase, the enzyme needed to convert choline to acetylcholine, is inhibited by exposure to excitatory amino acids.3 Taurine and the antiinflamatory compounds naturally formed from it, taurine bromamine and taurine chloramine, are able to provide protection against these inflammatory excitatory amino acids and, hence, are likely to help prevent the suppression of choline acetyltransferase formation resulting from exposure to excitatory amino acids.
Central Fatigue May Be Associated with Low Activity of the Vagus Nerve and Hence of Low Parasympathetic (Cholinergic) Nervous System Activity
Central fatigue is chronic fatigue, lasting six months or more, characterized by a persistent sense of tiredness, has been reported to generally correlate poorly with traditional markers of disease.1 “In general, hypoactivity of the hypothalamic-pituitary-adrenal axis, autonomic nervous system alterations characterized by sympathetic overactivity and low vagal tone, as well as immune abnormalities, may contribute to the expression of CF [chronic fatigue].”1 “Central fatigue generally correlates poorly with traditional markers of disease and is frequently associated with other psychosocial factors, such as depression, sleep disorder, anxiety, and coping styles, which suggests that dysregulation of the body’s stress systems may serve as an underlying mechanism of CF.”
For example, the authors explain that glucocorticoids, stress hormones, play an important role in the regulation of the sympathetic nervous system (SNS), restraining SNS responses after stress and under resting conditions. The paper suggests that although glucocorticoids are often considered immunosuppressive, it may be more accurate to call them immune modulators and that they can have important antiinflammatory effects via negative feedback to the immune system’s production of inflammatory cytokines. Thus, like the cholinergic antiinflammatory pathway, glucocorticoids help to keep the sympathetic nervous system under control.
Despite many attempts to pin down CF to specific immune abnormalities, to hypercortisolism or hypocortisolism, results have been inconsistent. However, the paper reports that a recent and robustly designed study2 showed that “fatigue not only in its severe and chronic form, as in CFS [chronic fatigue syndrome], but also in its milder forms, is associated with increased inflammation, as indexed by elevated plasma C-reactive protein levels and white blood cell counts, even after adjusting for depressive status. This study further supports the notion that the symptom of fatigue, rather than a diagnosis of CFS itself, may be what is clinically associated with inflammation.”
A 2005 paper1 reported a study by fMRI of the brain regions activated during orgasm by vaginal cervical mechanical self-stimulation in women with spinal cord injury. A number of areas of the brain were activated during orgasm, with the authors concluding that, “the Vagus nerves provide a spinal cord-bypass pathway for vaginal-cervical sensibility and that activation of this pathway can produce analgesia and orgasm.” The authors comment that some patients, both men and women, who have spinal cord injury described an intensely sensitive to the touch area of skin near their injury and which when stimulated in the right way, can produce orgasm. Just an interesting little tidbit here. Too bad they didn’t try choline supplementation in some of these patients.
The March 2004 USDA Database for the Choline Content of Common Foods tells you that the highest food sources for choline include egg yolk, raw, fresh (682.4 mg choline moiety/100 g of food), chicken liver, all classes, cooked, pan-fried (308.5 mg choline moiety/100 g of food), veal, variety meats and by-products, liver, cooked, pan-fried (411.0 mg choline moiety/100 g of food). Perhaps a more palatable source is one egg, whole, cooked, fried (272.6 mg choline moiety/100 g of food), while a hardboiled egg contained 225.2 mg choline moiety/100 g of food.
“Choline moiety” is choline contributed by free choline, phosphatidylcholine, phosphocholine, glycerophosphocholine, and sphingomyelin.
Inflamed By Love
A poem by Stendhal (Marie-Henri Beyle) includes this line:
“Love is like a fever which comes and goes quite independently of the will.”
Curiously, it appears that, although Stendahl could have known nothing about inflammatory cytokines, love is very likely to be like a fever in the sense of representing a state of systemic inflammation.
The researchers who published a recent paper1 were studying the possibility that social interactions of various types, particularly negative and competitive interactions, would be associated with heightened proinflammatory cytokines. Subjects were 122 healthy young adults who kept diaries for 8 days that described positive, negative, and competitive social interactions. Within 4 days they were subject to the Trier Social Stress Test in which oral fluids were collected before a laboratory-imposed stressor and at two time points after the stressor and analyzed for inflammatory markers.
The results showed that leisure time competitive activities did not correlate with increased proinflammatory cytokine levels, but competing for another’s attention, such as (the paper states this explicitly) a ROMANTIC PARTNER is correlated with increased proinflammatory cytokine levels as was academic/work-related (i.e. bringing home the bacon) competitive events. The authors propose that the leisure time competitive activities may be perceived as challenging rather than threatening, whereas competing for the attention of a romantic partner or competition in an academic/work-related situation might be considered threatening.
The authors’ analysis of the results are also interesting and consistent with what we know about the regulation of inflammation. They note that social stress increases sympathetic nervous system activity—for example, rodent models of social stress have been shown to increase sympathetic nervous system (SNS) activity, where SNS is based upon adrenergic neurotransmission, and to decrease parasympathetic activity (based upon cholinergic neurotransmission), which is inversely related to inflammation. The authors note, however, that only 522 competitive events (or an average of 4.28 per person) were reported and it would be helpful for looking at differences between different subtypes of competitive events if more participants were included.
Perhaps, then, the state of love that Stendahl called a “fever” might be mitigated by taking a supplement that increased parasympathetic nervous system activity, thereby reducing the hyperinflammatory state that love seems to induce in many as a response to the social stress it represents. It may seem strange to think of romantic “love” as a dysfunctional state that might be improved with appropriate “treatment” (in this case, a choline supplement or a cholinesterase inhibitor such as galantamine, which might help by increasing parasympathetic nervous system activity) but to many (if one is to judge by the book of love poems2 by famous poets that included the Stendahl poem the state of love can be almost akin to insanity, with alternating periods of ecstasy and agony. In another place (forget where at the moment), rock star Ted Nugent was quoted as saying that love was like a “tire iron,” presumably meaning that his experience of it was a bit overwhelming. Try a choline supplement, Ted, it might make the experience less stressful, more like a rubber mallet than a tire iron.
A couple of speculations: We wonder whether what is called “lovesickness” might be similar to the form of sickness behavior observed in animals and humans when they are in an inflammatory state with high levels of proinflammatory cytokines. One other oddity is that prolactin, another stress hormone that has proinflammatory effects,1 is released in large quantities during orgasm, adding yet another twist to the relationship between romantic love, sex, and inflammation.