Beyond endogenous retroviridae, the bugs that made you "you".

This paper has "misunderstandings" in an alliterative title, making it a sure-fire winner, despite verbosity.

Virus geeks will be familiar with the concept of endogenous viruses, and the advantages of heterogeneity in MHC selection are probably also familiar to most medical students. This paper, however, discusses the drive given to MHC diversity caused by the variety of pathogens a population is exposed to. This is really the teeth on the gears of epidemiology with regard to immunogenomics, and something worth thinking about. Population diversity increases in reaction to new pathogens, as novel selection forces influence the advantageousness of minority (or de novo!) alleles. It also gives some basic information about how genomics are assessed to establish the age of an allele, and also how the mechanisms of pathogen-mediated selection cannot easily be differentiated by researchers. Though the thrust of this paper might be a technically minded one about the state of the art, in passing it is a good primer for the uninitated.

Good learning, and, post champagne, Happy New Year (see last post)

Rohan

How to do an antidepressant trial properly

This study:

A Systematic Review of Comparative Efficacy of Treatments and Controls for Depression

Is fantastically considered. A Metastudy incorporating 13000 patients, the authors have gone to considerable length to seek out the truth. DSM classification of depression may have obfuscated the answer given that the trials used spread over DSM II, III and IV, but the authors considered this and retrospectively classified the patients acoording to various narrow classification systems to remove error, I only mention this to point out that these guys know what they're doing.

It begins sleazily enough, unblinded trials show more treatment effect than blinded ones. Published trials likewise perform better than unpublished ones.  Also, placebos had greater effects in unpublished trials than in the published ones, likewise blinded and unblinded trials respectively.

The study establishes the importance of rigorous methodology. Doubting unblinded trials is therefore very much justified. Furthermore, tests of publication bias are worth our attention. Also, the enhanced placebo effect of active engagement with patients is shown to be the most effective part of treatment, so we must always, therefore, include the counselling of the patient by the doctor in the consultation as a confounding factor. As they write, the data shows that the "type of treatment offered is less important than getting depressed patients involved in an active therapeutic program". Finally, very clinically, antidepressants alone do not perform better than various non medical interventions, like sham acupuncture.

Good Learning, and Happy New Year,

Rohan

Epigenetic influence on Neuroplasticity

It appears that neuroplasticity is governed by epigenetic mechanisms, which can be modulated to allow learning of absolute pitch (a.k.a. perfect pitch) beyond the normal age window (4-6 years in humans).
Absolute pitch is thought to require specific training, with association of conceptual labels to specific pitches. In this experiment, the authors report treating young adult men with valproate improved their learning of absolute pitch outside the normal window of opportunity.

Valproate is a drug used primarily for anticonvulsant effects in generalised epilepsy, and it is a known inhibitor of HDAC. Histone deacetylase (HDAC) is an enzyme responsible for removing acetyl groups from histones. Acetylation of histones makes them bind their DNA less tightly, increasing the DNA's accessibility and promoting transcription.
It should be noted that this effect is generalised across all histones.

The study design was randomised, double blind, placebo controlled crossover. The subjects were, interestingly, asked whether they knew which treatment arm was the active substance. 17/18 knew. This is a perfect example of how psychoactive drugs cannot be blinded in the typical way. Essentially the study was un-blinded, making it liable to more confounds.

If we look at the results, after crossover the effect of valproate disappears. This is important, as it puts the validity of the conclusion into question. The authors do not seem concerned, (having got the result they want?), and suggest that the subjects experienced memory interference having already mis-learned that task once while on placebo. They rightly suggest a larger, single stage trial to reveal the truth.

The results are interesting and deserve further attention but are not conclusive, especially given the lack of effect after crossover, with no falsifiable explanation for it.


Valproate reopens critical-period learning of absolute pitch
Gervain Judit, Vines Bradley W., Chen Lawrence M., Seo Rubo J, Hensch Takao K., Werker Janet F, Young Allan H   
Frontiers in Systems Neuroscience
2013

The Supplementary Motor Area and You

It is commonly understood that the primary motor strip, or M1, is where cell bodies of neurons are found in a organised manner, forming the first part of the path innervating striated muscle. But how are impulses through this area orchestrated to create the possible motor actions of our bodies?

Before the 21st century the supplementary motor area (SMA) was recognised as involved in motor activity because of increased blood flow. It lies just anterior to M1.
Another area, called the pre-SMA, is found more anterior and medially; on the superior frontal gyrus.
Compared to the primary motor cortex, the SMA's blood flow was greater during complex motor tasks, and even during visualisation of actions.
Pacing tasks on external stimuli (metronome, visual cues) or internal stimuli correlates with whether the SMA or pre-SMA are active.
Pre-SMA is correlated with novel tasks, or early during skill acquisition, whereas the SMA proper is with established, complex tasks (like playing scales).

It appears that the SMA may, crudely speaking, be necessary for coordinating simple or learned movements. In contrast the pre-SMA is probably necessary to train new movements.
This has clinical relevance for focal brain injury to the motor areas when considering how much function may be recovered with rehabilitation.


Motor areas of the medial wall: a review of their location and functional activation.
Picard N, Strick PL.
Cereb Cortex. 1996

Mental, Neurological, or Nervous system illness?

Psychiatry has been separated from mainstream medicine in part by diagnostic manuals, like the DSM or ICD, which advocate conceptual distinctions between 'mental' and 'neurological' diseases. The fact is that such distinctions are not apparent, being an allusion to the false mind-body dualism that pervades people's thoughts, and indeed our common language.

Evidence of changes to the brain organ in established psychiatric disease abounds; whilst primary changes to the brain from trauma or stroke exact repercussions on the mind and behavior of people. Clearly the mind is borne of the brain and change can occur from both direction.

A realistic view of humans or other animals must consider 'mental' and 'organic' as distinct realms but as methods of enquiry and interaction with a single, cohesive organism.

Some disorders, such as psychogenic non-epileptic seizures, get caught in the middle of each disciple to the detriment of those patients, and society as a whole.

Time to end the distinction between mental and neurological illnesses
P D White, H Rickards, A Z J Zeman 
BMJ 2012