M.A.D Lab Journal

Raindrops on roses ...

2009-11-26T08:55:00.013+01:00

For my new blog on migraine and other science topics go to Gray Matters.

... and whiskers on kittens;
Bright copper kettles and warm woolen mittens;
Brown paper packages tied up with strings; ...

Gray Matters

2009-11-22T14:35:00.006+01:00

Theoretical physics and clinical neurology are as distant as black and white for you? Well, maybe. But than we need gray. Gray matters.

This blog will soon move to a new place SciLogs under the name "Gray matters". My focus will continue to be on neurology and on converging technologies in the fields of physics, mathematical biology, and computational neuroscience that help us shape the future in biomedical engineering.

The Mission Statement of SciLogs is:

"Good Science is transparent and provides us with new knowledge about the world and ourselves. As an important part of our culture and society, science is never isolated. Informing about new results and recent developments as well as the dialogue with the public are characteristics of good science."

This blog will persist, but under the name M.A.D. Lab Journal. I will publish topics that I feel would not match the Mission Statement above. I guess, most of my posts are pursuant to this standard, but still, I like the idea to have in addition a lab journal.

Let's see how this works out.

My Vision and Scientific Achievements

2009-11-13T20:09:00.007+01:00

My current and proposed research focuses on challenging problems at the interface of neurology and applied nonlinear science, as a branch of physics. My vision is to design control methods that prevent progressive recruitment of cortical tissue into dysfunctional states occurring during migraine and stroke and transfer results from bench to bedside.

My work has significantly contributed to our understanding of migraine as a dynamical disease. In theoretical studies, I have predicted the generic nature of the nonlinear reaction-diffusion process in migraine, that is, its bifurcation structure. In experimental and clinical studies, I have provided solid evidence for this prediction.

The reaction-diffusion process is known in the medical literature under the name spreading depression or SD. It is a slowly traveling wave that invades human cortex at a pace of about 3 mm/min. It was long believed that SD can invade a whole cortical hemisphere in a full-scale migraine attack, except for the frontal lobe. So roughly speaking 50% of one hemisphere. My work showed that the invaded regions are much more confined (~5%) and, surprisingly, these regions are not predetermined by heterogeneities in the cellular composition of the cortex (cytoarchitectural borders), but determined by 3 factors: the ignition of SD, anatomical landmarks, and emerging universal patterns.

I firstly predicted that cortical perturbations that ignite SD all collapse into the same characteristic shape of a particle-like wave independent of the initial perturbation size. The collapse happens on a comparably fast time scale after which the emerged particle-like SD wave regularly propagates for a longer but again transient time. Eventually it vanishes having covered about 5% of one cortical hemisphere. In the language of nonlinear dynamics, the identified mechanism is called a ghost of a saddle-node bifurcation, a metaphor describing a bottleneck configuration in state space that sucks in all sufficiently largely perturbed cortical states and, while recovery is slowed down, a pattern with universal space and time scales emerges.

I mimicked experimentally in retinal SD the characteristics of this pattern formation process. My next prediction was that the path of such a SD wave depends on cortical folding, which is partly individual and provided therefore a key criteria in confirming the theory by clinical data. Using functional magnetic resonance imaging we establish a map between visual cortex and the visual field in a migraine patient who suffered from typical visual field defects during migraine. We showed that his moving visual field defects matched SD propagation in the patient's cortex precisely the way the model predicted. We obtained a spatial resolution unmatched by direct SD measurements.

I believe, and my colleagues share this view, that the proposed bifurcation structure will open up novel therapeutic approaches targeting migraines by changing the bottleneck passage time. Therefore, I studied in the last three years in detail control methods, in particular time-delayed feedback control (chaos control). Several studies both related to SD propagation but also others considering for example semiconductor systems and coupled excitable elements in networks resulted from this work.

In 2006, the first data of SD in humans during the acute phase of stroke was presented and the hypothesis formulated that SD worsens stroke outcome (recently called 'killer waves' in Nature Medicine). I began to investigated the emergence of re-entrant SD patterns that cycle around the infarct core. The infarct tissue provides an anatomical block for SD similar to the functional block I investigated ten years earlier in spiral SD waves. My particular interest was in an unifying picture that explains transitions form SD patterns related to migraine to those of stroke, because over the last 6 years we collected a data base of 200 migraine patients with persistent visual field defects (> 1 year) but without evidence from noninvasive imaging of migrainous infarction. In a recent study, we proposed a unifying mathematical framework of reaction-diffusion systems with augmented transmission capabilities to study the emergence and transitions between these observed clinical data.

I had the privilege to do all this in collaboration with very distinct colleagues and friends.

When a Headache is a Migraine

2009-10-07T18:51:00.037+02:00

This post moved to SciLogs.

DIY Migraine Research

2009-10-03T15:23:00.008+02:00

You suffer from migraine with visual aura? Learn how to do migraine research in less than a minute.

The video can be watch in widescreen (and HD) on youtube (go there). It may be too small if you watch it in-line in this blog post.

A detailed desciption will follow soon. In the meantime, you may want to read this post about this sort of moving visual fields defects and what we learn from this about our brains.

Please contact me, if you have similar data, or plan to perform these self-observations yourself.

Migraine aura simulation

2009-09-28T16:03:00.007+02:00

As an update to the blog post Seeing zigzags, I created a movie based on the neural network simulation described there.

By the way, my new brain arrived. No, the old one did not hurt too much, in fact, you may want to read how actually the migraine pain is generated.

The migraine headache

2009-09-23T16:18:00.034+02:00

Our recent understanding of the anatomy of headaches could lead to new treatments. One debated scenario is that a spreading depression wave causes the pain by releasing substances that activate pain-sensitive nerve fibers

Today, I ordered a human brain anatomy model. I had to choose from over two dozen models. The simplest version would have sufficed to demonstrate the migraine wave patterns propagating on the surface of the brain. I decided to go for the deluxe brain. Who wouldn't?

While waiting for my new deluxe brain, I thought it is a nice idea to kill time and explain where according to current hypotheses the roots of migraine headaches are. In fact, I really chose the deluxe version, because I need the add-on stuff like the arteries and the opened head base to explain to my physics students the pathway and anatomy of migraine headaches.

Usually, I do not talk about headache although I work in migraine research now for almost 18 years. No wonder, a safe bet is that I will be asked after a conference talk: What about the headache?

Well, I'm interested in pattern formation in brain tissue related to migraine. Neither gray nor white matter can hurt, simply because brain tissue lacks pain-sensitive nerve fibers. So I may open my talk mentioning that headache is a symptom while migraine is a disease and therefore one should not say migraine is a headache, but that is all. Unless being asked explicitly.

But our recent understanding of the anatomy of headaches suggests that these pattern formation processes that I study, that is, a reaction-diffusion wave called spreading depression causes the pain by releasing substances that then activate pain-sensitive nerve fibers in the brainstem. So finally I got interested.

Lithograph plate of the trigeminal nerve. This nerve is sends sensory information from the face to the brainstem. From Henry Gray's Anatomy of the Human Body

All sensory information from the face, that is, also pain, is sent to a sort of relay station, the trigeminal nucleus. It extends throughout the entire brainstem. During a migraine, this nucleus gets abnormally activated, which eventually causes the pain. Firstly, neurotransmitters are released from the spreading depression wave in the cortex. This in turn will activate the trigenimal network. Signals from the trigenimal nucleus will then be send upwards along the remaining pain pathway. They pass through another relay station, the thalamus before they finally reach their destination, the sensory cortex. There, the sensation of pain is created. As a consequence, if we could stop the wave process, which is believed to be at the start of this cascade, we also stop the headache.

A second scenario says that actually the brainstem causes both, the spreading depression wave and the pain. The pain is either activated by the induced spreading depression wave, as described above, or the brainstem could independently trigger the pathway to the sensory cortex.

It remains to be seen in which direction this debate is going. It will probably not be quickly decided. So my physics students have some time to learn anatomy, once my deluxe brain arrived.

Hassenstein's vision for migraine relief

2009-08-11T07:52:00.033+02:00

In 1979, Bernhard Hassentstein came to the truly remarkable conclusion that an avenue for migraine relief, cure or prevention may open up by investigating visual disturbances—30 years later, we stay at the beginning of this avenue

Bernhard Hassenstein, born in 1922, is a German behavioral biologist and one of the early founders of biological cybernetics. In 1981, he was asked to contribute a chapter to a book celebrating the 70th birthday of Klaus Piper, owner of the Munich-based publisher Piper Verlag. He thought about a topic that could be both enjoyable and academic. He came up with "Five variations about my migraine".

In his last, the fifth episode from 1979, Hassenstein describes very precise measurements of the position of his migraine aura within the visual field. He estimates that the disturbance, which causes his visual migraine symptoms, propagates in the gray matter surface of the brain, that is, the cortex, with a constant velocity. For this he assumed that the inverse cortical magnification factor increases linearly with eccentricity. Simply speaking, there is a rather simple scaling law how visual input from the eye is magnified in our brain so that acuity is largest in the center of gaze. Similar data were published, for example, later by Otto-Joachim Grüsser.

Hassenstein concluded (in his own words):

"private Migräne könnte dereinst zur besseren Aufklärung [...] beitragen und darauf folgend vielleicht sogar zur Linderung, Heilung oder Vorbeugung. Denn die Meßkurven beweisen, daß die Störung ... im Gehirn abläuft."

"... my private migraines could some day contribute to explain migraine and even to its relief, cure or prevention. For the measurements are evidence of a disturbance in the brain."
[my translation]

Full essay is only available in German:

I learned about this from Bernhard Hassenstein in the mid 1990ies during Manfred Eigen's famous Winterseminars "Biophysical Chemistry, Molecular Biology and Cybernetics of Cell Functions" in Klosters (Swiss). It inspired me to take a closer look at the spatio-temporal development of migraine aura symptoms, which—exactly 30 years after Hassenstein's first visionary self oberservations—led to the recent migraine fMRI study in PLoS ONE. This article is also described for a wider public in a separate blog post.

At the internationally renowned Technische Universität Berlin, we study in newly funded projects within the next years the unique set of data, which I collected over the last 15 years, linking physiological and mathematical pictures of migraine to further explore Hassenstein's vision.

Reference:
Pflieger M, Piper, ER (Eds). Für Klaus Piper zum 7O. Geburtstag 27. März 1981. ' Piper-Verlag, München 1981

The physics of migraines

2009-07-11T19:28:00.104+02:00

This blog post moved to scilogs

Tissue at risk

2009-07-08T22:32:00.061+02:00

On the future of therapy in acute stroke: Ideas are discussed how to miniaturize parts of a neuro intensive care unit and bring it in the brain: a lab-in-the-brain.

Today I presented a poster on the Berlin Brain Computer Interfaces (BBCI) Workshop 2009–Advances in Neurotechnology. Following my open science policy we published it the same day on Nature Precedings, a free online service that enables researchers in the life sciences to openly share preliminary findings. The title is "ECoG-based short-range recurrent stimulation techniques to stabilize tissue at risk of progressive damage: Theory based on clinical observations".

The aim of therapy in acute stroke

The research focus in acute stroke therapy is on the tissue at risk (TAR), that is, the zone in the brain surrounding a small infarct core, which develops during stroke usually within minutes (red in the illustration above). The tissue in the surrounding region (yellow) is at risk of infarction. In the chronic outcome it could be lost. The aim of stroke therapy is salvage of this tissue.

Whether in stroke outcome the lost tissue eventually includes much of the surrounding TAR zone or is mainly limited to the initial infarct core critically depends on certain partly unknown events that happen during a therapeutic time window of about two weeks. In this period waves of mass neural depolarization have been recored using Electrocorticography (ECoG) by an international group of clinical and basic scientists (called COSBID). ECoG is like EEG (Electroencephalography) but the electrodes, in this case an electrode stripe, are placed directly on the exposed surface of the brain. This COSBID group is now testing the hypothesis that such waves worsen stroke outcome.

lab-in-a-brain = brain-computer-interface + lab-on-a-chip

At the Institute of Theoretical Physics of the Institute of Technology in Berlin, we have investigated with computer models how to prevent such waves using time-delayed and nonlocal feedback techniques. This is a control method known as chaos control. However, we are using it not to control chaotic behavior but to abort waves such as those recorded by the ECoG electrodes.

As I cooperate with several COSBID members on seizure activity and migraines, it was a natural idea to suggest that our clinical and theoretical efforts should also be combined in the research field of stroke. Currently this project is in the stage of development and the device used in the neuro intensive care unit is running in an open loop condition, that is, there is no feedback in place. We plan to test this in a closed loop condition with an integrated lab-on-a-chip device together with Thomas Franke from Augsburg and Harvard University, an international expert in microfluidics and in lab-on-a-chip applications that enable miniaturized drug administrations on demand.

Above you see the front cover of a recent review by Thomas Franke and Achim Wixforth "Microfluidics for Miniaturized Laboratories on a Chip (ChemPhysChem 9, 2140)". Such minaturized devices allow for precise and local release of effective drugs on demand. Tiny volumes of picoliters (1/1000 nanoliter) can be controlled electronically to a designated position and delivered to the affected region in the tissue.

Bring the nurse in the brain and let chaos control tell her what to do

The task of this lab-in-a-brain is rather simple though not easy to accomplish: administering medication to the right place at the right time when certain events happen. Today the physician or nurse is interacting with the patient when the ECoG data indicates a stress situation. We just need to miniaturize the nurse and bring her into in the brain. Chaos control tells her what optimal time-delays for medication release are and what the optimal spacing between the release side and wave detection side is.

These studies were published in the journal Chaos (Volume 18, 026110. 2008 and Volume 19, 015110, 2009) and we are honored that both our papers were selected by the American Institute of Physics (AIP) and the American Physical Society (APS) for free online-publication in the Virtual Journal of Biological Physics Research to allow quick access in cutting-edge research fields.

Stroke-free cyborgs

How far in the future are you looking with this Blog post? Well there are cyborgs among us, like Prof. Kevin Warwick which probably would say it will happen yesterday.

Whether near or far future, the open exchange of such ideas is important and it is much supported by the Berlin Bernstein Focus Neurotechnology (BFNT), which has organized the workshop mentioned in the outset of this post. In another BFNT in Freiburg–Tübingen similar ideas are followed. There the aim is to investigate new migraine treatments by interacting with early precursors of migraine. The group around Holger Kaube, Cornelius Weiller, and Gerald Urban suggest a project: Real time metabolite sensing for feedback control of behavior in neurological disorders in which "[the] long term goal of the project is the development of implantable encapsulated microsensors in migraine patients, which will enable them to monitor and control local cortical metabolic activity within a physiological range to avoid breakdown of energy homeostasis with dysfunction and possibly brain tissue damage."

Are we on the avenue to become migraine and stroke-free Cyborgs one day? In any case, neurotechnology is amazingly fast moving forwards. Let me repeat a old Yiddish saying that Niels Birbaumer, one of the pioneers in this field, recalled today at the end of his talk:

"Fun lojter hofenung wer ich noch meschuge"
(I have so much hope that it drives me batty)

Following markusdahlem on twitter

2009-07-04T12:31:00.009+02:00

Thanks for clicking! Here’s what’s on offer.

What you can expect as a markusdahlem follower on twitter are posts with:

**information on my research activities on the following topics:

Neurology (Migraine with aura, Stroke, Epilepsies, Parkinson's, etc.)
Nonlinear dynamics (Chaos theory)
Networks and Dynamics (follow #twynamics and follow twynamics)
Neuroscience in Berlin
Upcoming talks

If you are interested in both Neurology and Nonlinear Dynamics with a focus on therapy follow #nonlinNeurol and see here.

I try to keep

**my own occasional musings
**retweets, and thanks
**questions

to a minimum.

If there is enough overlap with what you tweet and what you don't, chances are I follow you.

(Thanks to Todd Montgomery from whom I have stolen the idea to write this blog see his)

Twitter Dynamics

2009-07-03T08:53:00.020+02:00

Please tweet #twynamics in twitter & refer to this page as http://tinyurl.com/twynamics

This is an actual experiment! You are part of it right now, even if you decide not to continue reading, because than you are counted as a non-responder (which is fine).

You heard about the small world experiments conducted by Stanley Milgram and the Six degrees of separation? Well this in the next generation of such experiments using twitter.

I want to learn if it is possible to create #twynamic as a trending topics and how long it takes.

Suggested tweet text:
Please tweet #twynamics see http://tinyurl.com/twynamics

What I did so far is create a new twitter account "twynamics" and followed the first 20 suggested users. Moreover, I tweet these top three twitter users (according to http://twitterank.com):

@jowyang Please tweet #twynamics see http://tinyurl.com/twynamics
@TweetDeck Please tweet #twynamics see http://tinyurl.com/twynamics
@mitchjoel Please tweet #twynamics see http://tinyurl.com/twynamics

and followed them from my new twitter account. I also announced this experiment from my twitter account "markusdahlem". Finally, I followed the first three new followers, all wearing revealing clothing.

To be continued!

Chaos & Migraine

2009-07-02T18:14:00.069+02:00

This blog post was updated and moved to SciLogs

Open scientists have more and more early "Aha!" moments

2009-06-28T01:36:00.001+02:00

Why I am an open scientist
The other day, I wrote about developing public understanding of science, now I came across the somehow interlinked concept of being an open scientist: scientists shall engage in making their work as transparent as possible. And no, not just writing about completed projects to peers and public, but about the scientific work in progress. For example, an experimentalist could keep a public lab notebook.

Challenges are to be discussed, but I immediately felt that the idea is straight forward and the rewards would outweigh risks. Traditionally, you had a lab notebook holding your unpublished work, until the data is transformed into results presented in a journal article. Nowadays that could be, and should be if possible, an open access journal, so why not starting with making also your lab notebook open. So far the straightforwardness: open access to information, maybe not entirely so, but at least during all stages to a certain degree. I guess, I do not need to mention the risks. What about the rewards?

What came as a reward into my mind was the early creation of "Aha!" moments. An "Aha!" moment or event indicates a change in the cognitive state. I first heard about this concept from Frank Ohl and Henning Scheich, former colleagues, but recently also found it in the Wall Street Journal: A Wandering Mind Heads Straight Toward Insight, which serves as a better introduction. These moments need an environment in which they can flourish. As far as my moments are concerned, they come—surprisingly—reliably but only if I write about my work with the reader in mind. Most of my articles changed quite dramatically in the process of writing, although I used to start writing, only when I thought the creative work is seemingly finished. I learned nothing could be more wrong. So for me being engaged in making my work more transparent by writing about it at an earlier stage, while it is still in progress, is nothing less than forcing insight.

Seeing zigzags

2009-06-12T05:56:00.015+02:00

You can literally see how your brain works during a migraine with aura and learn first hand about cortical organization

In the article that starts with the question "Does the migraine aura reflect cortical organization?", published in the European Journal of Neuroscience, I considered the old idea that flickering zigzag patterns seen during migraine with aura reflect properties of our neurons. Let me explain this briefly.

It is well known that neurons fire much more frequently if the condition they are tuned for is met. For example, one of your neurons may only fire if you see a vertical line at a specific location in your visual field. We know very well how such neurons are organized on the surface of your brain. This is called cortical organization. In general, this concept denotes how sensory conditions that must be met for neurons to fire—such as edge orientation, but also color or any other feature of the outside world—are spatially organized on the surface of your brain. Sometimes, this is also called a cortical feature map.

It seems natural to suggest that hallucinatory zigzag patterns seen during migraine with visual aura reflect the organization in the visual cortex representing the feature edge orientation. What other than a pattern of edges is a zigzag? That migraine aura reflects cortical organization was proposed by many scientists, but how to prove or at least support this hypothesis?

My idea was to translate our current knowledge of both cortical organization and migraine pathophysiology into a neural network model. I should then be able to reconstruct the flickering zigzag patterns seen during migraine in a computer simulation. The result is displayed on the right. In fact, the actual computer simulation is animated, but I chose a still image. Otherwise this blog would become unreadable for those who suffer from migraine. Flickering patterns can trigger migraine. For an animated version, please see my scholarpedia article Models of cortical spreading depression. We now have sample movies that can be compared with the zigzags seen during migraine, like we measure tinnitus by sample noise.

Public Understanding of Science

2009-06-11T09:17:00.009+02:00

One half scientific lobbying to increase the understanding of the value of science to society, the other half engaging the public in science to increase knowledge

For good or bad, public understanding of science becomes more and more an essential prerequisite for both getting adequate funding of research activities and finding a permanent faculty position. To my mind this is actually a good thing because the rapidly expanding Internet technology allows scientist to easily reach out to the public. (blogs in particular: it took 10 minutes to figure out how to create my own blog and here am I. The web still amazes me.)

To call for developing PUS as a task for scientists is quite different from the controversial concept of "publish or perish", a common advice how to sustain a career in academia. I admit, I like rather spending time developing my original research than writing papers. But once a paper is published, why not writing three short paragraphs to explain to the public what I did or maybe only why I did this research? I am doing both basic research carried out to increase our understanding of fundamental principles and applied research. Not always is an immediate benefit to the society obvious. But I can answer questions like: What has driven my curiosity to do this research. Why do I think this is a fundamental principle? What is my vision?

Do I spend much time pondering about these questions? Yes and no. Yes, I spent a large fraction of my time on thinking about the general significance of my work. Where will I go next, and why? This is part of my job. I will not spend much time for writing this blog. Frankly, in many cases I will just copy and paste text from my research proposals. There, I have to provide a clear flow of thoughts starting from the broadest scope of my research. Moreover, I get e-mails very other week from people asking about their migraines and what I think. So, I hope, this blog will actually safe me time for I can now refer to it.

Seeing your brain anatomy without fMRI scan

2009-06-05T07:08:00.039+02:00

Migraine sufferer literally sees his brain surface being curved
In the article entitled "Migraine Aura: Retracting Particle-Like Waves in Weakly Susceptible Cortex", published in the open-access journal PLoS ONE, my colleague, Nouchine Hadjikhani, and I uncovered in a rather unconventional manner the spatial form and temporal evolution of pathological activity patterns in human cortex during migraine with aura. We compared symptom reports of visual field defects with the topographic representation of these symptoms on the cortical surface obtained by non-invasive functional magnetic resonance imaging (fMRI).

Migraine maps and other maps

A keen engineer provided us with fascinating data. He marked the progression of his visual disturbances with a pencil on a sheet of paper. For about half an hour, every minute he newly outlined the location of his visual field disturbance while keeping his gaze fixed on a cross that he had drawn on the paper when the attack started. So we got many drawings, he called them migraine aura maps, each with about thirty lines.

Nouchine recorded then another map from his cortical surface—called retinotopy—using fMRI. In this map, positions in visual field are marked on the cortical surface, for example with a color code ranging from cyan (lower hemimeridian, 6 o'clock position) via blue (horizontal hemimeridian, that would be 3 o'clock) to red (upper hemimeridian, you got it). Let us first use this color code in the picture above, voilà.

What you see below is a 3D picture of the primary visual cortex with the same color code as used for azimuthal positions in the visual field.

The primary visual cortex is a credit card-size large area in the brain receiving visual information from the eyes. The cross with the 4 letters c,r,d,v mark anatomical directions and cuneus, lingual gyrus, CS, and occitipal pole are just names for anatomical landmarks known to the specialist. Important is that the primary visual cortex is organized retinotopic, that is, neighboring points in the cortex process information from neighboring points in the visual field. Without retinotopic organization, the picture would be not smoothly colored but randomly.

This retinotopic mapping allowed me to reconstruct the spatial patterns that correspond on the cortical surface to the engineer's lines in the aura map. I compared the aura map with his typical anatomical landmarks and we uncovered that the engineer actually saw his curved brain from within because there where remarkable correlations between his aura map drawing and the curved shape of his primary visual cortex.

Towards novel therapeutic methods using chaos control

These patterns revealed valuable information about the self-organization principles behind migraine pathophysiology. The gained knowledge, namely the confined location of the activity, opens up entirely new therapeutic methods based on chaos control. I work currently on intelligent neuronavigated transcraniel stimulation techniques that can be used in combination with biofeedback training via a brain-computer interface to persistently decrease susceptibility to this pathological activity in exactly the right location. My hope is that location is the key to non-pharmaceutical medical therapies using biomedically engineered approaches.

Suggested further reading:
Chaos and Migraine.