Yoga, A Cognitive Exercise

In August 2009 Annals of the New York Academy of Sciences Volume 1172 was released, containing within it 31 peer-reviewed articles which attempt to “study the impact of Indo-Tibetan practices on longevity and health.” If our brain cells are rewiring themselves based on our habits and thought patterns, suddenly our hobbies and pastimes are rocketed to the center stage of mental health. What you or I do in our free time is habitual and over time can optimize our brains for said activities while allowing other regions to decay. Yoga as a physical exercise has demonstrated incredible ability to affect mental health, including but not limited to focus and emotional regulation. The following papers contained within the volume are of particular interest:

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Feed Your Head – Aβ, Tau & APOE

Aβ plaques & Tau tangles

Fig 1: Pathology of AD showing plaques and tangles.

Some would say a soul is the collective memories and personality traits of an individual. So, what is left if those memories and traits are erased? You and I might be far from old and senile (well I’m not old). But you know someone near & dear to you, who will have to deal with this existential crisis in their golden years. Alzheimer’s disease currently has two culprits, Beta amyloid (Aβ) which can form plaques on the brain and Tau protein, whose over expression can cause neurons to tangle up (NFT).

These pathologies appear to be affected by the APOE gene, certain variations of which are now recognized as dead-ringers for Alzheimer’s. The mechanism however is still very much in the process of being understood. More so, when considering the role of Tau.

Fig 2: Constant expression of plaque causing Aβ with varying levels of Tau shows little difference in pathology. Plaques and tangles remain present. Thus deletion or over expression of Tau is not enough to prevent AD pathology.

Although the signs of Alzheimer’s on a cellular level remained steady while playing with the knobs of Tau expression, the authors did find a difference is the cell & organism survivability. Hypothesizing that Tau helps the neuron deal with excitotoxicity, the damage to nerve cells through stimulation.

Don’t lose hope, although it’s difficult to get a full picture, we may have enough glimpses to make a clinical difference. Eventhough, we don’t quite understand the role between APOE, lipoproteins and Alzheimer’s pathology, on a higher symbolic level APOE is a great predictor of who is at risk for AD and sometimes even when. Best move for now is probably just to get your parents genotyped and planning active mental lifestyles for them, there should be a fix by the time I’m grey.

Citations: Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer’s disease mouse model by Roberson, et al.

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Decided? No, we just finished saying Good Morning: Sage Congress 2011

“Therefore a sage has said, ‘I will do nothing (of purpose), and the people will be transformed of themselves; I will be fond of keeping still, and the people will of themselves become correct. I will take no trouble about it, and the people will of themselves become rich; I will manifest no ambition, and the people will of themselves attain to the primitive simplicity’ ”  reads Ch. 57 of the Tao Te Ching. How chillingly the 2 millennia old caricature of a wise-learned man holds true to this day.

Sage Bionetworks is a medical research organization, whose goal is “to share research and development of biological network models and their application to human disease and biology.” To this end, top geneticists, clinicians, computer scientists and pharmaceutical researchers gathered this weekend at UC San Francisco. We were given an inspirational speech by a cancer survivor, followed by report of the progress since last years congress. Although admirable on their own, the research and programs built in the last year seemed to remind us all again that in silico research was still closer to the speed of traditional life-science than the leaps and bounds by which the internet moves.

Example of an effort which aligns with & was presented at Sage

Projects like GenomeSpace by the Broad Institute give us hope of what’s possible while watching hours of debate and conjecture at Sagecon.  There were many distinguished scientists, authors , nobel laureates and government representatives, the totality of whose achievement here was coming to agreement on what should be built, who should build it and by when. Groups were divided into subgroups, and then those divided yet again. All the little policy details, software choices and even funding options would be worked out. There was a lot of talk.

Normal Conference VS Developer Conference. SHDH Illustrated by Derek Yu

Attending gatherings for software developers in silicon valley, their hackathons leave much to be desired at events like Sagecon, the least of which being the beer. I doubt anyone enjoys sitting in a stuffy blazer listening to talks for hours on end. The hacker events are very informal, there is no set goal, yet by the end of 24 hours there are often great new programs, friendships and even companies formed. Iteration rate is key to finding solutions and the rate-limiting step in the life-sciences & medicine isn’t the talent or resources it’s the culture; an opinion echoed by Sages’ own shorts-wearing heroes Aled Edwards & Eric Schadt.

“You must understand, young Hobbit, it takes a long time to say anything in Old Entish. And we never say anything unless it is worth taking a long time to say. “

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Biotech for Hackers: Computational Genomics 1 of 2

A low hurdle to entry along with the ability to iterate rapidly is key to taking on problems & creating solutions. What do these solutions look like in genomics and why can hackers lead the way? Fig 1 shows something very similar to social interaction maps one comes across at places like Facebook.

Fig 1: Interaction map of genes implicated in Alzheimer's. Genes were grouped by those that have similar functions (squares) and those with different functions (circles). Modules with a red border have high confidence interactions. While the weight of the connecting green lines corresponds to the number of interactions between two sets.

The map above is of individual gene relationships where an algorithm began with 12 seed genes that previous experiments have shown to play a role in Alzheimer’s disease. These seeds were compared with 185 new candidate genes from regions deemed susceptible to carrying Alzheimer’s genes. From here, both experimental and computational data was combined to generate Fig 1, which the authors dubbed AD-PIN (Alzheimer’s Disease Protein Interaction Network).

Fig 2: Interactions discovered by the Hig-Confidence (HC) set generated by this study in context to known relationships in the Human Interactome (created in past studies).

What we learn by simply tracking genes already known to play a role in Alzheimer’s is the discovery of new regions of genetic code that are  also participating in the expression of related functions, in this case those being affected by the disease, such as memory. In Fig 2 we see that between seeds this algorithm produced 7 high confidence interaction results, of which 3 were  in common with previous studies. In addition to almost 200 new interactions, which can each lead to new therapies, blockbuster drugs and better understanding of the disease itself.

Many software developers have extensive experience and interest in dealing with large data sets, finding correlations  and creating meaningful solutions. However, much of our generation has had little exposure to these problems. Often resulting in the bandwagon effect, as one recent article put it “the latest fucking location fucking based fucking mobile fucking app.” Progress has often been linked to literacy, from books to programming, being able to read and write in life-code just might be the next stage.

Original published study: Interactome mapping suggests new mechanistic details underlying Alzheimer’s disease by Soler-Lopez et al.

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Live @ Future of Genomic Medicine IV: Juan Enriquez – Understanding Life Codes

Managing Director at Excel Medical Ventures and CEO of Biotechonomy. Begins with talk of economy, dangers of bank leverage. BofA lends out $47 per $1 in-hand. Banks fail, gov tries to help, banks bring gov down as well. Dancing in the flames, this is our [researchers] arena, technology is a larger wave than any financial crisis, you will either be washed away or surf  it. Moving from digital code to life code. Man vs mouse 5% difference. Humans transmit code through time. Tribe vs empire as result of standardized code. Changes in code matter, the dominant code is changing, from “01” to “ATGC”. Life is imperfectly transmitted code, imperfection is important. Life code will be the big driver of the global economy. Aileron, protein stabilizers, $1.1B deal. You can order bioreactor and organ printers from Harvard Regenerative Medicine magazine. Community matters, if you’re around happy people you are happy, if you are around obesity than you are inclined to be obese, importance of startup culture to medicine. Can’t genomics be dangerous? Prove to me it will never hurt anyone and we’ll allow you to sell it, in this scheme table salt would not pass FDA clinical trial. Must innovate information infrastructure to handle genomic data.

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Library of Life: Genomic Databases & Browsers

DNA at it’s heart is enormous chunks of information. The genome of an organism like  yeast, mice or humans contains an ocean of data. Currently there are several on-line genomic databases, a great example being SGD dedicated to the yeast S. cerevisiae. SGD has become a necessary tool for life-scientist over the past 10  years but at the same time has not kept up with information technology, resulting in a platform which works like a 10 year old website.

SGD is clunky but necessary, for now

Above we see a typical SGD search, it takes  5 windows to arrive at the sequence data of 1 gene. Nevertheless, SGD is used by drug companies trying to find the next big hit, academic labs trying to cure cancer and field biologists studying wildlife.

DNA is extracted and placed through a sequencing machine which spits out the information into a computer file.  Just as having an aged internet browser affects our productivity the browser one uses to view these files can have a large impact. Following the web-browser analogy we take a look at 3 different sequence browsers, starting with Vector NTI.

Vector NTI is enterprise software.

Vector NTI is well established and often bundled with hardware. It has many features but can often seem like information overload, causing most users to stumble through it’s many menus and windows. A step up in usability comes from the third-party software suite Sequencher, popular amongst mac users.

Sequencher is your friend

Sequencher strikes a healthy balance between features and usability. But is a fairly resource intensive program requiring CDs and hard drive space to store local algorithms. However, the most up to date browser is likely to be the free and light download, 4Peaks.

4Peaks Simplicity & Usability

4Peaks allows the user to go in, read their sequence file and get out. What it lacks in features it makes up for in simplicity. The end result of any software or database is to help researchers wade through all this information and continue their studies. In this environment services such as GENEART offers to perform much of the genomic related leg work on a given project.

These are all tools, the databases, browsers and services, which enable researchers to answer the questions that line our horizon. The progress of our tools has always directly correlated with our advancement, the life sciences adoption of information technology is a necessity as we discover so much of life is condensed data in every nook.

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The Polymerase Chain Reaction, A Microcosm

Creating a new life-form is an awe-inspiring experience. Writing DNA like a mere sentence and watching creation unfold in the mechanism of life is both breathtaking and humbling. None of this would be possible without the Polymerase Chain Reaction (PCR). A simple process where all the ingredients for DNA: a teaspoon of reagents, a pinch of polymerase enzyme and a handful of the “letters” that make up our genetic code are thrown into the oven, literally, well a very accurate oven that can step temperatures rather quickly. Within hours the sentence you had written out on a computer screen, is now molecules floating around in a tiny tube ready to be put into a cell, which will read the instructions and attempt to build or act accordingly. Using this simple idea the human race has been handed over the keys to the Build a Life Workshop, however this simple process often goes without scrutiny, without improvement.

Basic Principles of PCR

Much of the drug discovery in both academia and industry is now focused on protein mechanics. How does this receptor behave? What buttons turn this enzyme on and off? Focusing on protein structure and mechanism often makes PCR a boring chore that most researchers have to grudgingly get past before they can get to the interesting part. As a result, the basic process of PCR has remained the same for decades. I literally remember when a P.I. gave me a paper from 1985 to look up what settings I should use for my reaction. All this wouldn’t be a problem, except people are often wasting weeks to months trying to get the right PCR outcomes. At the root of the problem & the solution is information. PCR is a “black box” process, in that you throw all the ingredients together turn on the machine and hope that all the right molecules will bump into each other at the right times. Traditionally, it has been a exasperating trial & error based system. Now however, information technology has given a glimpse of a solution and a way to move forward to the next chapter in the development of this life-science staple.

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Neurophysiology of Meditation, 2 of 2

These articles have taken steps to identify and understand physiological differences in well-focused minds compared to lay people, it is analogous to a study showing that professional athletes have more muscle mass, in a manner communicating to those of us who seek to perform better at either a physical sport or become better problem solvers, that the mind, like the body must be trained and shaped to overcome difficult challenges. The papers in these two posts converge in that both studies show meditation increases activity and over long-term practice, cause structural changes in regions associated with focus and concentration.

Fig 1 Larger GM volumes in meditators (co-varied for age). Views of the right orbito-frontal cortex, right thalamus, and left inferior temporal gyrus, where GM is larger in meditators compared to controls. The color intensity represents T-statistic values at the voxel level.

Where the last post attempts to capture a snapshot of the mind during a meditative act the paper in the following post attempts to show structural changes caused by long-term, regular meditation. The underlying anatomical correlates of long-term meditation-Larger hippocampal and frontal volumes of gray matter, by Luders, et al., asked a simple question: does regular meditation over many years cause any neuroanatomical changes in the meditator.

Image from National Geographic magazine

To find the answer the authors took 22 meditators with mean meditation experience of 24.18 years and acquired images of their brains using MRI. The images were then passed through Voxel-based GM volume analysis, at a local and global level. Next the images passed through Parcellated volume analysis software, combined the various software analysis would help to distinguish grey matter volume differences between the 22 long-term meditators and 22 control subjects with no meditation experience. As a result, this would to some degree, help the authors identify regions with grey matter (GM) differences, however it is not so clear how those changes can be specifically attributed to meditation alone. The data in figure 1 reveals increased GM differences in areas shown as activated by meditation in previous studies. The authors believe the results of this study provides enough positive data to continue to examine the relationship between meditation and GM volume, they nevertheless do acknowledge that on a global level there was no GM difference, only on a local level.

The future for neurophysiological research of focus and the clarity of thought relies significantly on better imaging technology; we must be able to see what pathways are becoming activated, when and during which thoughts. With increased complexity in our everyday lives, less time and more tasks to complete, being able to focus on the everyday problems and the overarching issues that are inherent with existence will become more relevant, research such as this may help to aid individuals and societies alike.

Citations:
Luders E, Toga AW, Lepore N, & Gaser C (2009). The underlying anatomical correlates of long-term meditation: larger hippocampal and frontal volumes of gray matter. NeuroImage, 45 (3), 672-8 PMID: 19280691

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Filed under Meditation, Neuroimaging, Neurophysiology, Neuroscience

Neurophysiology of Meditation, 1 of 2

Fig 1. Expert meditators & non-meditators asked to focus on a dot for extended time. A) 12 expert meditators had greater overlap of increased activation of attention-related brain regions. B) 12 non-meditators had less overlap and activation. Orange hues equal higher correlation between individuals & activation. Blue hues equal little to no correlation between regions of activation.

We have all found ourselves struggling to concentrate on a thought through all the chatter and imagery in our minds. Often, it is a work related problem, other times we try to understand our relationships and throughout our lives we attempt to ponder existence itself. The predicament with focus and the clarity of thought presents itself as an enticing case for study at a neurophysiological level. Meditation as a set of techniques that requires the practitioner to regularly conduct thought exercises or hold steady attention on an internal/external stimuli, can help to identify & understand neural structures implicated in concentration. There are several recent research papers which provide some excellent insight into the contemporary study of how the brain behaves and is ultimately changed through meditation. In Neural correlates of attentional expertise in long-term meditation practitioners by J. A. Brefczynski-Lewis & A. Lutz, et al. the authors scanned the brains of 3 groups as they were asked to concentrate on a dot, using fMRI.  The groups consisted of 16 non-meditators (NM), 11 non-meditators who were given an incentive of $50 if they were able to hold their attention (INM) and 14 expert Buddhist meditators (EM). Furthermore, the EM group was sub-divided into those with most hours of practice, with a mean of 44,000 hours (MHEM) and those meditators with less, mean of 19,000 hours (LHEM);each subgroup containing 4 meditators. Compared to NMs & INMs, EMs were found to have increased activation of attention-related brain regions of interest (ROI), while simultaneously having far less activation of regions unassociated with the task at hand, Fig 1. One of the most interesting results came from the comparison between expert meditator groups MHEMs and LHEMs; whereas LHEMs showed increased activation of ROIs & decreased activation of unassociated regions, MHEMs showed less activation of all brain regions while maintaining the most attention.

Fig 2. Bar graphs for amplitude of activation in the ‘‘early’’ part of the meditation block (the first 10 sec, excluding the first 2 sec because of hemodynamic delay) and the ‘‘late’’ part of the meditation block (120 sec to 200 sec)

What this all means- with a decent amount of practice one can cause greater activation of attention-related regions of the brain, while simultaneously reducing the level of “chatter” and the activation of unrelated brain regions. More interestingly, we see that even amongst expert meditators those with a mean 44,000 hours of meditative practice shows far less activation of all brain regions, including attention related ROIs, compared with meditators who have half as much practice(Fig 2); this demonstrates networks involved in meditation become optimized with increased use, that is it requires less activation, less resources to have the same concentration. Whatever goal one has, having greater focus with more ease will ensure greater success. This paper gives some live data of what is happening in the brain as one performs meditative tasks while showing us that those with extensive practice have a significantly different response, hinting at structural changes. What those changes could possibly be, is discussed in part two of this post.

Citations:
Brefczynski-Lewis JA, Lutz A, Schaefer HS, Levinson DB, & Davidson RJ (2007). Neural correlates of attentional expertise in long-term meditation practitioners. Proceedings of the National Academy of Sciences of the United States of America, 104 (27), 11483-8 PMID: 17596341

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Practice makes perfect: Dendritic Pruning & LTP

Dendritic trees

It was about two years ago today, when I began to get a clearer picture of how the cells of the brain physically change as a result of our thoughts, experiences and actions. The mind is a result of a network of billions of individual brain cells, neurons, that exchange information with each other; much of the communication between neurons occurs through structures known as dendrites. These tree-like structures emerge from the main body of a neuron, the tips of each branch exchanging information with other neurons. As we develop habits & recurring thoughts, the neurons who communicate the most with each other begin to strengthen the dendritic branches that connect them. Simultaneously, the connections between neurons who don’t often speak with one another begins to atrophy, the dendrites start to prune themselves. These processes together encompass the much larger idea of neuroplasticity, the idea that our brain physically changes and adapts.

Dendritic Pruning

One of the best examples of this concept can be seen when drendritic trees of young mammals are compared with adults, we see extensive branching on the younger brains relative to the adults, supporting the idea that with experience unused connections are pruned off. One proposed mechanism by which the brain is capable of such adaptability is long term potentiation (LTP). The speed of neural communication is largely attributed to the electro-chemical nature of the transmission, allowing for large chunks of information to be rapidly shared across networks of millions of cells every second. LTP is a specific pattern of signaling between neurons where hundreds of bursts of electrical currents of a particular frequency are sent between two neurons; resulting in enhanced communication between the two neurons and strengthening of the dendrites involved, from that point onward. There’s a decent amount of speculation currently, looking to LTP as the mechanism by which our neurons prune their dendritic trees. What this means for you & me: the more we repeat an action or thought, the more the neurons involved in that process communicate with one other, resulting in a streamlining & strengthening of the connections between them; by the same token, routine will cause the number of neurons who can communicate with each other to degrade, possibly limiting what we can learn and understand as we age.

A: Neuron of Child | B: Neuron of Adult

More than ever before, we can observe how our physical minds change as a result of our actions and have a measurable candidate for the mechanism behind this adaptability. If the 20th century belonged to physics, the last several decades to genomics, it may not be a stretch to see the recent future of science be dominated with answering the questions of neuroplasticity and our minds as a physical structure.

Citations:
Yi Zuo, Guang Yang, Elaine Kwon & Wen-Biao Gan (2005). Long-term sensory deprivation prevents dendritic spine loss in primary somatosensory cortex Nature, 436 : 10.1038/nature0371
Kelly D. Hartle, Matthew S. Jeffers, Tammy L. Ivanc (2010). Changes in dendritic morphology and spine density in motor cortex of the adult rat after stroke during infancy. Synapse, 9999 (9999A) : 10.1002/syn.20767
Daniel McGowan (2006). Pruning processes Nature Reviews Neuroscience : 10.1038/nrn1997

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Filed under Neurophysiology, Neuroscience