neuroscience

Biological systems are extremely complex. This nugget of wisdom may seem trivial but it is a lesson the scientific and medical communities have been learning over and over again for a couple of centuries. Every time we think we understand a biological system we find there is a deeper level of complexity, or another layer of interactions we had not previously taken into consideration.

This is why we need high quality clinical trials to feel confident about the net health effects of any intervention. A treatment may make sense based upon our current understanding of human biology, but that’s not enough. We need to know what it actually does to people.

This is a lesson, however, that the supplement industry has not learned (and does not appear interested in learning). I have nothing against supplements themselves, only how they are regulated and marketed. I prescribe supplements all the time, when they are evidence-based. But the supplement industry has pulled off a marketing coup – the holy grail of marketing: turning their hype into accepted conventional wisdom. For example, the public generally believes that “natural” is always better, that supplements are always safe, and that we all need to take supplements – the more the better. None of these things are true.

A more subtle marketing deception often employed by the supplement industry is the use of pre-clinical basic-science evidence to support clinical claims for their products. In other words, they cite studies in which some marker in a petri dish is increased in the presence of their supplement, then extrapolate several steps to an ultimate clinical application. One of the most common manifestations of this I encounter is looking at some marker of immune function, claiming that it is increased, then extrapolating from this that the supplement “boosts the immune system” and then further extrapolating that it will therefore help the body fight off cancer.

Antioxidants are another example – extrapolating wildly from pure basic science evidence that antioxidants reduce oxidative stress. When clinical studies started coming in showing no benefit the antioxidant sellers claimed that the doses weren’t high enough. Now we have data showing that high doses of antioxidants are associated with increased risk of heart disease. It turns out (gasp) that the biological system was more complex than we though. Oxygen free radicals are also used as signaling chemicals that trigger important cell functions, and suppressing them has – unintended consequences.

Now we potentially have another story to add to the law of unintended consequences – calcium supplements and heart disease. Osteoporosis – the thinning of bones through loss of calcium – is a serious medical problem for the geriatric population. After about age 50 (and post-menopause for women) men and women start to lose calcium from their bones. The best way to prevent this from becoming a problem is to maximize your bone density by age 50, and this is done through weight-bearing exercise. Exercise after age 50 will also help stave off bone loss to a lesser degree.

There is an ongoing controversy about the use of calcium supplements, calcium plus vitamin D, and the use of prescription medications to increase bone density and reduce osteoporosis. This is a complex area of medical evidence, but the quick version is that calcium supplements by themselves are likely not of any significant benefit in preventing and treating osteoporosis and reducing fractures. Calcium plus vitamin D has modest benefit for bone density. In some patients with osteoporosis and not responding to supplements and exercise alone, pharmacological treatment may be necessary to reduce the risk of fractures. It also is likely true that calcium and vitamin D supplements are only helpful if a person is deficient in one or both. If you are getting sufficient calcium and vitamin D from your diet, taking additional supplements is likely of no benefit.

This is a quick summary of a lot of evidence, and there are still many open questions that need to be addressed by further research. Meanwhile the pharmaceutical industry is doing what they can to push prescriptions for osteoporosis and osteopenia (a milder form of bone loss). And the supplement industry is pushing calcium and vitamin D supplements.

In addition to the fact that there is little evidence to support the use of these supplements in most people, there is the question of safety. Again – there is the common assumption that supplements can do no harm, so even if the evidence for efficacy is weak there is nothing to lose from taking supplement for nutritional “insurance.” This is not a good assumption.

A new study published in the BMJ, in fact, suggests that calcium supplements are associated with a 30% relative increased risk of heart attack (but not death, and only a tiny increase in stroke risk). This is a meta-analysis of previous studies, and the authors found:

Calcium supplements (without coadministered vitamin D) are associated with an increased risk of myocardial infarction. As calcium supplements are widely used these modest increases in risk of cardiovascular disease might translate into a large burden of disease in the population. A reassessment of the role of calcium supplements in the management of osteoporosis is warranted.

So calcium supplements are of questionable benefit, and may increase the risk of heart attacks. The authors point out that prior studies did not find the same increased risk from a diet high in calcium, so it only seems to apply to calcium supplements. This is yet more evidence for the general principle, supported by clinical evidence, that it is better to get your nutrition through a healthful varied diet than through supplements.

This study also demonstrate the utility for researchers to keep going back and asking questions about interventions. Biological systems are complex, and we have to look at interventions from multiple angles before we get a handle on their net health effects. And this study is not the final word – it takes many studies over years of research for a consistent picture to emerge. All we can say at any point in time is the best interpretation of existing research. Right now for osteoporosis it seems that the best strategy for bone health is to have a healthful diet with sufficient calcium and to exercise regularly (funny how evidence seems to be coming back to that same conclusion). Regular doctor visits will also determine if this is insufficient and you need further targeted therapy.

Interesting work from Dolan's group on how we modulate expected aversive outcomes:

The value assigned to aversive events is susceptible to contextual influences. Here, we asked whether a change in the valuation of negative events is reflected in an altered neuronal representation of their expected aversive outcome. We show that experiencing an aversive event in the past, and choosing to experience it in the future, reduces its aversive value. This psychological change is mirrored in an altered neural representation of aversive value in the caudate nucleus and anterior cingulate cortex. Our findings indicate that subcortical regions known to track expected value such as the caudate nucleus, together with anterior cingulate cortical regions implicated in emotional modulation, mediate a revaluation in expectancies of aversive states. The results provide a striking example of a contextual sensitivity in how the brain ascribes value to events, in a manner that may foster resilience in the face of adversity.

Interesting stuff from Phan et al:

Brain reward circuitry, including ventral striatum and orbitofrontal cortex, has been independently implicated in preferences for fair and cooperative outcomes as well as learning of reputations. Using functional MRI (fMRI) and a “trust game” task involving iterative exchanges with fictive partners who acquire different reputations for reciprocity, we measured brain responses in 36 healthy adults when positive actions (entrust investment to partners) yield positive returns (reciprocity) and how these brain responses are modulated by partner reputation for repayment. Here we show that positive reciprocity robustly engages the ventral striatum and orbitofrontal cortex. Moreover, this signal of reciprocity in the ventral striatum appears selectively in response to partners who have consistently returned the investment (e.g., a reputation for reciprocity) and is absent for partners who lack a reputation for reciprocity. These findings elucidate a fundamental brain mechanism, via reward-related neural substrates, by which human cooperative relationships are initiated and sustained.

Although their genetic underpinnings differ, Alzheimer's disease, Parkinson's disease and Huntington's disease are all characterized by the untimely death of brain cells...

People who experience rapid eye movement sleep behaviour disorder (RBD) may go on to develop conditions such as dementia with Lewy bodies, Parkinson's disease, or multiple system atrophy. The researchers studied the medical records of 27 people with these three neurodegenerative conditions who had also experienced RBD earlier in life...

Boston Scientific Corporation (NYSE: BSX) announced U.S. Food and Drug Administration approval of two spinal cord stimulation (SCS) leads for use with its Precision Plus™ Spinal Cord Stimulator System, the world's first rechargeable SCS device for the management of chronic pain of the trunk and/or limbs...

Shionogi Inc., a U.S.-based group company of Shionogi & Co., Ltd., announced the U.S. Food and Drug Administration approval of CUVPOSA™ (glycopyrrolate), the first liquid treatment for patients ages 3-16 who suffer from chronic severe drooling associated with neurologic conditions such as cerebral palsy. CUVPOSA™ was designated an Orphan Drug by the FDA...

Cascades of genetic signals determine which neurotransmitter a brain cell will ultimately use to communicate with other cells. Now a pair of reports from biologists at the University of California, San Diego, have shown for the first time that electrical activity in these developing neurons can alter their chemical fate - and change an animal's behavior - by tweaking this genetic program...

Scientists at the Stanford University School of Medicine have identified a molecular pathway responsible for the death of key nerve cells whose loss causes Parkinson's disease. This discovery not only may explain how a genetic mutation linked to Parkinson's causes the cells' death, but could also open the door to new therapeutic approaches for the malady...

A new study reveals that an enzyme linked with multiple disorders is also involved in the generation of toxic, neuron-killing protein fragments in Huntington's disease (HD). The research, published by Cell Press in the July 29 issue of Neuron, provides insight into Huntington's pathology and proposes new therapeutic strategies for this devastating incurable disease...

The cognitive style known as central coherence is receiving increased attention across a variety of clinical neuroscience disorders.  I had not been familiar with this concept of central coherence.  Essentially, central coherence describes a style of thinking on a spectrum.

On one end of the spectrum, you have individuals who tend to think globally or using a gestalt perspective.  The big picture is seen rather than paying attention to details.  The other end of spectrum includes individuals who are detail-oriented.  Their perspective bias is to focus on details.

Being on either extreme of the spectrum can produces problems.  Very high central coherence can lead to problems with missing important details that need attention or action.  Those with very low or weak central coherence can be detail bound, losing sight of important global interpretations of the situation or environment.

The imaging correlates of coherence are being explored.  Higher central coherence appears to involve increased right and left brain activation with problem-solving.  Weak central coherence has been accompanied by less bilateral activation with tasks.

Children and adults  with autism spectrum appear to have weak central coherence and are overly focussed on details to the expense of a global perspective.  This could explain typical autistic behaviors such as valuing sameness, attending to parts of objects and persistence in behaviors related to details.

Rhonda Booth and Francesa Happe from the Social, Genetic and Developmental Psychiatry Centre at the Institute of Psychiatry in London have published a study of central coherence in children with autism, ADHD and controls.

There study involved a simple sentence completion task.  The example provided is--Complete this sentence "Hunting with a knife and".  Child with weak central coherence typically finish this sentence with "fork".  Normals tend to expand on a global response like "catch a bear".

The authors tested a ten question Sentence Completion Task with the following findings:

• Completion scores (central coherence) increased with age--children younger than 13 had lower completion scores
• Most (but not all) children with autism showed weak central coherence on the task (more local error responses)
• Children with ADHD did not differ from controls on the task
• Inhibition difficulties did not increase the weak coherence local response rates

The authors conclude "the Sentence Completion Task appears to be a simple and easy-to-administer test capable of tapping local processing bias, or weak coherence, in a range of populations".

You will likely be hearing more about the neuropsychological concept of coherence in a variety of studies across the clinical neuroscience disorders.

Photo of Electrical Power Line Fire Courtesy of Yates Photography
Booth, R., & Happé, F. (2010). “Hunting with a knife and … fork”: Examining central coherence in autism, attention deficit/hyperactivity disorder, and typical development with a linguistic task Journal of Experimental Child Psychology DOI: 10.1016/j.jecp.2010.06.003
Lee PS, Foss-Feig J, Henderson JG, Kenworthy LE, Gilotty L, Gaillard WD, & Vaidya CJ (2007). Atypical neural substrates of Embedded Figures Task performance in children with Autism Spectrum Disorder. NeuroImage, 38 (1), 184-93 PMID: 17707658

American neurologists and sleep experts suggest in a recent study that rapid eye movement (REM) sleep behavior disorder could be an early sign of Parkinson's disease or dementia that develops up to 50 years later. You can read how neurologist and sleep specialist Dr Bradley F...

Here is the conclusion quoted from a recent New England Journal of Medicine (NEJM) review article on acupuncture for back pain:

As noted above, the most recent wellpowered clinical trials of acupuncture for chronic low back pain showed that sham acupuncture was as effective as real acupuncture. The simplest explanation of such findings is that the specific therapeutic effects of acupuncture, if present, are small, whereas its clinically relevant benefits are mostly attributable to contextual and psychosocial factors, such as patients’ beliefs and expectations, attention from the acupuncturist, and highly focused, spatially directed attention on the part of the patient.

Translation – acupuncture does not work. Why, then, are the same authors in the same paper recommending that acupuncture be used for chronic low back pain? This is the insanity of the bizarro world of CAM (complementary and alternative medicine).

Let’s break down their conclusions a bit. They have reviewed the clinical evidence, as I and others have done before, and found that when real acupuncture is compared to various forms of sham acupuncture (the acupuncture version of a placebo) there is no difference. As I have written many times before – it doesn’t matter where you stick the needles, or even if you stick the needles. Since acupuncture consists of sticking needles in acupuncture points, the only reasonable conclusion from this evidence is that there is no specific effect from acupuncture – acupuncture does not work.

The phrase, “contextual and psychosocial factors, such as patients’ beliefs and expectations, attention from the acupuncturist, and highly focused, spatially directed attention on the part of the patient.” is a fancy way of saying “placebo effects.” In other words, there are some non-specific subjective benefits to getting attention from a practitioner. There is this assumption, however, that these benefits are real and worthwhile. However, they are likely to be illusory – an artifact of observation and reporting, not a real improvement in the patient’s condition. In real science-based medicine, that is the underlying assumption – placebo effects are largely illusory – a variable to be controlled for.

But there has been recent controversy over the role of the placebo effect in ethical and evidence-based practice. This is, in my opinion, largely a back door attempt to justify CAM treatments that do not work. The claim is that placebo effects are real and useful. But a systematic review of the placebo effect in clinical trials concluded:

We did not find that placebo interventions have important clinical effects in general. However, in certain settings placebo interventions can influence patient-reported outcomes, especially pain and nausea, though it is difficult to distinguish patient-reported effects of placebo from biased reporting. The effect on pain varied, even among trials with low risk of bias, from negligible to clinically important. Variations in the effect of placebo were partly explained by variations in how trials were conducted and how patients were informed.

In other words – for any objective outcome, there is no important placebo effect. For outcomes that are subjectively reported by patients, there is a highly variable placebo effect. It is plausible that the expectation of benefit could result in the release of dopamine and endorphins and produce a physiological decrease in pain, for example, in a subset of people, and there is some evidence for this. But this is, at best, a transient symptomatic effect – not therapeutic.

Such effects are also non-specific – meaning they do not derive from the intervention itself, but from the therapeutic ritual surrounding the intervention. Even treatments that do not work may therefore provide these non-specific benefit. My opinion is that the non-specific benefits of the ritual of treatment should be combined with an actually effective treatment, not magic pretending to be medicine. There are many reasons for this. One is the ethics of patient autonomy and informed consent – giving a fake treatment to a patient violates the patient’s rights, in my opinion.

Further, there is potential downstream harm from convincing patients that fake magical treatments are effective, because of placebo effects. Then using obscure language to hide the fact that the treatment actually does not work. This distorts the public’s view of medicine, and of what works, and sets them up to be victims of fake treatments when their ailment is not subjective or self-limiting. In other words – refer them to an acupuncturists when they have back pain and they may rely upon acupuncture, or some other non-scientific intervention, when they have a more serious illness.

The authors of this article recommend:

He has specifically requested a referral for acupuncture, and we would suggest a course of 10 to 12 treatments over a period of 8 weeks from a licensed acupuncturist or a physician trained in medical acupuncture.

This contradicts their own conclusions. Why is training in acupuncture necessary? That training largely consists of identifying acupuncture points, knowing which points to use on an individual patient, and knowing the technique of needle insertion – but none of these things matter. The sham ritual is all that matters – you can literally fake it and get the same response. I bet a 10 minute video is all that is necessary. In fact I bet even that is not necessary – you could probably fake it well enough to get a maximum placebo effect without any prior demonstration.

What the authors of this article have done is something that is increasingly common in CAM (when it is trying to infiltrate academia and peer-reviewed journals like the NEJM) – reviewing the evidence, admitting that the CAM treatment does not work, then making an elaborate and misleading appeal to placebo effects, and ending with a recommendation to use the treatment that does not work. Specifically, they not only recommend using the treatment, but in its fullest magical form, complete with all the disproven claims (that is what “medical acupuncture” is). It’s a bait and switch con game, nothing more. Come for the placebo effect, then be treated with magical nonsense.

Researchers in Heidelberg and Stanford have discovered a new signalling pathway of brain cells that explains how widely used antihypertensive drugs could keep inflammation in multiple sclerosis (MS) in check. The peptide angiotensin not only raises blood pressure but also activates the immunological messenger substance TGF beta on a previously unknown communication pathway in the brain...

Someone, somewhere, can look you straight in the eye and say "I've got a PhD in booty call research".

A new study just published online in the Journal of Sex Research investigates where the booty call falls on the spectrum of relationships.

Positioning the Booty-Call Relationship on the Spectrum of Relationships: Sexual but More Emotional Than One-Night Stands

Peter K. Jonason; Norman P. Li; Jessica Richardson

Journal of Sex Research

Most research on human sexuality has focused on long-term pairbonds and one-night stands. However, growing evidence suggests there are relationships that do not fit cleanly into either of those categories. One of these relationships is a “booty-call relationship.”

The purpose of this study was to describe the sexual and emotional nature of booty-call relationships by (a) examining the types of emotional and sexual acts involved in booty-call relationships and (b) comparing the frequency of those acts in booty-call relationships to one-night stands and serious long-term relationships.

In addition, the manner in which sociosexuality is associated with the commission of these acts was also examined. Demonstrative of booty-call relationships' sexual nature was individuals' tendency to leave after sex and infrequent handholding.

In contrast, the romantic nature of booty-call relationships was demonstrated through the frequency of acts like kissing. The results suggest the booty-call relationship is a distinct type of relationship situated between one-night stands and serious romantic relationships.

Guys, if you need a post-doc... just call.

Link to booty call study in the Journal of Sex Research (via @NoahWG).

Someone, somewhere, can look you straight in the eye and say "I've got a PhD in booty call research".

A new study just published online in the Journal of Sex Research investigates where the booty call falls on the spectrum of relationships.

Positioning the Booty-Call Relationship on the Spectrum of Relationships: Sexual but More Emotional Than One-Night Stands

Peter K. Jonason; Norman P. Li; Jessica Richardson

Journal of Sex Research

Most research on human sexuality has focused on long-term pairbonds and one-night stands. However, growing evidence suggests there are relationships that do not fit cleanly into either of those categories. One of these relationships is a “booty-call relationship.”

The purpose of this study was to describe the sexual and emotional nature of booty-call relationships by (a) examining the types of emotional and sexual acts involved in booty-call relationships and (b) comparing the frequency of those acts in booty-call relationships to one-night stands and serious long-term relationships.

In addition, the manner in which sociosexuality is associated with the commission of these acts was also examined. Demonstrative of booty-call relationships' sexual nature was individuals' tendency to leave after sex and infrequent handholding.

In contrast, the romantic nature of booty-call relationships was demonstrated through the frequency of acts like kissing. The results suggest the booty-call relationship is a distinct type of relationship situated between one-night stands and serious romantic relationships.

Guys, if you need a post-doc... just call.

Link to booty call study in the Journal of Sex Research (via @NoahWG).

Ortho Kinematics, a privately held spine diagnostics company focused on revolutionizing spine motion analysis, announced today that it has begun a multi-site clinical study of the KineGraph VMA™, and that the initial 23 patients have been enrolled. The study will help determine which types of patients are best evaluated with KineGraph VMA testing...

Here is a cute study that attempts to gauge  our mood (more accurately, the 7% of American who use Twitter) throughout the day.  Play through the video that shows regional and time of day differences.  From the quickie NYTimes mention of the work: "you’re probably happiest in the morning and least satisfied about noon. Analyzing words in those posts, researchers found that Thursday is the saddest day; Sunday, the happiest. People on the West Coast who post are happier than their counterparts on the East Coast. The moods were mapped, showing happy times (greener areas) and unhappy (red areas)."

Gneezy et al. add an interesting twist to studies of how we buy things. Companies loose money in attempts to enhance sales with pay-what-you-want pricing, and adding a charitable contribution to standard pricing has little effect. However, in a variation of pay-what-you-want with half going to charity, a more reasonable profit was returned. (It is not clear whether the charitable giving by the company generated additional generosity by the consumer or created additional social pressure.)

A field experiment (N = 113,047 participants) manipulated two factors in the sale of souvenir photos. First, some customers saw a traditional fixed price, whereas others could pay what they wanted (including $0). Second, approximately half of the customers saw a variation in which half of the revenue went to charity. At a standard fixed price, the charitable component only slightly increased demand, as similar studies have also found. However, when participants could pay what they wanted, the same charitable component created a treatment that was substantially more profitable. Switching from corporate social responsibility to what we term shared social responsibility works in part because customized contributions allow customers to directly express social welfare concerns through the purchasing of material goods.

Attempts to treat the world's most common form of dementia may have been attacking its symptoms, not its root cause