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Preview: Physiology physics woven fine

Physiology physics woven fine

Physiology is like software, while anatomy the hardware in human bodies. Physics, including biophysics, can explain many mechanisms of these 'software operations', in physiology and other allied medical disciplines. This blog emphasizes on this analytical

Updated: 2018-04-14T19:19:39.793+05:30


Life after Death, A journey into The Unknown


It was 4:30 in the morning and this man was preparing himself for his daily chores when he felt a sudden pain in the back. It was excruciating. He suffered a grand mal seizure and passed into unconsciousness. The doctors put him into ventilation with a diagnosis of meningo-encephalitis. He was in deep coma. The CSF glucose level read 1. He was as good as dead, with a total neocortical shutdown. But it was in this abyss of unconsciousness Dr. Eben Alexander discovered the hyper-reality of the superconscious. And he came back, to recount his tryst with the unfathomable.What is life, what happens when we die, do we really die, or does the soul (or whatever) continue to live on? These are indeed quite hard to comprehend or imagine. Erwin Schroedinger, the renowned quantum physicist, in his book ‘What is Life’, assumed that living organisms defied entropy by “‘drinking orderliness’ from a suitable environment” and thus avoiding itself falling into the decay of atomic chaos. Could it be that we are drawing from a single super-conscious entity by means of some kind of tuning in much the same way we tune our radios? From a human perspective each life can be said to have its own unique consciousness, essentially the “I”ness which seems intimately connected with the physical body. This might automatically point to the possible presence of as many souls as there are physical selves. Schrodinger surmised that the apparent plurality of souls was nothing but an illusion, the same way we perceive so many images in an array of mirrors and he drew a parallel to the mystic Indian Maya. Now, let us go back to Dr. Alexander’s Near Death Experience (NDE) revelation. He felt like he was a speck on a butterfly’s wing, and he wafted like a breeze from flowers to flowers amid a sweet hymn-like melody on its wings. There were countless other butterflies around, flowers were blossoming right in front of his eyes, indescribably beautiful waterfalls and “angels”. He also saw a beautiful orb of light, he was with the Divine presence! All this while he was in deep coma with a Glasgow coma scale of 6 to 7. Could all this arise from O2 lack, CO2 build-up, from previous religious conviction or something psychological? Or was it simply the manifestation of the diseased state? Dr. Alexander, a reputed academic neurosurgeon himself, strongly dismisses this. The ‘hyper real’ state which was so vivid and crisp, he argued, could just not simply occur in any other case or disease, or in ketamine induced dissociative anesthesia. Also NDE experiencers across different cultures spread far apart narrated a very similar incident and it did not tally with the person’s education or religious background. Eben himself had no previous bias, rather he was the typical science guy sort. There had to be life beyond death and he was certain that he witnessed that. So, does all this conflict with science? Does or can consciousness/soul reside outside of our brain or our physical realm? While purists would stick to the reductionist approach that soul existed only within the realms of the brain, Dr. Alexander thinks otherwise: “I think part of the problem is it’s like the guy looking for his keys under the streetlight. Reductive materialists are under the streetlight because that’s where they can see things.” Thus it would be foolish to analyze such an esoteric matter in the light of prevailing science. Our existing knowledge about neurons flounders helplessly to explain how a single neuron can recognize objects or landmarks (Halle Berry neuron).Even panpsychism, the theory that proposes that soul pervades everywhere and everything, is a good candidate. According to Integrated Information Theory (IIT), any system that has Integrated information above zero has consciousness, and the noted neuroscientist Christof Koch argues that the Internet could be 'conscious'. Recent advances in artificial intelligence research may also throw light in this regard and even radicalize the definition of  'consciousness'. Also, consciousness or qualia cou[...]

A Treatise on the Physics and Psychology of Heavy Metal Music


Though the metal fan-base is largely young, white, male, and blue-collar, and that it has been often associated with "brutally aggressive music played mostly for minds clouded by drugs", I must confess that I am a devout heavy metal music fan and a typical headbanger. However, I seem to take as much interest in other genres of music as well, including classical Indian music, old Bengali songs as well.But let me clear things a bit first. I am not a white, no longer in my youth, not a blue-collar and not an avid drug user. Yet the music just fills me with adrenaline rush, I feel energized and above all, the melodies just mesmerize me!Perhaps you may argue that metal song lovers may have a 'low self esteem', as this study might suggest; but I have evidence to the contrary too! You certainly can't dismiss these young physicists doing their research in the 'high energy' domain of the giga-electron-volts at the LHC labs in CERN, Geneva, as mere dolts!  Here is a 'sonification' of some of their mathematical findings into music as they delve deep into the Heisenberg's Uncertainty of finding the 'God particle', the revered Higgs' Boson! They, kind of, selected their data from a chosen hexadecimal set and then converted them into the more familiar octave formats, compressed them and mixed them with some bass/drums to make the more metal friendly. The 4-lepton part of this song could even strike a chord between the pro-Christ and the anti-Christ theme of heavy metal in some dark corner of your psyche, as they reach toward a low entropy, in a very similar way matter and antimatter behave. [Sonification in the context of science isn't a new kid on the block. Proteins (amino acid sequences) have already been heard and listened].Well, you guessed it right. I find a lot of physics and maths in it. Whereas most of you would disagree on the issue that hard rock had anything to do with any melody of any sort and would label it as high decibel noise, a very organized pattern of music can be discerned if one just judged it from a neutral and impartial standpoint. However, to be really be able to get into the heart of it, one ought to have a high musical processing power in 'real time', akin to having a faster CPU (Central Processing Unit) in computer jargon. What (musical tone) gets interpreted as a square wave to one's auditory cortex (or along the tonotopic pathway/basilar membrane), may actually turn out to be a composite of various other frequencies (their harmonics). This can be decoded in mathematical terms by the Fourier Transform. Thus what seems to you as a guitar belching out a harrowing 'noise' may actually be two or three guitars which differ slightly in phase, frequency or tune on careful scrutiny. It could be that I follow the music so well because I don't pay much attention to the lyrics or that English is not my first language that I can drift myself to the luxury and intricacy of the wafting melodies. Anyway, I must mention that some lyrics such as Iron Maiden's are so hard to overlook for they are so rich in Philosophy! Psychedelic drugs may enhance in understanding and following these artistic intricacies by inhibiting the dominant left hemisphere and thereby allowing the art-interpreting right half of the brain to be in charge.Then the length tension relationship the guitar string has to follow a particular frequency (tune) is governed by physics as well. It's amazing how the performers manage to pluck the chords at exactly the same place and with the same displacement on the time scale so reproducibly well. Moreover, the two guitarists play the tune in unison ! Maybe the drummer gives some kind of 'global clock source' for synchronization or perhaps 'mirror neurons' might play a role. Well I don't care, who does?Another aspect that baffles me is that how the 'disorganized' crowd synchronize themselves into the organized dancing movements at live concerts [see video:Lamb of God-Walk with me in hell; warning: explicit lyrics]. This might throw some light on herd behavior[...]

Innocentive NASA Challenge: Medical Consumables Tracking


As I am not authorized to share the details of the challenge, as per the agreement signed by me, I am sharing the overall structure of the problem here. Once you are through you may now look for the solution that I submitted, some more than 4 years ago. I am omitting "My Solution: • Introduction and Background: " part; as it may divulge  information from the challenge itself, which is prohibited. The below portion has not been altered post-submission, even though I could find many faults looking back. [I particularly could better have done without resorting to the undue rigmarole under this subheading: "Electronic cascading method". Should have explained my idea in simple terms and perhaps with some schematic, self explanatory diagrams. What I really meant was that each box would be like an element in an array of a 3D matrix (where the 3D matrix represents the array of medicine boxes for each day), and that each element/box would be assigned a unique value identifying it, corresponding to their orientation in space. This could be achieved by a process similar to DTMF encoding. The actual counting would still be done optically and the data sent to a memory module/register. Counting could be implemented by cascading binary coded decimal (BCD) counters.]  Below is the submission, uncut. "• Detailed Description of the Solution: The requested problem may be solved in a much better way than being done by standard bar-code (UPC= Universal Product Code=bar code) in a number of ways: such as, quick access time, minimum medicine handling, far higher accuracy, holds more data and ‘potential’ tracking to the ultimate end-user. An RFID device (Radio Frequency Identification) may look like a rectangular card, a ring, a wristwatch, wrist band, a bracelet or anything we may want it to be of the ‘required’ shape. We will concentrate upon both the ‘passive RFID tag’ (fig. 4), a batteryless device; as well as an ‘active RFID’, a battery incorporating device having an inbuilt antenna. They may be used both in a spacecraft and aboard the ISS. Before describing them it is pertinent to point out that the astronaut wear an ‘active RFID reader’ (interrogator module), whereas the medication boxes will contain RFID tags. Although this will marginally increase the power consumption, but it will certainly save more box space.    The ‘passive RFID label’ contains a batteryless circuit which may be inductively (Loop of wire) or capacitively coupled. Although we prefer the capacitively coupled one, here we briefly discuss the actions of an inductively coupled one, as it is easier to understand. A miniature in-built coil within the RFID label produces ‘induced electricity’ that powers the rest of the circuit, when it nears an RFID reader (the wristband). The EMF (from ‘induced electricity’) then transmits all the data, the RFID has been preloaded with. It may include user data, time, quantity in stock etc., which the ‘wristband or ring device’ sincerely relays to a nearby computer, PDA, mobile phone (??Service provider in Space!), or a USB memory stick.RFID is already in use in tracking cattle, dispensing medicines, checking medical inventory, managing expired/counterfeit medicine, etc.; and it is approved by the FDA for most of those stated. The tracking may be employed in two major ways:1). The conventional method: (Step A): The ‘inventory’ would be designed as shown in fig.1. A postage stamp has been pasted on the ‘main’ door to symbolize the ‘main’ RFID tag. Behind the main door are an array (fig.2 & 3) of medical boxes arranged in a week’s course (the grid may be modified according to need). Each day-numbered-boxes has their own unique ‘sub’ RFID labels (tags). These RFIDs have been exemplified in fig.3, as red/black circular pads. All the RFID tags will have information regarding the type of the medicine, quantity, expiry and other[...]

Innocentive Theoretical Challenge: Heart Implantation of a Medical Device


I must say that I am not authorized to share the details of the challenge, as per the agreement signed by me. Yet you can have a glimpse of the overall structure of the problem here. Once you have seen the salient points you may now look for the solution that I submitted to them way back in 2010. I am free to publish my proposed solution, which also sheds some light on the deeper requirements for the leadless device. However, I am omitting "My Solution: • Introduction and Background: " part, as it may divulge  information from the challenge itself. The truncated portion that appears below has not been altered post-submission, even though I could find some faults retrospectively. Below is the un-altered submission. "• Detailed Description of the Solution:As is conventional with these procedures, the patient is venepunctured (using aseptic and anesthetic precautions) in the groin and the femoral vein is accessed.  The Leadless Device is introduced retrogradely to the inferior vena cava and thence to the right atrium of the heart. All these procedures should be undertaken while under fluoroscopic control is assisted by echocardiographic guidance.  The LD may be conveniently delivered to its location, discussed later, by using a fiberoptic endoscope, which in addition to ‘being guided’ by the fluoroscopic/ echocardiographic screens; can visualize the anatomy of the right atrium and the right ventricle that lie proximally. In a study by Fujimura et al (fig 1, =Ref 3) a 3.6 mm diameter fiberoptic endoscope (with a latex balloon) was used to study the right heart anatomy of anesthetized dogs. The distal tip was inserted into the right atrium, where the balloon was inflated with air in 5 mL increments. Thus, it seems very likely that we could explore the human heart using a fiberoptic device having a diameter of around 4mm. The endoscope will, in fact, help to locate the best anatomical co-ordinates in the right heart (ventricle) where the LD may attach (reversibly). The LD must be secured to the RV (septum, wall or the apex). This could be done in the following ways:1. Modifying the LD shape (fig 1), so as to incorporate a ‘groove’ in it (fig 2) or as a ‘O’-ring at its ends (fig 2), which could act as an anchor for LD to the RV.2. The ‘modified’ LD may then be either sutured to the right ventricular myocardium using:a)atraumatic suture using fiberoptic guidance,b)Better still; secure the LD, with the help of silastic rings, as is done in male sterilization.c)An inflatable occlusion balloon (as in Foley’s catheter); that may be deflated, when necessary, for re-implantation (fig 3); BUT the volume of the balloon may interfere with the stroke output of the Right Ventricle, though that is miniscule, by physiological standards.d)Or, depositing the device in the pocket of the moderator band (septomarginal trabecula) (fig 4)Whichever way the LD is secured, the LD should be preferably anchored in a transversely approach, as a longitudinal placement may enable the LD to a ‘greater strain’ (RV axis; Ref 1) while the ventricle is contracting.It is quite obvious that some coverage of anti-thrombotic episodes must be provided during the procedure. This may include low molecular weight heparin therapy or therapy by aspirin or other pharmaceutical agents, so that the implant does not initiate a thrombotic episode, due to the LD’s irregular (or, perhaps its wettable surface) surface terrain.However, once the LD is implanted in the cardiac tissue; the irregularities in surface may, in fact, stimulate cell growth and adhesion (chronic endothelialization) (Ref 2; Patent application number: 20100063562 )Thus, the LD will finally adapt to the cardiac tissue in a way that the LD will not be a deterrent to normal functioning of the heart.• References and Notes: Ref 1: Septomarginal trabecula (also see wikipedia:, the s[...]

Revisiting the Sternocleidomastoids: Accessory Muscles of Respiration


We know that sternocleidomastoids (strap muscles of the neck), scalene muscles and alae nasi are considered accessory muscles of breathing, although some controversy exists. If you saw an asthmatic individual in his desperate attempts at breathing or an agitated person or a person exercising vigorously, you could watch these muscles in action. However, that wasn't exactly what I had in mind while I was doing this experiment. I was really thrilled to chance upon it. Kind of a serendipitous discovery in its own right. You too can figure this out easily. The placement of the surface leads were as shown on the right. Red dots were for the reference and recording electrodes whereas the blue dot represents the ground (as usual).  The neck muscles of each side were tested one at a time. For example, This wav file (open it Audacity or BYB neuron recorder) was obtained from EMG recording from the right sternocleidomastoid; the leads were placed on the right side and the ground lead on the manubrium. The head was at mid-line (neutral position) to start with. Next, it was turned to the right, then midline again, then to the left (without any external resistance applied), then against resistance applied by the left hand. The muscle of the right side moves the head to the left. Finally, the head was again restored in its neutral position. An improvised notation could be N to R to N to L to L+ to N (Legend: N=neutral, R = right, L=left, L+ = left against resistance).  Similarly, the left side was tested in a likewise manner (N to L to N to R to R+ to N). And this is the waveform obtained. The surprise awaited me, I was in for an ambush! While the leads were still on the strap muscles of the left side of my neck, I observed the EMG waveform in real-time. I noticed that as I was taking a deep breath, the EMG activity increased significantly. I didn't have to turn to my head to the right anymore! I then maintained this position by holding my breath. The activity continued. Here's the recorded .wav file. The associated camera recording will speak for it (see below: Youtube). Yes, it proved that it was indeed an accessory muscle called in to address forceful inhalation. I then did a forceful exhalation, but no increase in EMG activity was observed, buttressing my observation.  allowfullscreen="" frameborder="0" height="315" src="//" width="420">As you may have noticed that I have used the terms inhalation and exhalation, in lieu of, inspiration and expiration. Well, inspiration, it definitely is! Expiration? No way!Further analysis still awaits.Spikerbox recordings may also possibly illustrate simultaneous EMG activities in protagonist and antagonist muscles. More of these later.To be continued............This work by Amiya Sarkar is licensed under a Creative Commons Attribution 4.0 International License. Last modified: never Reference: hyper-links, unless specifically mentioned[...]

Making a Human Interface Device Using SpikerBox


Q said to Bond: It's activated by nerve impulses from the wrist muscles. This dialog from the 1979 James Bond movie, Moonraker, seems to fit into place when we talk about interfacing biosignals (surface EMG, in this case) with an actuator. [Watch a clip from the movie below] allowfullscreen="" frameborder="0" height="315" src="//" width="560"> In order to achieve this human-machine interface using our good not-so-old spikerbox, we need to estimate the output signal amplitude coming from the extensors of the wrist (around 5 mV), amplify the signal by some 300 times by cascading two LM 386 IC (or any opamp taking care that the device doesn't go into saturation) to about 1500 mV. We can then connect the output from pin 5 of the IC via the 250 MFD to a *1K resistor (* = value to be experimented with) to ground. Next we connect a wire from negative terminal of the electrolytic capacitor to pin 13 of CD 4066, a quad bilateral switch IC. The Boolean output (on/off logic) signal may then be driven into terminals of a 'laser pointer', whose push button terminals will have to be replaced by the output from pins 1 and 2 of CD4016/4066. A sketch of it is shown below. Pardon my bad drawing 'skill'! Interfacing should not be a problem as the power supply is 5V and CMOS ICs are happy with that. Output level of LM386 is at half the supply voltage level (i.e. at 2.5 V). At +5mV signal level, voltage at pin 5 becomes + 4.0 V [2.5 + (5*300*10^-3)], making the control pin of 4066 go logic high. A low resistance (250 ohm) path is established between pin 1 and 2 of this IC, hopefully switching the laser on. We better not play with darts at this moment! Another idea is to hook up an optical mouse in such a way that its internal potentiometer is swapped with a twin light-dependent resistor (LDR) as shown below. The picture at the left/top panel shows the component side of the mouse and the soldered side at the right. The three leads in the rectangle 'marked' in the right/bottom picture panel on the soldered side may be replaced by the new pot using a twin LDR, as shown in the middle panel (its middle two leads connected to form the central/common lead of the new three terminal pot as shown in red arrows).  The input maybe obtained preferably in stereo from the sternocleidomastoids of both sides. And the output amplified and fed into two LEDs separated by a window which communicate in a 'line of sight' with the 'twin LDR' setup. This would couple the two circuits (the SpikerBox setup and the laptop via the 'doctored' mouse) optically. The scrolling function (up/down) may then be undertaken by moving the neck sideways. The experimental setup may be as per this link. Details to be updated at a later date. You too may contribute.Disclaimer: This circuit is a mere prototype, liable to have errors. I will check it at a later date, got to hone my electronic skill a little and get out of any further procrastination.This work by Amiya Sarkar is licensed under a Creative Commons Attribution 4.0 International License. Last modified: Apr20, 2014Reference: hyper-links, unless specifically mentioned[...]

Surface EMG from Thumb: Strongly 'Opposed' ?


(image) Lead placement for the experiment, as shown on the right.
As I have already mentioned, the ground electrode sits atop
the manubrium sterni, on the upper chest (breastbone).

The camera recording is shown below. You can see the Piezoelectric crystal's spark and also hear its sound on snapping. However, I haven't yet had time to analyze if the spark did contribute some 'useful' static on the trace (open & watch this .wav file in BYB software).

allowfullscreen="" frameborder="0" height="315" src="//" width="420">

Method: Pressing on a piezo crytal (from a cigarette lighter) by 'opposing' the thumb against the base of the little finger (as shown by the figure). Electrode placement shown in red & green markings [the ground electrode sits atop manubrium sterni]. Muscle (mainly) contracting is "opponens pollicis", a small, triangular muscle in the hand, which functions to oppose the thumb. [Strictly speaking, opposition of the thumb refers to the tip of the thumb touching the tips of other fingers. But that way, generating enough force without creating an unnecessary torque that topples the piezo is quite a challenge! After all, I had no assistant, and had to hold the camera too with the other hand]

Concept: A fixed and constant amount of force is necessary each time before the spring yields and the piezo fires. This end point is supposed to be caught in the trace 1) as a sharp spike after the surface EMG pattern or, 2) can be 'used' as a 'static'.

EMG amplitude and rate of spikes will need to be analyzed in short, discrete time intervals by simple counting.

This work by Amiya Sarkar is licensed under a Creative Commons Attribution 4.0 International License.
Last modified: never
Reference: hyper-links, unless specifically mentioned

Interpreting Rate Coding Data: Counting Spikes in a Tracing & Consequent Plotting of Firing Rate Versus Time


We acquire data by using the following device configuration (the green laptop cable will go to the laptop mic input, running on battery power) as shown below. Please see this link to learn about the anatomy of a coaxial cable, so that you can make a ground connection off a coaxial cable.You can also take the ground off the reference point used for the Faraday cage clip, if you'd like. Incoming analog signals from the spikerbox will go into the internal ADC (Analog to Digital Converter) of the Conexant HD audio port of the laptop, whence the signal will be digitally processed. After a signal has been stored either in Audacity or in the BYB neuron recorder, we can open the'.aup' or the '.wav' file respectively later.Here, I am attaching a typical wav file captured by striking the quadriceps tendon with a percussion hammer (knee jerk). This is a deep (tendon) reflex. I'll post more on this later. You need to open it using either of the two softwares listed. I am posting a screenshot on the right.You can see three large spikes in the tracing. These spikes are actually not single/solitary, as they might innocuously suggest, but they are a conglomeration of many individual ones.The below tutorial explains how to interpret these raw data. allowfullscreen="" frameborder="0" height="315" src="//" width="560"> By the way, there's no simple way to count spikes! First, we need to define spikes. We can fix an arbitrary threshold, beyond which we will label them as one. Here are some very rudimentary thoughts on counting:Coupling/buffering the output from the laptop audio-out port via ICs like ULN 2004 Darlington transistor arrays to drive filament lamps [these filament lamps are a modest way to an integrator as the heat takes time to dissipate off]. The more the spike rates, greater will be the brightness. Then pick-up this optical signal by an LDR (Light Dependent Resistor) and then noting the resistance change [precalibration is necessary]. We can use capacitors too (using their exponential charging/discharging equations) or a linear optocoupler like MOC5010.Software: writing some code snippets to Matlab/Python programs Using a Foster-Seeley phase discriminator: However, a new algorithm should be developed.Converting the electrical signals to mechanical tracings on a rotating Kymograph [speed adjusted] may make it easier to read and countAllowing only signals above a certain 'predefined' threshold voltage to pass through. We may use diodes for this cut-off estimation. Next, employ a CD 4520, a dual 4 BIT binary up counter that advances from LOW to High transition on clock input '0' (CK0) when CK1 is high, after the signal has been "gate"d . We can use an appropriate crystal to this counting purpose. Many optically based circuits are available on the net.We can think of using a frequency to voltage converter IC like LM 2907But presently, i'll be counting them manually. My time limitations and fading electronic experiences precludes any pursuits of above kind.After we have successfully counted the 'rates' of 'action potential's, we can plot their number/spikes vs time plot in a linear or logarithmic scale. Here's where I positioned the ground electrode, on the manubrium sterni, on the upper chest (breastbone). The overlying hairs had been shaved and cleaned with spirit to reduce the input impedance. In all the spikerbox experiments the placement of the ground remained the same unless otherwise stated. To be continued....This work by Amiya Sarkar is licensed under a Creative Commons Attribution 4.0 International License.[...]

Basic Concepts and some 'Assumptions' in SpikerBox Biopotential Experiments


Exploring signals of very low amplitude, as is usual in most bioelectrical signaling, is not an easy job. In many instances the power line hum often drowns these weak electromagnetic dialects. In fact, our body acts as an antenna in receiving these wayward disturbances. We can curb these interference by the following means:Opting for battery operated power for the sensing device (the bio-instrumentation amplifier) as well as the data acquisition inputs, for example, a laptop that runs on battery. The brightness of the laptop display maybe set to maximum, as some laptops may emit significant stray noise when brightness is not saturated.Switching off any fluorescent lightsBy proper Earthing of the equipmentUsing differential op-amp configuration for adequate noise suppression by eliminating common mode signalsUsing a preamplifier; and coupler gels that reduce electrical impedance (resistance) between the electrode (lead) and the body surfaceChoosing an operational amplifier having a high CMRR (common mode rejection ratio)By using a unity gain amplifier (voltage follower) configuration that has a very high input impedanceEmploying a noise cancelling mechanism like the 'right leg driver'Using a Farady Cage for effective 'shielding' from electromagnetic interference (static)Employing a hardware filter (band stop or Notch filter) or a software program to eliminate/reject a particular frequency band (e.g. 50 Hertz or 60 Hz cycle frequencies)There's many more options to tackle the undesirable gatecrasher, the 'hum'. Yet it is so difficult to achieve. Easier said than done!To probe a physiological or pathophysiological response, a stimulus requires that it be precise/ accurate in timing, amplitude, reproducible, relatively less damaging and that it leaves a 'desirable' stimulus artifact so that we can calculate the delay in response in the tracing. Of the various types of stimuli available we generally prefer electrical stimulation over others; such as, mechanical, thermal and chemical, for the above reasons. Yet, we sometimes need to take recourse to other forms; as I was kinda forced to use mechanical stimulation to elicit a 'knee jerk' or that I had to abandon an interesting project (Hoffmann's reflex) as the TENS (Transcutaneous Electrical Nerve Stimulation) unit would invariably inject more than enough electromagnetic static into the waveform to render it useless. Marking the exact instant of an applied mechanical stimulus is bothering. I tried to circumvent this by making an "induction circuit", the makeshift switch of whichwould be placed on the patellar tendon and 'close' on tapping by a hammer, thus sending an intended static. Also tried to sandwich a piece of piezoelectric material between the percussion hammer and the quadriceps tendon. But none worked so far. I had to remain contented by recording with a camera simultaneously, so that it picked up the sound of patellar impact!The experiments I have done so far were mostly on obtaining 'surface Electromyography (EMG)' and nerve conduction velocity studies (NCV or NCS). The signals were fed into the SpikerBox input through coaxial cables into its RCA jack inputs, where it was amplified by an integrated circuit (IC) INA 2126P, an Instrumentation Amplifier. There was also a provision for rendering the electrical impulses 'audible' following amplification of the signal by LM 386, which was set at its default gain of 20. [For a more complete detail, please visit "Backyard Brains Wiki"] Thus, we could hear the action potentials and also interface the output with a laptop or a smartphone by softwares such as Audacity, Backyard brains neuron recorder (my own personal favorite) etc for real-time viewing, as well as, for recording for later storage, retrieval and analysis. The EMG recordings was done when the muscles were at rest[...]

Suspended Animation: The Resurrection


"Video killed the radio star" went the famous song by The Buggles. Well, to put it into context it would be only fair to say that after more than 3 long years of inactivity on this blog, that I  finally summon myself together to write yet another blog post. True, I was goaded by some of my readers particularly PC, a doctor and a little girl who was only in her 10th standard then, who got inspired to become a radiologist after going through my blog, yet I was still reluctant to oblige. Like almost everyone else, I was into the nebulous domain of Facebook, Twitter and the like. I was also doing numerous courses, now widely known as MOOCs, offered by different Universities across the world. I did electronics course, genetics, statistics and lots other courses which I thought was relevant to my subject of  interest and research activities. Surely, I learned a lot. But learning isn't all. You've got to educate, think over what you have learned and write about it. Only that shows the potential weaknesses of ones understanding when you start explaining them to the masses.And this ultimately catapulted me into writing blogs again. The Phoenix is raising its head now. My immediate plan was to share the solutions that I developed for Innocentive, a global network of millions of problem solvers who combine to help their clients to find rapid and financially viable solutions to varieties of challenging tasks encompassing the broad gamut of economics, physics, chemistry, agriculture and many diverse fields. They also offer huge sums for those who meet the clients' demands. I was drawn to it because of the challenges (innovation) and not for the incentive part. Albeit, no denying, that would definitely be nice too! I obtained permission from them so that I could share my own solutions with my readers in my blog. I got their approval in Aug-Sept 2012, still 'microblogging' held its overwhelming sway! Not any more.In the next few articles I will write on my theoretical and experimental approaches towards probing the physiological responses in nerves and muscle tissues in reaction to different stimuli. The instrument SpikerBox (figure appears below), that I'll be using has been provided for free by Harvard University,and it has been elegantly designed and manufactured in beautiful Michigan by smart guys who have formed a company called Backyard Brains. Their objective is to bring neuroscience to the masses at a nominal cost.A schematic circuit diagram for one of the electronic appliance is given below for the circuit enthusiasts.The course that is offering neuroscience education for free is being taught by Prof David Cox and other bright fellows goes by the fancy name MCB80x.The next few posts would thus elaborate my tryst with SpikerBox. The articles will undergo tremendous revision and improvisation with time as these experiments/protocols are very dynamic by nature. So, the next offerings will be rather a draft than a full blown article. I also have only 2-3 days to report to the overseers of the project, mainly an energetic and bubbling Greg Gaze.So, watch out my next post and do suggest any modification. We all love feedback.Last modified: never Reference: hyper-links, unless specifically mentioned[...]

Studying Genes the Ophthalmic Route by MRI, and That too in Living Subjects


It is said that the eyes are the windows to the soul, though science is yet to prove that given the elusive nature of ‘soul’. But researchers has now been able to probe genes in a traumatized brain using the eyes as a gateway.The brain is normally ‘secured’ from the circulating blood directly, so that endogenous and exogenous toxic substances, macromolecules can not gain entry easily into (and out of) the brain. More importantly, this ‘firewall’ like barrier, called the ‘blood brain barrier’ maintains the constancy of ions inside the brain such as K+, H+, Mg++, Ca++, which is vitally important for the neurons to function normally.The ‘blood brain barrier’ (BBB: see picture) results from the ‘relative’ impermeability of both the capillaries supplying the brain as well as that of the ‘choroid plexus’ covering the brain. Actually, the endothelial cells of the capillaries are tightly packed (tight junctions) and they are non-fenestrated too. In addition, end feet of astrocytes, a type of glial cells (cells that support and aid neurons), cover these capillaries.But there are disease conditions in which the BBB becomes leaky. For example, in traumatic brain injury, cardiac arrest, stroke and multiple sclerosis the blood brain barrier is breached, to different extents. In Alzheimer’s disease too, there is thinning of the capillaries as the disease progresses. As expected, the supporting glial cells, particularly the astrocytes, jump into action to seal the leaks. They proliferate, resulting in ‘gliosis’. Gliosis is also found in a tumorous condition of the glial cells called ‘glioma’.These glial cells contain a protein in them called the glial fibrillary acidic protein (GFAP). Naturally, there is an mRNA for it that ‘translates’ its formation in the cytoplasm. Scientists target this mRNA molecule because tagging it will track the GFAP and consequently the astrocytes in whom GFAP is expressed.Previously scientists had to inject MR contrast agents intra-cerebro-ventricularly or by other invasive techniques to map these leaking areas. Scientists at Harvard embarked on a novel idea. They produced a short cDNA sequence ‘complementary’ to the mRNA of GFAP. This short stretch of this ‘antisense’ oligodeoxynucleotide (ODN-gfap) would latch onto the GFAP mRNA just as a lock would to its key. They then tagged it with a paramagnetic molecule that they designed, called superparamagnetic iron oxide nanoparticles or SPION, a magnetic resonance susceptibility contrast agent. The SPION-ODN ‘report’ any inhomogeneity in transverse magnetization in ‘T2 star’weighted MRI scan, due to the paramagnetic properties of iron oxide. Liu et al also used a sequence complementary to the mRNA of beta-actin as well (actin is the most abundant protein in mammalian cells and its mRNA is found in all types of cells) to act as a ‘control probe’.They then anesthetized the mice, the animal model they selected; and caused BBB leakage by inflicting a small puncture or by performing bilateral carotid artery occlusion (BCAO) for 60 minutes. They also tried other methods (see reference). They subjected another group of mice to a sham (=false) operation (no puncture or vessel occlusion but the same operation) at the same time. BBB leakage was checked by T1 weighted Gadolinium-DTPA contrast MRI scan. Gd-DTPA was injected into the jugular veins of the mice. Leakage would show up as enhanced areas on T1 weighted scan (normally Gd-DTPA does not cross the BBB). Due to repair process to seal the leak, glial cells would be recruited and gliosis would result.The telltale signature of gliosis (and BBB breach) may be found in postmortem tissue samples of the brain. Previously, the GFAP antigen was detected by immunohistochemical methods. But the Har[...]

fMRI, BOLD and the Beautiful


When we want to examine the brain of a person noninvasively by Computed Tomography (CT) or MRI, we get a ‘snapshot’ of the anatomy (or pathology, if any) of the subject’s brain. We are however clueless as to its functional aspect. fMRI or Functional Magnetic Resonant Imaging allows us to do just that. The difference is not unlike a ‘still picture’ versus a ‘video of a moving train’. PET scans, previously described, also can asses the functional state of the brain.Whenever we do a task, think, dream, memorize, speak or see things, the brain is not activated as a whole; but only certain portions of it are activated. Activation, here, means increased metabolic activity of neurons in certain areas of the brain. Naturally, these ‘metabolically active’ neurons would demand more energy which would power them. The blood supply to these areas increases as a result of this metabolically driven vasodilation. The arteries then bring in glucose and oxygen with them, with Oxygen being transported in the form of Oxyhemoglobin (oxygenated hemoglobin or HbO2). Neurons on the other hand use up the oxygen contained in the blood, thereby reducing it to de-oxyhemoglobin or simply Hb. However, the alteration in tissue perfusion exceeds the extraction of oxygen by the neurons, so the concentration of deoxyhemoglobin within ‘the areas’ decreases. This causes molecular inhomogeneities in the magnetic field.Oxyhemoglobin is diamagnetic, meaning that they align perpendicularly to magnetic field lines. On the other hand, deoxyhemoglobin is paramagnetic, i.e. it aligns parallely and proportinately with the intensity of the magnetic field. This causes the inhomogeneity within the magnetic field (magnetic susceptibility) in the tissue sampled. This inhomogeneity is exploited in fMRI in terms of decay of transverse magnetization, T2*, with longer T2* values in HbO2 blood and shorter values in Hb (paramagnetic) blood.Since this stems from the oxygen content in blood, fMRI is also known as the BOLD ((blood oxygenation level dependent) effect.The machine is essentially the same as the MRI machine with echo planar imaging technology that permits faster imaging due to faster gradient switching, improved algorithm and faster CPU processing power. The patient/subject is placed inside the magnetic chamber and MRI signals are acquired, Fourier transformed and corrected for artifacts. Finally the computer reconstructs a 3D fMRI image out of this.As is obvious, we can learn about the motor areas of a patient by asking him to grasp an object or giving him any motor task and noticing which area(s) of the brain lights up. A neurosurgeon can then be cautious about not hurting these areas. Similarly, the mapping will help spare motor and other vital areas like auditory, visual and language areas from damage in radiotherapy procedures, in addition to neurosurgery. It can also detect occult Alzheimer’s disease and cognitive deficits including those of the autism spectrum and dyslexia (reading disorder).fMRI can also be employed to ‘read peoples’ minds’, thoughts, intentions including lie detection. Watch the video below which explains how an fMRI scan is done and interpreted.Thus the legal and forensic implications are obvious. However, in fMRI, correlation doesn't always mean causation. Whatever it may be, it seems that fMRI is very much here to stay, both in the clinics as well as in cognitive neuroscience research. It may also be combined with tractography, MRI or other diagnostic radiologic modalities.Hardenbergh et al combined Tractography techniques with fMRI, using a technique capable of rendering multiple color-coded functional activation volumes and fiber tract bundles. Many pharmacologically active drugs have effect on memory impairmen[...]

The World of Tractography Where The White Matter Tracts Appear Colored


The Central Nervous System (CNS) communicates with the exterior (sensory e.g. gets visual, tactile information etc. on the one hand; and motor, performs limb movement, posture regulation etc. on the other) via the peripheral (somatic) nervous system. It also connects with the interior (our viscera or organs) via the Autonomic Nervous System. That is, it does its job in a bidirectional way: by the motor or the actuator arm, and sensory or the receptor arm. For such ‘actions’ to occur, cables of nerve fibers are laid within our body. Wouldn't it be nice if we could visualize these cables, their dispositional anatomy or any pathology that could afflict them?Schematic of a 'peripheral' myelinated axon The brain and spinal cord together constitute the CNS. We also know that there are about a hundred billion neurons in the CNS. Each neuron has a cell body (soma), an axon wrapped by myelin, and many dendrites. (See figure). It is the axon that carries the information in the form of action potential. These cables (bunch of axons, called tracts) are not laid haphazardly. Nature tries to conserve space, length, energy and so on and thus the axons form into tracts in a topologically efficient way. They run up and down (also front-back and sideways) the cord to the brain, the organ that we will now concentrate upon.Your electrical wiring to your ceiling fan would include a switch and the fan itself. The wire (cable) from the switch would ascend vertically up the wall, make a 90 degree angle, and then reach the fan horizontally up in the ceiling. Likewise, in our brain, which is made up of two hemispheres, would connect. Three broad fiber types are seen: from one hemisphere to the other (commisural fibers), restricted to one hemisphere (front to back or antero-posteriorly are association fibers) and finally vertically (up down orientation go the projection fibers).Exploring the tracts can now be done in live animals including humans. Improvement in MRI technology has enabled us to see the tracts (tractography). Improved gradient coils, faster processors and superior software have shortened the scanning time, thereby reducing 'blur' due to organ movement (e.g. diaphragm) and patient movement. This procedure called Echo Planar Imaging (EPI) has given birth to Functional Magnetic Resonance Imaging (fMRI), Diffusion Weighted Imaging (DWI), tractography and many other diagnostic and research procedures.Consider the neuron shown in the above picture. Water molecules in the axon (yellow) are constantly in Brownian (random) motion due to thermal energy within. Hence they tend to diffuse constantly to come to equilibrium. In most of the cerebrospinal fluid spaces these microscopic motions are equal in all directions. This is called isotropic diffusion. But in myelinated neurons, as in the white matter fiber tracts, water motion is constrained due to the fatty nature of the myelin sheath (in blue) which hinders water flow across it. This anisotropic diffusion allows the flow of more water molecules along (parallel) the direction of the nerve fiber. The apparent diffusion coefficient (ADC) is thus more along the nerve fiber. Diffusion Weighted Imaging (DWI) can capture this microscopic water flow and delineate anatomically the orientation of nerve fiber tracts.Pyogenic abscesses hinder diffusion by virtue of their increased viscosity, a rheological property. In the early stages of acute cerebral infarction there is reduced diffusion too, giving rise to high signal intensity. However, in most pathologies of the brain the ADC is increased. Diffusion Tensor Imaging (DTI), a diffusion MRI technology, tracks fiber orientation by assigning values in ellipsoid voxels (VOlume piXEL). Ellipsoid because unlike isotropic di[...]

Relaxation in the Nuclear Microcosm


All of us want to give themselves a hard earned ‘rest’ after a “hard day’s night”, don’t we? So do the protons, perturbed by the destabilizing magnetic component of the radio-frequency pulse [which previously ‘happily’ aligned themselves to the externally applied magnetic field; one way (parallel) or the other (antiparallel)] applied at the Larmor frequency. It is like slapping an individual in a “merry go round” each time he came near a person who is paid just for slapping that person. But, when we call ‘spin’, we do not mean ‘spin’ the way we see them in a classical world. [We’ve given various names to the ‘quarks’: up, down, strange, bottom etc. depending on ‘something’ called ‘flavor’; and red, green and blue depending on ‘something’ called ‘color’.However, spin, flavor, color etc.‘in the quantum world’ have ‘no relevance’ to what we usually attribute to them in our everyday life. Things are a bit crazy in the quantum world, but I will take recourse to some ‘classical world’ analogies to make the description lucid.]Thus, the already aligned nuclei (parallel or anti-parallel to the applied steady external magnetic field B0), has now been perturbed owing to the ‘knocking’ by the ‘magnetic component’ (B1) of the electromagnetic RF pulse. The nuclei gain energy and sway away from the perpendicular to the horizontal (90 degree) depending on how long the RF pulse is applied. So, now the nuclei behave like ‘punch-drunk’( like a person who’s been reeling due to a strong blow to the head!). Remember, that this new angular momentum is also a vector quantity having magnitude and direction. It can be resolved in terms of a horizontal component (Mxy) and a vertical component Mz. Anyway, the proton does recover from this situation, after some time, once the external RF field has stopped. Typically, Mxy component decays faster than the recovery of Mz.The excited proton recovers in two ways and both forms occur simultaneously: (1) The excited nuclei which now have been ‘forced’ to lie horizontally (90 degree), ‘re-align’ themselves back to their ‘original position’ as they were before the RF pulse (perpendicularly towards the field of externally applied field B0); and (2) the energized protons dissipate their energies to the surrounding nuclei (horizontally) at their level. The first example, obviously, is called the (spin-lattice, or longitudinal) relaxation; while the second one, transverse relaxation (T2). There is little energy loss due to RF emission.T1 relaxation, also known as, longitudinal relaxation or spin-lattice relaxation can be best understood if you see the following Youtube video. [The spiral trajectory, in this case, reminds me of the laser experiment I did to satisfy my lesser friends. Analogically, the trajectory would be such, if the power supply were switched off.] In T1 relaxation, the proton loses energy to the surrounding lattice, by interacting with nuclei in the lattice which are in vibrational, translational and rotational motion. Clearly, the surrounding nuclei (lattice) having the same (or nearly same) Larmor frequency will efficiently absorb energy of the excited proton, resulting in a tiny rise of temperature.T2 relaxation (transverse or spin-spin relaxation) on the other hand, does not involve exchange of energy with the lattice.The magnetic moments of the protons merely changes phase. Here, the nuclei exchange “quantum states” (kind of, what Einstein called ‘spooky action at a distance’): an excited nucleus (proton) will transfer its energy and relax, while the neighboring nucleus in the lower energy state that absorbs it becomes excited. This loss of phase[...]

Understanding the Basic Principles of Nuclear Magnetic Resonance Imaging


Nuclear Magnetic Resonance Imaging (NMRI), better known as Magnetic Resonance Imaging (MRI) in medical parlance, is an invaluable tool in the study of the neurological system, soft tissue and musculo-skeletal system disorders. The word “Nuclear” was intentionally dropped later, as the procedure could then be wrongly interpreted by patients in relation to “ionizing radiation”, which certainly is not the case. However, the term Nuclear Magnetic Resonance (NMR) continues to be used in other (non-medical) fields of science, such as analytical chemistry, physics, biochemistry, petroleum industry, analysis of biological samples etc. In either case, the procedure and the basic principles remain the same. Paul Lauterbur was one of the pioneering inventors of this seemingly tough technological field.Matter is made up of atoms, which in turn, are composed of negatively charged electrons orbiting around the nucleus (look at the animation of a Helium atom on the left), consisting of positively charged protons and charge-less neutrons (with the exception of Hydrogen 1H nucleus, which contains a single proton and no neutron). These subatomic particles (electron, proton etc) somehow, can not be understood in terms of shape or color; instead they are denoted by their charge, mass or spin (angular momentum). An even number of them will cancel each other’s spin [just like two revolving spheres, in touch with each other would, in a ‘classical world’ (if one rotated clockwise, the other would rotate anticlockwise, canceling any resultant spin)].Hence, a net resultant spin would result in the nucleus only if it contained an odd (unpaired) number of protons, an odd number of neutron or both. [The concept that certain nuclear species had angular momentum was first suggested by Wolfgang Pauli, while explaining the fine structures in the Atomic spectra. In the presence of an external magnetic field, the spectral lines got split, depending on the strength of the field (Zeeman Effect).]Since nucleons bear a net charge (owing to the protons contained), the spinning nuclei will generate a magnetic field (since moving charges generate magnetic field). Each of these charged spinning ‘spheres’, hence, may be thought of as a tiny bar magnet having a magnetic dipole (that is a north-south orientation). [Electrons, similarly, have their own angular momentum though, responsible for molecular structure which nature uses, but they are not used by humans (Milestones in Spin podcast)] When we talk about “MRI” in humans, we mean proton nuclear magnetic resonance; i.e. NMR that detects the presence of hydrogen (proton) nuclei.Our bodies have a plentiful of Hydrogen atoms: from the water within us, in cells and in extracellular fuid, (and to a lesser extent to the adipose tissue (fat)). These charge-carrying ‘unpaired’ protons (Hydrogen nuclei) rotate around their axes, but since all are spinning in a random fashion (as there’s no coordinator of any sorts); their net spin is zero, or in other words, their net magnetic moment is zero (as shown on the left).Understanding spins aren't easy either. But, Prof. Stephen Hawking made it quite simpler for us using the real classical world analogy of ‘playing cards’ in his famous book A Brief History of Time (follow the link to learn more about ‘spin’). Having said that, the unpaired, positively charged protons having half integer (1/2) spins, behave like magnetic dipoles; it may now be understood easily that the spinning protons (nuclei) would align themselves to an externally applied magnetic field.Thus, in a static magnetic field, the randomly oriented ‘tiny bar magnets’ align themselves up according to [...]

Mobile Phones' Impact on Health


Mobile phones have drastically transformed our lives. Also known as cellular phones or cell phones, these gadgets not only incorporate a phone, as the name suggests, but also a lot of other technologically advanced features. They include a camera, a sound recorder cum music system, a Bluetooth device and many more depending on the model and the maker of the phone. They are called mobile phones since they can be used while on the move.A mobile phone maintains a two way (transmit and receive) communication with the nearby tower within a cell. Even when you are not talking on your mobile, it is constantly in touch with its ‘cell’. A cell may be thought of as the operational unit of a ‘base station’. A city or area may be likened to a bee hive, each hexagon representing a ‘cell’ having its own tower. As you move from one honeycomb to other, your mobile will change contact from one tower to another (another cell).Cell phones radiate high frequency (hence, microwave, as wavelength is inversely proportional to the frequency) electromagnetic radiation as a means of communication. One could easily demonstrate this electromagnetic emanation by putting a mobile flashing sticker close to a phone when it’s being used. This radiation can pierce our body tissues, particularly the head. But they could also microwave our scrotum if we keep them inside our pant pocket, as the phone is constantly in touch with the tower and emitting radiation unceasingly.The rapidly alternating electromagnetic field makes the polar molecules in our body move back and forth, as a tiny magnetic compass would move if the external magnetic field was allowed to change. This molecular movement results in heating of the tissues. Scientists were curious if this could harm us.Previously, it was thought that they could cause brain cancer but it was later found out that there was no significant relationship. There were some unconfirmed reports suggesting an association between mobile phone usage and an increase in the incidence of acoustic neuroma, a benign tumor of auditory nerve. The thermal effects arising out of the to-and fro effects of the polar molecules could give rise to the increased production of a class of proteins, called ‘heat shock proteins’ or stress proteins.Some drugs (like glucocorticoids, estrogen and progesterone) enter inside the cells where they combine with molecules called receptors, in the cytosol. This drug-receptor complex then translocates to the nucleus and commands the DNA into producing protein molecules by transcription. The resulting proteins typically account for the actions of these steroidal drugs. Heat shock proteins (like Hsp90) cover the DNA binding domain of the cytosolic receptors, preventing interaction with the DNA. When a steroid molecule attaches with the receptor, a conformational change occurs in the receptor releasing the Hsp, thereby freeing the DNA binding domain. Naturally, more stress proteins would mean more blocking of steroid receptors.Studies have also shown that microwave radiation at doses considered harmless caused DNA damage after two hours of exposure. All these led authorities in some countries advice Bluetooth usage and to keep your head away from your mobile. Read the next few lines if you really should keep your head away!Having said all those, let me state that the WHO, the American Cancer Society and the National Institute of Health have concluded that there was no scientific evidence that cell phone use had any adverse health risks.A University of South Florida research team wanted to find out any association of Alzheimer’s disease with cell phone usage. In the past, several s[...]

Mirror Neurons: Resonant Circuitry in Brain?


Back in the time of the “black and white” motion picture days, when “talkies” weren’t even born, we still could make out the essence of what Charlie Chaplin had to “say”. We understood his unspoken words, courtesy a system of neuronal networking, called the mirror neuron system. Another example: you observe a man kissing ‘his’ girlfriend, ‘your’ neuronal network that would otherwise activate when you ‘actually’ kissed her, would fire! Mirror neurons are at work. Seems to me a bit like ‘mechanical resonance’, where the string of a guitar resonates (vibrates at the fundamental or overtone frequency of its chord's natural frequency of vibration) when a second guitar/chord is strummed nearby.It all began with the experiment led by Giacomo Rizzolatti, a neuroscientist at the University of Parma. His team wanted to locate regions in the brain which controlled hand and mouth actions in monkeys, such as grasping or licking of an object. So, they had placed electrodes in the ventral premotor cortex, a part of the brain, [see fig] of a macaque monkey with the hope that whenever ‘that part’ of the brain were activated, the electrode would activate an electronic circuitry and give an audible beep. But all hell broke loose when a student entered the lab with an ice cream in his hand. Every time he was raising the ice cream to his lips, the system responded with a beep! Thus, although the monkey wasn’t having the ice-cream himself (and not moving his limbs), the mere observation of ‘the act’ fired the neurons that would otherwise be stimulated if the monkey ‘actually’ indulged in ‘the act’. The mirror neuron area, ventral premotor cortex, is also known as ventral premotor area F5.Mirror neurons are defined as ‘those’ neurons that fire when an animal performs some work and also when the animal observes the ‘same work’ being performed by others. In humans, the activity has been traced down to the ‘premotor cortex’ and ‘inferior parietal cortex’ regions of the brain. When a part of the brain ‘fires’ (discharges), it becomes metabolically active and the areas of this enhanced activity may be mapped by a procedure called fMRI (functional Magnetic Resonance Imaging). In a study by Iacoboni et al, 23 right-handed participants were shown different types of image clips (figure on the left). The pictures consisted of a teapot, a mug, cookie jar and related objects in different contexts, action and intention. At the same time the subjects were shown the pictures, the participants’ brains were also being mapped by fMRI to assess the regions of the brain that lit up during the procedure. The premotor cortex and some other parts of the brain showed a significant signal increase on fMRI scans in the action and intention clips. But the signal increase in the Intention condition was much higher compared to the Action condition, with high activity recorded in visual areas and in the right inferior frontal cortex, they noted. Thus the mirror neuron areas of right inferior frontal cortex were involved in understanding the intentions of others, in addition to action recognition.This ‘sniffing’ of intention behind action is essential to social animals like humans and a deficit in understanding this is seen in autism, a developmental disorder where there is lack of social smile, aloofness, absent eye to eye contact and marked impairment in interpersonal interaction. Autistic children can see sad or happy faces but they fail to ‘read’ the underlying emotions (sadness or happiness). Normally, children acquire mirror neuron activity by the time they are 1[...]

Fourier Analysis: The Art and Science of Finding The Needle in a Haystack


Every time I listen to the heavy metal band Pantera my wife would invariably wonder aloud why I listen to all this ‘noise’. True, many music lovers would rather refer bands like Pantera as quintessential noise than music; there are persons like me who can dissect the melody from the apparent chaos of runaway frequencies of guitars, drums and so on. I can even analyze and follow individual instruments over time. This is what Fourier is about, or stated otherwise, my ear & brain can be said to be doing a Fourier transform on the said musical piece.Joseph Fourier, a French mathematician, realized that all periodic waves could be ‘synthesized’ by mixing sine waves of right frequency, amplitude and phase. For example, a square wave could be prepared by ‘adding’ the fundamental frequency (the lowest frequency; say 70Hz) with an infinite number of its odd harmonics (e.g. 210Hz, 350Hz, 490Hz and so on. Harmonics are multiples of the fundamental frequency.) This is Fourier synthesis. Similarly, you could break down a periodic signal in which the amplitude varies over time into one of a frequency versus time graph. This is Fourier analysis, and it can be seen that here we are actually ‘decomposing’ the ‘signal’ into its frequency spectrum, over time. The process of decomposing a function into its constituent frequencies is known as Fourier transform. You can have a ‘hands on experience’ at what a square wave ‘looks’ or ‘sounds’ like and how a periodic wave is decomposed into its constituent parts here. Do experiment on the sine, cosine, triangle wave and square wave functions as well and turn on the sound of your PC while you are at this site!While Fourier originally devised this to solve the problem of heat propagation, the impact of Fourier analysis can now be felt in almost every field of science, instrumentation, entertainment and telecommunications, and even arts. Whenever you use your audio graphic equalizer to suit a piece of musical performance to your taste, you are doing a Fourier. Here you are boosting some particular audio frequencies while suppressing others, obtained by a Fourier analysis of the audio signal. You are assigning relative weights to the frequencies by sliding those sliders. Likewise, when you compress a picture (graphic) file using software such as JPEG, an inbuilt program does a Fourier transform,--> eliminates the weaker components from the analysis and--> then saves the information in a compact way.In Nuclear Magnetic Resonance Imaging (NMRI), the emitted radio frequency is Fourier transformed to give frequency versus time, throwing valuable information about nuclear spins. Fourier analysis may also be employed to remove mains AC hum frequencies, in mobile telephony and many other situations.One day, we may expect, that Fourier analysis may be used to pick up the ‘right frequency’ in the brain EEG waves and may put the study of ‘mirror neuron’ and ‘thought controlled devices’ into a whole new domain.Last modified: May15, 2013Reference: Fourier analysis (Wikipedia),Explained: The Discrete Fourier Transform[...]

A Tale of a Microprocessor, RISC and a Few Loops of miRNA


The word ‘microprocessor’ is generally used to designate VLSI and SLSI (Very/Super Large Scale Integrated circuits) devices which accept, decode and execute instructions presented in binary coded forms. They may be called the heart of the computer. RISC (Reduced Instruction Set Computer), on the other hand, is a type of microprocessor architecture that uses a simplified, yet highly-optimized set of instructions to deliver good performance. However, like ‘cell’ and ‘nucleus’, they too have been adopted in biology, and not without reason!Proteins are essential for cells as they perform various functions as enzymes, ion channels, receptors and so on. They are manufactured in the ribosomes, organelles present in the cytoplasm, under the instruction of messenger RNA (mRNA). This instruction code is encoded in the sequence of nucleotides that make the mRNA molecule. However, the sequence of nucleotides in mRNA is dictated in turn by the DNA that is present in the nucleus. Messenger RNA carries this message from the nucleus into the protein production units. But what would happen if we interfered with the ‘message’?RNA interference (RNAi) would occur affecting the regulation of gene expression. Micro RNAs (miRNA) are one of the small RNAs that regulate the expression of protein-encoding-genes, after the mRNA strand has formed. miRNAs have partly or fully complementary sequence to one or more mRNAs. This enables them to latch on to the mRNA molecule masking the ‘instruction codes’ in the mRNA strand, interfering with protein formation (translation). In other words, the gene has been silenced!miRNAs are first transcribed from DNA by the enzyme RNA polymerase II into primary miRNA (pri-miRNA). pri miRNA is then cleaved by another enzyme, RNAse III, called Drosha, into precursor miRNA (pre miRNA) (see the picture on the left). However, Drosha (an RNAase III endonuclease) is assisted by Pasha (partner of Drosha), another enzyme, in this task. Later, it was found out that these two resided in a 500 kilo Dalton complex, called the microprocessor (micro RNA processor). So far, all these have been happening in the nucleus of the cell. The pre miRNA then moves into the cytoplasm through the exportin 5 pathway. Next, Dicer, another RNase III endonuclease, makes a mature miRNA duplex, which is then ‘uploaded’ into a complex called RISC (RNA induced silencing complex). RISC then prevents translation of the mRNA strand, as the ‘partially’ complementary miRNA strand interferes with the translation of the mRNA molecule into specified amino acid sequences can not occur. We can compare complementarity of nucleotide bases in terms of a pair of gloves and its corresponding fingers. The information of the gloves' coordinates gets obliterated by the occupying fingers. This RISC dependent mechanism occurs in parts of the cytoplasm, called P bodies (‘p’ for processing).RNAi is very important for plants as they lack an immune system. Invading organisms can not dictate foreign protein formations as their RNAs are destroyed, not merely inhibited, as is usually seen in higher animals (animal miRNAs exhibit only imperfect homology to the mRNA in contrast to plants, and thus they only inhibit translation). Some of the tumor suppressor genes inhibit tumor formation by the action of miRNAs and not through protein formation. In humans, exploiting RNAi may be a useful tool in combating diseases such as cancer, AIDS etc. So it remains to be seen whether the microprocessor can bring a revolution in medicine and research as its counterpart in electro[...]

Metallica Goes The Stem Cell Way


I had previously written a little about stem cells. While researchers still don’t yet know exactly how the four factors transform the fully differentiated fibroblast cells back into pluripotency, possible explanations are pouring in.Pluripotency (by which the stem cell may become any tissue; muscle or nerve, for example) and “self renewal” (cells should not only differentiate, some ready stock of stem cells must be there for future need) are important determinants for stem cells.According to Shinya Yamanaka, the steps could be somewhat like this: c-Myc first confers the open chromatin state and immortality to the skin fibroblasts. But it also induces apoptosis by acting on the p53, “the guardian of the genome”. Apoptosis or cellular senescence causes the cells to die. Klf4 inhibits p53 induced apoptosis. Again, if we added only Klf4 and c-Myc we would get tumor cells (both being oncogenes). Oct4 here acts and makes ES like cells (ES= Embryonic Stem) out of what was destined to be tumor cells. Sox2 confers pluripotency and you’ve got what you wanted.Now, we just have to hand pick the right cells from the petridish. Scientists can do it either by looking for Fbx15 expression or the expression of nanog in the treated sample. Both Fbx15 and Nanog are targets of Oct3/4 and Sox2; but Nanog is found to be more closely associated with pluripotency, as is evidenced by adult chimera formation (chimera is a monstrous fire breathing creature like dragon of ancient mythology).There have been some important modifications. Researchers have shown that one could still get human induced pluripotent stem cells (iPSC) without the need of the c-myc oncogene. The mode of delivery of these four factors could also be undertaken by plasmids, rather than the traditional retroviral vector approach. Retroviruses (like c-Myc) could potentially induce cancer. You may like to hear this Nature Podcast where both Yamanaka and Rudolph Jaenisch give a very good summary. As a bonus, you may also appreciate another way of creating iPSC. Replace the genome in “early embryonic cells” or zygotes (fertilized eggs) during cell division. During cell division, the nuclear membrane disappears and the factors are no longer in the nucleus. They are in the cytoplasm. Dieter Egli explains that if you replaced the genome of this zygote with another (genome) while the cell was still dividing, the new genome would adapt to the new cytosolic environment and get instructions from the factors in the cytosol. It will go ‘back in time’ and become a stem cell.Now, a bit of refreshment. Watch this awe inspiring Metallica video called 'All nightmare long'. It portrays the Tunguska event, A-bomb, Soviet Revolution, American supremacy (?) and ‘revival of organisms’. Some key phrases are: “like a split worm, a part of the organism can reconstitute the whole”. Check about Planarians (flat worms, picture on the left), they not only reconstitute but also become separate individuals!“Instead of offspring, they become skin cells, nerves and muscle”- just as we described! Seems Metallica is well informed! Do see this wonderful video in YouTube (Metallica All Nightmare Long (Official Music Video)) Reference: hyper-links andOkita, K., Ichisaka, T., & Yamanaka, S. (2007). Generation of germline-competent induced pluripotent stem cells Nature, 448 (7151), 313-317 DOI: 10.1038/nature05934Developmental reprogramming after chromosome transfer into mitotic mouse zygotes, doi:10.1038/nature05879[...]

Atomic Force Microscopy: Feels The Atoms, Sees The Bonds


When it comes to viewing things on the atomic scale, one has to be very careful and innovative. To understand how an atomic force microscope works, we should better discuss a bit about its predecessor: the scanning tunneling microscope (STM). STM was invented by Binnig and Rohrer for which they got the Nobel Prize in Physics. Binnig and colleagues later went on to develop the first Atomic Force Microscope (AFM). Both AFM and STM are types of Scanning Probe Microscopy, which employs a probe that scans the sample.STM consists of a sharp probe tip, which scans over the specimen as the adjoining picture shows. First, the probe tip is brought near the sample manually, and then the finer adjustment of maintaining probe sample distance (height) is done by piezoelectric control. A voltage applied between the tip and the sample causes electrons to tunnel from the tip to the sample. As we have seen in Ohm’s law, the tunneling current will depend on the applied potential difference (voltage bias); and the height of tip-sample separation and the local density of states (factors determining ‘resistance’). If we know two of the three unknowns, we can calculate the other, which is actually done by the computer by data acquisition.We can do STM in two ways. We can keep the tip position (height) fixed as it scans the specimen topography (constant height mode). Here the voltage and height are both held constant, while the tunneling current varies. In constant current mode, the tip is always at a specific height over the specimen. That is, as the tip hovers over the rugged terrain of the sample surface and comes close to a raised spot, the tunneling current will increase. The increased current will be sensed, amplified and passed to the feedback electronic circuitry which will ‘lift’ the probe-tip by applying a voltage to the piezo crystal. Hence the electronic servomechanism maintains a constant tip sample distance in constant current mode. Piezoelectric crystals translate pressure changes into electricity (and vice versa) as we see in oven gas lighters and in mobile phone speakers.But STM has its inherent drawback: the sample has to be a conductor or a semiconductor, in order for tunneling to occur. Hence, biological tissues, non conducting polymers can not be imaged. So, the need for atomic force microscopy arose. Here again, Gerd Binnig played a pivotal role.Atomic Force Microscopy operates on a similar principle. First, let’s discuss how the music on gramophone record grooves is translated. The stylus (which overlies a piezo crystal) feels the groovy surface of the vinyl LP disc which revolves on a turntable. The mechanical vibration sets in a voltage in the piezo via the stylus. We get the surface topology in the form of music. Another great way of viewing how the AFM scans and interprets a sample is how a blind person ‘feels’ a surface by using a stick (see picture).In AFM, a very sharp tip (made of silicon or silicon nitride) is scanned over a surface with similar feedback mechanisms that maintain the tip at a constant force (to get height information), or height (to obtain force information) above the sample surface. This sharp tip is mounted on a cantilever, a rod like structure whose other end is fixed and unmovable. As the probe tip raster scans (i.e. scans in a zigzag fashion as done in TV scanning) the surface of the sample, a laser light is made to fall on the back of the cantilever. The light gets reflected off from this side and is detected by one of a dual photodiode. T[...]

To Unfold The Secret of Protein Folding, Foldit!


Genes in living cells dictate the cellular machinery to form proteins, the ultimate product of genetic information that is encoded in the DNA. These proteins perform various functions in the body. Some maintain the structure of the cells, some act as enzymes thereby catalyzing reactions, some act as pumps and ion channels thus maintaining ionic equilibrium and events like muscle contraction and action potentials in neurons, some act as receptors which recognizes ligands and binds them and so on.However, genes merely determine the sequence of amino acids in the protein. These amino acids form the primary structure of proteins by joining themselves by peptide bonds, just as different colored beads make up a string. Some amino acids in the protein undergo post-translational modification such as carboxyllation, phosphorylation, once the primary structure has been determined. Then the protein folds in such a way that it is most stable in the tissue conditions like pH etc. Indeed, living tissues try to make order (stable protein configuration) out of seeming disorder (random amino acids) in an apparent violation of the second law of thermodynamics.Folding also saves valuable space. But why and how should the protein fold? There are interactions between amino acid residues in the form of covalent bonding such as disulfide bonds; non covalent interactions like hydrogen bonding (between hydrogen and oxygen atoms in the peptide backbone), electrostatic or salt bonds between oppositely charged residues, and hydrophobic interactions whereby hydrophobic (water hating) portions of the molecule stay away from water. So, the protein folds to a conformation where the conflict is kept to a minimum. X-ray crystallography, NMR spectroscopy, computational biology and atomic force microscopy are useful tools in elucidating protein structure. Although the way it folds has been simulated in the computer, having humans do it as a computer game and then trying to figure out how the computer did so is surely worth trying. That’s where Foldit comes in.I first knew of Foldit about a week ago in the print version of the August edition of HHMI Bulletin. After a user downloads the program and installs it, he can see proteins as multicolored structures. All he has to do is to grab the mouse, then pull, twist and wiggle the structure so that it has the most optimal position using the mouse. The program will give you a hint should the atoms be too close or if the hydrophobic ends are sticking out. The program relies on the pattern recognition ability and visuospatial scratchpad (of the working memory) of individuals. Intuition plays a big role and thus scientists may not be much good at this game. The ABCs of Foldit are Apart(sidechains), Buried (hydrophobic domains) and Compact (protein).Users could also play online so that their scores were kept on the servers, and collaborated with each other evolving the game further (Online Darwinism?) Persons having exceptional folding solving abilities are aptly called 'foldit savants', possibly deriving its name from 'idiot savants', persons belonging to the autism spectrum but having extraordinary abilities in certain subjects like mathematics. Albert Einstein was thought to be autistic.Previously I have used Wolfram’s Mathematica and NanoCAD written by my friend Will Ware. NanoCAD is indeed an outstanding tool, given that it was programmed more than 10 years ago. The basics of NanoCAD and Foldit look rather similar to me, only the complexity and[...]

Of Twinkling Nanostars and the Possible Application of Stroboscopes in Biological Imaging


Imagine a strong crowd, as you see in a Manchester United versus Liverpool football match and you wished to concentrate on a particular person. How would you do it? Make him wear a fluorescent shirt and dye his hair (don’t do it in the middle of the crowd, I can’t guarantee your safety).Purdue University researchers have been successful in focusing at the cell of interest among a background of equally noisy and boisterous biomolecules and other metabolically active cells. Currently, researchers use immunological techniques to create an antibody to a molecule and then visualize the ‘molecule of interest’ by tagging the antibody to a radioisotope or a fluorescent dye; and flow cytometry can sort out different types of cells.The Purdue University team used gold coated nanoparticles with an iron oxide core that was impregnated in the cell they wished to see. They then subjected the specimen to a periodically changing magnetic field. The superparamagnetic cores (superparamagnetic nanoparticles have no net magnetization, but an external magnetic field can magnetize them) responded by rotating as the magnetic field rotated around them. The rotation could be seen in the ‘near infra-red’ light spectrum, as the incident light bounced off (scattered) the specially designed arms of the gold nanostar as it revolved. The rate (rpm) of this gyromagnetic (gyros means to rotate) twinkling could be externally controlled by varying the rate of the externally applied field. You now could identify the cell by its characteristic ‘twinkling’ (lighthouse type) effect.I am tempted to go beyond what’s been achieved so far. Here I go. I guess you are all familiar what happens to the rotating ceiling fan blades when you turn on a fluorescent lamp. Don’t you see a momentary snapshot of the three blades (some have 4)? That’s what where stroboscope comes in. It consists of a Xenon lamp (ordinary fluorescent lamps could do, but incandescent lamps won’t work as the glowing filament takes time to extinguish) flashing at a controllable rate. The electronic circuitry may be had here.Suppose that the fan is revolving at 1200 RPM and it is not changing. Set your stroboscope to flash at this rate. You’ll ‘see’ that the fan blades are absolutely not moving, which is certainly not true! But be there any mechanical defect in the fan, it will stand out as the centrifugal force widens it (provided that the fault is more or less tangential to the axis of rotation). Here also we are looking at our object of interest, aren’t we?Now lets look what implication it might have in biological imaging. We now know that the gamma subunit of mitochondrial F type ATP Synthase ‘actually’ rotates when it is synthesizing ATP (reverse rotation occurs when ATP is hydrolyzed). There are other locomotive units within the cell as well. They comprise of actin and myosin based molecular motors. Could we study them using an externally adjustable stroboscope? The optical (electromagnetic) signals so obtained may then be similarly broken down into simpler trigonometric (sine and cosine) functions by Fourier analysis (Fourier transform) as was done in the ‘twinkling nanostars’ experiment. At least, we expect to get rid of some 'noise' and some good still photos. But if we wanted better resolution and used higher frequency (electromagnetic) for it, some extraneous error will be introduced. It's a trade-off!Last modified: neverReference: hyper-links, unless specifi[...]

The Versatile GABAa Chloride Channel Receptor Complex


In today’s industrialized society we are constantly exposed to work related stresses. Consequently, anxiety and insomnia (sleeplessness) have become quite common. No wonder, we are using anxiolytics and sedatives more often; to get relief from the anxiety and insomnia respectively.Benzodiazepines such as diazepam (Valium), chlordiazepoxide (Librium) can effectively treat anxiety and insomnia. They do so by binding with a receptor (called Benzodiazepine-GABAa-chloride ion channel complex [henceforth to be referred to simply as GABAa receptor]) in nerve cell membranes. It is known that most drugs (medicines) exert their actions by combining with receptors: macromolecular complexes present in the cell membrane or within the cytosol or the nucleus.The GABAa receptor is a very versatile receptor complex (a hypothetical model is shown at the bottom). Its main action is to inhibit transmission along neurons in which they are present. Normally, proper functioning of the brain is ensured by a balance between the action of excitatory and inhibitory neurotransmitters [henceforth to be referred to simply as NTs]. Simply put, excitatory NTs (for example, glutamate) give a green or go signal; while inhibitory NTs (such as GABA) tell the nerve not to fire (red or stop signal). In this connection, it must be said that GABA (gamma amino butyric acid) is the most important inhibitory NT. When GABA binds with the GABA receptor ionophore complex, the receptor changes shape (conformation); and then a centrally located chloride channel, that is a part of the receptor itself, opens. Since the concentration of the chloride ions (Cl-) is much more on the outside of the cell than on the inside, Cl- now rushes in due to the increase in chloride conductance. The cell voltage goes further down and the interior of the cell becomes more negative (hyperpolarized) with respect to the outside. The cell becomes less excitable and is thus inhibited.Apart from maintaining the much needed critical balance already mentioned, they also ensure that the brain works in a relatively noise free environment. Billions of neuronal units are always firing in the background creating a constant ‘noise’. A constant release of GABA by the brain drowns out this noise thus improving the ‘signal to noise’ ratio, making the brain’s task of finding the proverbial ‘needle in a haystack’ a lot easier.The GABAa receptor not only binds with GABA, but it is a binding site for various other ligands. But before we discuss them, let us briefly analyze its structure first. The receptor has a pentameric structure which means that it consists of five subunits, and each subunit has four membrane-spanning (transmembrane) domains (see picture). And there are many of the polypeptide subunits to choose from a vast array consisting of alpha, beta, gamma, delta, pi, rho and so on. (In addition, there are six different forms of alpha, 4 beta and 3 gamma subunits). Thus, it’s no wonder that a great variety of GABAa receptors will be found, given the possible permutations!This receptor heterogeneity explains actions of various pharmaceuticals on the receptor. One major form of GABAa receptor (found throughout the brain) consists of two alpha1, two beta2 and one gamma2 subunits. In this isoform, GABA ‘somewhere’ between alpha1 and beta2 subunits, and benzodiazepines bind with the BZ1 (also called omega1) pockets located between alpha1 and gamma2 subunits. Benzo[...]

Errors, terrors, statistics and a confession


Past three months have been a bit too hectic for me. I had to finish the whole 3-year-course of physiology during that period, since by nature, I am a late starter. Now that the results are out and I passed my MD, I can breathe more freely.During those periods of forced 'bibliomania', I did not write any article for my blog, though I checked mails and sometimes I checked Sitemeter stats for my blog. I do this sometimes to see where my visitors were coming from, what they look for and for how long and so on. Almost everyone does it. It gives me pleasure when I see people from many different countries and educational institutions visit my blog. I noticed how the visits per day dropped from about 70 to below 35 during the period. I also noticed some errors in some of my pages, I'll rectify them as early as possible. Meanwhile, please point out errors so that I may correct them.I was in for surprise when I found a US military site (.mil domain) as one of my hallowed visitors. What on earth have I done? I clicked on the landing page; it was "Show me the enemy and I'll take action". The reason was now obvious, it was just some kind of 'code sequence identification algorithm' (pattern recognition) giving a 'false positive'. One puzzle I am yet to crack is what my friend from Ljubljana, Slovenia find so interesting in "cerebellum, electronically speaking". He (she?) visits my site at least 3-4 times per day. I guess, he has configured his browser this way so that this was the opening page each time he started the browser. Anyway amigos, have a good day and do visit.While I did commit some inadvertent errors in some of my pages (of my blog); the mistake I committed on the examination (viva part) eve was unpardonable and was least expected of a medical person, to be very honest. After finishing a summary of my thesis work, I sat down to prepare a powerpoint presentation on "water reabsorption in the kidneys". After finishing the two, the clock ticked 4 AM. I took 5 mg of Valium (diazepam) orally. (Diazepam, a member of benzodiazepines family interacts with the GABAa receptor-chloride channel macromolecular ionophore complex and help us to get sleep.) Then I went on to burn them onto a CD. But sleep wasn't really coming. I took another 5mg of valium, this time chewing the bitter drug and keeping it inside my oral cavity (this route would bypass the portal circulation) for about 5 minutes [THIS ROUTE FOR DIAZEPAM IS NOT RECOMMENDED IN ANY TEXTBOOK I KNOW]. I increased the buccal pressure (for better absorption) by blowing my mouth, while keeping my mouth shut (resembles Valsalva maneuver) during this time. Then I took a cup of hot tea to facilitate its entry across the mucosa (also hoping it would induce diuresis so that I would have less amount of of the drug next time I voided urine). It was 5:30 AM when I finally went to sleep, and I were to wake up at 7:00 AM!Thus you see how many mistakes I committed at one go: sleep deprivation, intake of a drug for sleep that causes psychomotor slowing and impaired cognitive performance, being fully oblivious of its half-life of 20-80 hours! It takes 4-5 half-lives for a drug to be 'considered' eliminated from the body. Next, if a person was aroused from REM sleep while on diazepam, he could become irritable and anxious. Moreover, there is the specter of anterograde amnesia (inability to remember lessons learnt during the drugs' duration of action).[...]