Thursday, August 11, 2005

CNS Update: Sleep Medicine

Michael Rack, MD, (blog: sleepdoctor) scooped me on this one: ramelteon (formerly named TAK-375, now called Rozerem® - Takeda Pharmaceuticals North America) was recently approvedFuture Headquarters Campus for Takeda Pharmaceuticals by the USA FDA for treatment of insomnia.  Check his post for details.  Basically, it acts on melatonin MT1 receptors, so it should be nonaddictive and should be extremely safe in overdose.  That latter point is of great interest to psychiatrists.  

Melatonin is a popular "natural" substance used to treat insomnia.  Success is highly variable.  It helps some people, but it seems that most people get no benefit.  There is no FDA quality control for nutritional supplements, so some OTC versions of "melatonin" actually contain no active ingredient.  That is one reason why traditional MD's tend to be skeptical of such products.  Plus, there was a small case series of patients with bipolar disorder who did not improve when treated with melatonin; one developed a free-running (unentrained) sleep-wake cycle after melatonin withdrawal.  I hope Takeda is watchful for this kind of thing in their post-marketing surveillance; it's the kind of thing that is unlikely to show up in phase I-III studies, but may show up when a larger, more heterogeneous population is exposed.

Practical matters aside, it is time to move on the the fun part: pure, preclinical, science, with no obvious practical application.  One such thing that caught my attention recently was this:
Regulation of brain-derived neurotrophic factor (BDNF) during sleep apnoea treatment
R Staats, P Stoll, D Zingler, J C Virchow and M Lommatzsch
Department of Pneumology, University of Rostock, Germany

Background: Patients with obstructive sleep apnoea syndrome (OSAS) often display persistent cognitive dysfunction despite effective treatment with continuous positive airway pressure (CPAP). Brain-derived neurotrophic factor (BDNF) is a key mediator of memory and cognition, but its regulation in OSAS and during CPAP treatment is unknown.

Methods: Serum and plasma BDNF concentrations, BDNF secretion by peripheral blood mononuclear cells, and overnight polysomnography were evaluated in 17 men with newly diagnosed OSAS (as defined by a respiratory disturbance index of >10/hour with >70% obstructive events and corresponding daytime symptoms) and 12 healthy control men. In the patients all the parameters were monitored after 1 night and 3 months of CPAP treatment.

Results: There was no significant difference in baseline serum BDNF, plasma BDNF, or spontaneous BDNF secretion by peripheral blood mononuclear cells between untreated patients and controls. After 1 night of CPAP treatment there was a steep fall in median serum BDNF (from 18.0 ng/ml to 4.1 ng/ml) and plasma BDNF (from 58.7 pg/ml to 22.0 pg/ml) concentrations. Following 3 months of treatment BDNF concentrations did not return to baseline. In contrast, BDNF secretion was not suppressed by CPAP treatment.

Conclusions: Patients with untreated OSAS have normal serum and plasma BDNF levels. CPAP treatment is associated with a rapid decrease in serum and plasma BDNF levels which may reflect enhanced neuronal demand for BDNF in this condition.
This is one of those really cool situations in which a biomarker is normal in both the diseased people and the normal people, but becomes abnormal when the patients are treated.  This is not what one would expect, ordinarily.  The authors hypothesize that this may reflect an increased need for BDNF in the patients with OSA.  

In commentary on Medscape (Free registration), the authors state:
Dr. Marek Lammatzsch and colleagues at the University of Rostock note that BDNF has been shown to be essential for cognitive function and consolidation of memory. It has been speculated that the interplay between sleep and cognition may involve BDNF.

Despite successful CPAP treatment, they add, many sleep apnea patients continue to display persistent cognitive dysfunction. To investigate the effect of CPAP on BDNF, the researchers studied 17 men with sleep apnea and 12 healthy controls. [...]

The researchers hypothesize that "this phenomenon reflects increased neuronal demand for BDNF during treatment, since neurons can acquire peripheral BDNF to change neuronal activity and synaptic transmission."

Dr. Lammatzsch told Reuters Health that "deficits in memory and learning often persist even after sleep restoration in patients with sleep apnea. Our observations open the door to a completely new understanding of this condition and might thus lead to a specific therapy in the future."
I will state again, that often nonscientist-journalists conclude their articles with a statement like this: "...might thus lead to a specific therapy in the future..."  I assume they do that so that the reader gets the impression that the research might have some practical significance.  Personally, I deplore this practice, because the implication is that research has to have a practical application in order to be important.  This is a disservice to the public.  Sure, it would be great to find a way to restore cognitive function to normal in those patients with OSA who continue to have problems even after successful implementation of CPAP, but that is not why the study is important.  

The thing is, there are a zillion things we would need to figure out before having any hope of developing something clinically useful, and even then, it probably would take about 10-20 years to get it to market.  

First, we would have to figure out exactly why BDNF goes down when patients are treated, and find out whether it eventually goes back toward normal.  We would have to figure out exactly what regulates the level of BDNF.  We would have to find out if anything dreadful happens to people if their level of BDNF is increased artificially.  We would have to find a practical way to increase it, and see if it actually helps anyone.  

Interestingly, we already have at least a partial answer to one of these questions, uncovered by an undergraduate student at UCLA:
The Role of Serotonergic and Noradrenergic Systems in the Regulation of BDNF Expression. Autumn Ivy, (Amelia Russo-Neustodt), Department of Biology, California State University, Los Angeles
Depression, aggression, agitation, and apathy are among the most common and problematic systems in neurodegenerative diseases such as Alzheimer's disease (AD). Brain-derived neurotrophic factor (BDNF), which enhances the growth and maintenance of various neuronal mechanisms, is diminished in the brains of AD patients. Animal studies have suggested that BDNF mRNA levels are increased by physical activity in the rat hippocampus. The aim of this study is to determine whether the 5-HT and/or the NE systems are involved in the up-regulation of BDNF expression occurring with exercise. Rats were treated with either Propranolol (2 mg/kg), which blocks the NE receptors, or Ketanserin (5 mg/kg), which blocks serotonin 5HT-2 receptors. At the same time, rats underwent voluntary exercise via a running wheel. BDNF mRNA levels were quantified in the hippocampus by in situ hybridization and computer densitometry. The NE receptor-blockade agent Propranolol appeared to reduce the up-regulation of BDNF mRNA normally expressed, suggesting that the activation of the NE system may be important in BDNF up-regulation. On the other hand, the serotonergic system receptor-blockade agent Ketanserin did not attenuate BDNF expression, which suggests the possibility that the 5-HT system is not involved in the observed BDNF regulation. An understanding of the mechanism of BDNF up-regulation could lead to the development of faster acting and more effective therapeutic approaches to AD.
So it appears that BDNF, at least the BDNF mRNA, is increased by exercise, at least in rat hippocampus, and that norepinephrine (NE) may play a role.  We also know that plasma norepinephrine is increased in untreated OSA patients.  So perhaps the drop in BDNF after treatment of OSA reflects a normalization of plasma NE.  To my mind, these findings indicate that we are looking at a complex system that does not necessarily act the way one's intuition might suggest.  

There could be important clinical benefits to increasing BDNF, as indicated by this Wikipedia snippet:
Exposure to stress and the stress hormone corticosterone has been shown to decrease the expression of BDNF in rats, and leads to an eventual atrophy of the hippocampus if exposure is persistent. Similar atrophy has been shown to take place in humans suffering from long-term depression. On the other hand, voluntary exercise, caloric restriction, intellectual stimulation, and various treatments for depression (such as antidepressants and electroconvulsive therapy) strongly increase expression of BDNF in the brain, and have been shown to protect against this atrophy.

Various studies have shown possible links between low levels of BDNF and conditions such as depression, Obsessive-compulsive disorder, Alzheimer's disease, Huntington's disease, and dementia, though it is still not known whether these levels represent a cause or a symptom.

If it does improve cognition, then we have to deal with the thorny ethical issue of whether it should be given to non-diseased persons who want to improve their cognition.  

However, given the complexity of the system, if anyone is planning on artificially manipulating BDNF levels in actual humans, it sure would be nice to understand the entire system beforehand.  Obviously, if treating something life-threatening such as Alzheimer disease or Huntington disease, a little risk would be no big deal.  But for treatment of depression, or residual cognitive impairment in treated OSA patients, we would want to see a firm assurance of safety.  It is hard to get that kind of assurance until the entire system is understood.

Therefore, the reason the Staats et.al. study is important is that it brings us one step closer to understanding a complex system that may play a role in many disease states.  If any actual treatment is found, that would be icing on the cake.

Lest all this neurochemisty lead us to forget why sleep is so important:
Sleep sleep sleep
deep magnificent sleep
cradles me like
a mother holding
her newborn
for the first time.
I close my eyes and feel
the warm sensation
of precious pure sleep
immortal sleep outside
of a mixed up world.
Sweet vanilla scent
from dreams of beauty
holding me forever,
brings me everything
I need to stay a
sleep sleep sleep.

-- Charles Lara

Categories: science, sleep disorders, neurochemistry
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Sunday, August 07, 2005

Antidisestablishmentarianism In Action

What does antidisestablishmentarianism mean?  
[...] pick up the Oxford English Dictionary. Turning to page 59, we find that antidisestablishmentarianism is indeed a word. The definition is as follows: “Properly, opposition to the disestablishment of the Church of Bush England, but popularly cited as an example of a long word.” Catching the irony here? [...]
We will try to catch the irony.

If one were to read an essay (Darwin's Compost) that decried the influence of "the elite", meaning scientists and everyone else the author doesn't like, you might expect to find the essay on a site called 'Humility in Action,' or perhaps 'The Washers of the Feet.'  Instead, it appears on the pompously-named site "The American Thinker".

This story, while ludicrously biased, contains a sign of hope: it is a measure of the elite establishment’s fear that the Darwinian grip on culture is slipping. In the elite’s frantic attempt to protect their shrinking scientific turf, they must insist on a “scientific consensus” – the phrase the Washington Post earlier this summer cited to editorialize against the showing of an Intelligent Design documentary at the Smithsonian – that doesn’t exist, and they must treat any deviation from this fictional consensus as evidence of kookery. This politically correct policing of conservative dissent is getting more aggressive because that dissent is spreading rapidly, and to precincts the elite assumed they had tamed.
I won't bother to fisk the anti-anti-Intelligent Design essay itself, that task being well beneath my elitist prétentions.  Rather, I will try to explain to my humble antidisestablishmentarianist friends why scientists and other thinkers are upset by Mr. Bush's proclamation that Intelligent Design should be taught in schools.  And why it is so dangerous.

Chris, posting on his excellent blog Mixing Memory, which I found via a link on Follow Me Here, comments on the roiling of the ID controversy:
But, and that's a big but, there does seem to be something somewhat disturbing going on here, of which Bush's remarks are only a symptom.
I take a similar view: Bush's remarks are only a symptom.  However, my diagnosis is a bit different than Chris'.  He is troubled by the notion that what is taught in school could be determined by public opinion about what constitutes valid science.  Indeed, that is a problem.  Personally, though, I think the bigger problem is that Bush's statements follow a pattern.  The Republican hijackers have included support for ID as part of a strategy to pollute the American political system.

The danger comes, no so much from the specific case of ID, but from what it represents.  The notion of teaching ID in a science class, presented as a reasonable alternative to evolution, is an example of a political tactic that appears to be part of a larger strategy.  

Let me take a moment to clarify my position: I am not a believer in "the vast right-wing conspiracy."  I do think there is a right-wing conspiracy; I think the conspiracy is rather small.  I am one of those who thinks that the Republican Party has been hijacked, not by a vast conspiracy, but by a minority of people who make my elitist pretensions look like Dorothy's scarecrow.  

My elitist pretensions

To clarify further my position: I have no beef with those who choose to believe in Intelligent Design.  But I really don't want ID to be presented as an alternative to a valid scientific body of knowledge.  As  I have alluded, I think that it is dangerous to do so.  

I would like to think that I am not, like Dorothy's scarecrow, seeing danger from every little spark.  Indeed, I've been known to take a risk or two.  

Corpus Callosum astride the San Anreas f
Corpus Callosum astride the San Andreas fault

I climbed that mountain just like Tom Cruise in the second Mission Impossible...  

My mission today is to explain the what the Republican hijackers are doing.  It is subtle and clever; difficult to see clearly: it is a tactic that obscures itself.  All politicians do it, so I am not picking on Republicans here.  I think America would be a better place if everyone would stop doing it.  The Republican hijackers, though, are pushing it farther than anyone else in recent history.

To understand this tactic, we first must take a couple of little detours.  First, into the land of Psychology.  The human brain has numerous sensory inputs, all of which are active all of the time.  There is much more information that the conscious mind could ever process.  As a result, most of the information is filtered out as being irrelevant, not salient.  

My favorite example is this: in July 1990, I began working in a building in Ann Arbor, on the north side of the Broadway bridge.  I lived south of there, so I drove over the bridge often.  One day, I noticed that there was a sign there, warning that the bridge might be icy.  Naturally, I noticed it on the first cold, wet day that I drove over the bridge.  In July, I hadn't noticed it; it was irrelevant.  On the day that my brain decided it was relevant, I noticed it.  

This is the fundamental principle used by magicians, who are adept at manipulating the perception of salience.  Likewise, politicians have a similar aptitude.  

The process in the brain, of sifting through the mass of information presented by the sensory system, and picking out the bits that are important, is enormously complex.  Yet we all do it, all the time, mostly without thinking about it on a conscious level.  
Our next detour goes into the land of Information Theory.  Consider for a moment the concept of signal to noise ratio:

Ignore this

(Ignore the formula above; it is just a pretentious decoration.  I don't actually understand it, and it is irrelevant anyway.)  

In common usage, signal to noise ratio describes the ratio of useful information to false or irrelevant information.  Recall that the brain is constantly flooded with information, most of which is irrelevant.  Noticing the relevant bits is challenging enough, even if all you are doing is driving over a bridge.  If you have to do something that is really complex, such as electing a President, it is likely that you will not be able to notice, assimilate, and process all of the relevant information.  And the more noise there is, compared to the amount of relevant signal, the harder it gets.  

That is not a particularly new concept.  We all get flooded by noise during any campaign, and we all get annoyed by it.  Again, all Parties do it, and again, America would be a better place if they would stop doing it.  It is part of the Republican hijacker strategy, but it is not the really devious part.  

The devious part is this: after increasing the signal to noise ratio, they subvert the filtering process.  

All sensory input is suspect; that is, we know, right from the start, that some of it is false.  In order to filter out the false stuff, we use the concept of reasonable doubt.  As the bits of information come in, they are organized into packets: "that's a chair," "that's a ham sandwich," etc.  The packets then are examined for reliability.  You can't filter out all the packets for which there is any doubt about their reliability, because that would filter out everything.*  Instead, you have to let packets through the filter if the doubt about their reliability is not reasonable.  

Each person has her or his own way of determining the reasonableness of a doubt.  Each person's threshold for reasonableness is susceptible to manipulation.  The Bush administration is doing exactly that.  They do so by giving credence to individuals and small groups that promote administration-friendly positions despite have either little or no solid evidence.  

The fact that the current administration does this extensively and methodically has been well documented by the Union of Concerned Scientists (1 2 3) and by US Rep. Henry Waxman (1 2).  Also see my prior posts (1 2 3).

Back to the point.  This is the main point of the entire post:  When the President portrays ID as having some scientific validity, and when he gives equal credit to the few scientists who disagree with the notion of global warming, he manipulates people's threshold for reasonable doubt.  Suddenly, all scientific findings are open to doubt.  

The fact is, all areas of science, and all areas of human endeavor, have at least some controversy.  If we all were to adopt Bush's proposed threshold for reasonable doubt, nothing would ever get done; no conclusions ever would be drawn.  If any decisions were made, they would be made solely on the basis of charisma and persuasion.  Facts would become irrelevant.  This, I believe, is was Ron Suskind was getting at when he wrote, in his notorious essay:
In the summer of 2002, after I had written an article in Esquire that the White House didn't like about Bush's former communications director, Karen Hughes, I had a meeting with a senior adviser to Bush. He expressed the White House's displeasure, and then he told me something that at the time I didn't fully comprehend -- but which I now believe gets to the very heart of the Bush presidency.

The aide said that guys like me were ''in what we call the reality-based community,'' which he defined as people who ''believe that solutions emerge from your judicious study of discernible reality.'' I nodded and murmured something about enlightenment principles and empiricism. He cut me off. ''That's not the way the world really works anymore,'' he continued. ''We're an empire now, and when we act, we create our own reality. And while you're studying that reality -- judiciously, as you will -- we'll act again, creating other new realities, which you can study too, and that's how things will sort out. We're history's actors . . . and you, all of you, will be left to just study what we do.''
This is the way the Administration wants the world to work.  The facts you believe are chosen for you by those to whom you have political allegiance.  Whoever is better at posturing and sleight-of-hand gets to declare the truth.  A case in point: Congresspersons who do not support an investigation (HR 375, Rep. Barbara Lee) into the Downing Street Memo do not see a need for an investigation.  The Big Brass Alliance is wasting their time and bandwidth.  After all, the People already know what they believe.  A few annoying facts won't change anything, so why bother looking for the facts?

Who cares if there is evidence that Bush had already planned, by February 2001, to invade Iraq?  Who cares if the Administration had, in March 2001, drawn up a list of "Foreign Suitors of Iraqi Oilfield Contracts"?  Who cares if plans were in place by February 2003 to make use of Iraqi oil?  Do we really need to know when all the plotting started:
From the exclusive Harper's report by Greg Palast:

Within weeks of the first inaugural, prominent Iraqi expatriates -- many with ties to U.S. industry -- were invited to secret discussions directed by Pamela Quanrud, National Security Council, now at the State Department. "It quickly became an oil group," one participant, Falah Aljibury. Aljibury is an advisor to Amerada Hess' oil trading arm and Goldman Sachs.
Who care what the "mobile labs" really were?  Who cares what the aluminum tubes were for?  Who cares if Iraq really tried to buy uranium from Niger?  Who cares if the President deliberately lied about the uranium in his State of the Union Address?  No need to investigate the Valerie Plame matter.  We already know what to believe.

Who cares if the "facts" we present look like a pleasant California valley from above, but really collide like the San Andreas fault when you look under the surface.  Logical inconsistencies are not really dangerous, not really a sign of trouble up ahead.  

So, the uproar about Bush's promotion of Intelligent Design Theory is just the tip of the iceberg.  What is upsetting to scientists is the broad disregard, not just for science, but for facts.  It is not merely the rejection of one body of knowledge (evolution), rather, it is the rejection of the empirical method.  The implications go beyond the realm of science; domestic and foreign policy are affected just as badly.

*People smarter than me have pointed out that when you make the leap from pure logic to mathematics, you have to make at least one assumption.

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