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 impairment, which can be seen in ‘telltale’ fMRI scans. Sperling et al studied the effects of lorazepam (a benzodiazepine) and scopolamine (an anticholinergic drug once used as ‘truth serum’ by the CIA) on healthy volunteers and found that they did impair memory and their functional coordinates could be reproducively mapped on fMRI scans (see figure on the left). I still shudder at the thought of what happened during my PG exam when I took a benzodiazepine.

Last modified: Mar 09, 2014
Reference: Integrated 3D Visualization of fMRI and DTI tractography
Gore, J. (2003). Principles and practice of functional MRI of the human brain Journal of Clinical Investigation, 112 (1), 4-9 DOI: 10.1172/JCI200319010

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 coherence of spins can be clearly seen in this beautiful video.

It can be understood easily that T1 and T2 values would depend on the surrounding molecular environment (tissues, for example). Hence, the values differ in different tissues. Again, since Mxy decays faster, as described, it may be understood why T1 is greater than T2 (usually, T1=5T2). Both T1 and T2 contribute toward contrast in tissues. T1 relaxation time is the time needed for 63% of protons to return to their previous equilibrium state. Likewise, T2 relaxation time is the time needed for 63% of protons to become dephased owing to their interaction with nearby protons. The contrast, naturally depends on the water content of the tissues. Grey matter has about 10% more water than white matter and this creates a contrast. We can also create contrast by varying TR and TE times.

TR (Repetition Time) refers to the time gap at which consecutive RF pulses are applied; while TE (Echo Time) refers to the time delay between the applied RF pulse and its reception (echo). T1 weighted images (T1W) are produced by keeping TR and TE relatively short, while T2 weighted images (T2W) are produced by keeping TR and TE relatively long. Water molecules being relatively light spins much faster than the Larmor frequency, making energy transfer rather tough (exchanging of packets of energy becomes more efficient as the relative angular velocity narrows). Consequently, water has a long T1 time. Proteins and nucleic acids being rather heavy, spin slowly. They also have problem with energy exchanging, and thus have a long T1. Cholesterol, a medium sized molecule, precesses near the Larmor frequency, efficiently absorbing the energy and giving a small T1 value.Thus (fat) liquid cholesterol in craniopharyngiomas, a benign tumor, appears bright on T1W images (T1 being small, the rate at which RF energy is released is fast. Hence, the signal intensity in NMR is high).

Subacute hemorrhage also has shorter T1, due to the presence of paramagnetic iron in methemoglobin present in the tissue, hence high signal intensity. Cerebrospinal fluid (CSF), edema (collection of fluid in tissue space or ECF) having more water content have both long T1 & T2 relaxation time. They give low signal intensity in T1 (dark) but higher signal intensity (bright) in T2W images. T2W images are superior to their T1 counterparts in case of infarction, edema, demyelination etc. Contrast agents like the heavy metal Gadolinium, a paramagnetic substance, has been used to reduce both T1 and T2 times by introducing inhomogeneity in the magnetic field. Gadolinium is complexed (chelated) with a substance called DTPA to prevent toxic build-up inside body tissues. This gives high signal in T1W but a low signal in T2W. It (the complex) does not cross the blood brain barrier (BBB); but disruption in the BBB or parts of the brain where it is deficient (circumventricular organs), take-up the substance and affects relaxation properties.

Below is an MRI showing changes in Subacute Sclerosing Panencephalitis, a complication of measles. Note: Panels A and C are T1-weighted images; B and D are T2-weighted images. The hypointense (darker) signal on the T1-weighted image (arrow in A) and a hyperintense (bright) signal on the T2-weighted image (arrow in B) can be clearly seen.

Given all these, it can be said that relaxation parameters of nuclei have enabled us in visualizing biological tissues nonivasively, identifying chemicals spectroscopically and a lot more as we shall see later.

• References: Magnetic Resonance Imaging: David D. Stark, William. G. Bradley, Jr.

• NMR spectroscopy
• Magnetic Resonance Imaging
• Principles of NMR
• William P. Dillon. Neuroimaging in Neurologic Disorders. In: Harrison's Principles of Internal Medicine, 17th Ed., Volume 2, McGraw Hill; 2008. p. 2491-2497.
• Ian L. Pykett, Ph.D., Jeffrey H. Newhouse, M.D., Ferdinando S. Buonanno, M.D., Thomas J. Brady, M.D., Mark R. Goldman, M.D., J. Philip Kistler, M.D., & Gerald M. Pohost, M.D. (1982). Principles of Nuclear Magnetic Resonance Imaging Radiology
• Time constants

Last Modified: Aug 19, 2010

Capturing Thought, in Real Time

Wouldn't it be nice if we mapped how the thought processes traveled across our brain, in real time? That's exactly what Mazahir Hasan et al of Max Planck Institute for Medical Research in Heidelberg, have enabled us to view, when an action potential (AP) is underway in the central nervous system (CNS). The researchers introduced fluorescent calcium indicator proteins (FCIP) into the brain cells of mice by means of viral gene vectors. Each time an AP was underway, a lot of ionic phenomena happened. For example, the fast Sodium channels (Na+) opened (letting positive charges to the interior of the cell) leading to depolarization, Potassium (K+) channels opened (to bring back the resting membrane potential to normal, since K+ egress out of the cells) and so on.

Next , the impulse is transmitted to the post-synaptic neuron through the agency of neurotransmitters. But, for this 'coupling' between the presynaptic and postsynaptic neurons to occur; Calcium ion (Ca++) levels in the synaptic knobs of the presynaptic neurons must rise for effective degranulation of the presynaptic vesicles. And that's precisely these researchers were banking upon.

Just before the degranulation of synaptic vesicles begins; calcium ion concentration surges. Such short calcium currents peak within milliseconds, making them the appropriate ions for studying fast neuronal activity. Previously scientists had measured such currents by using microelectrodes implanted within the brain; but this method was quite unsuitable in studying moving animals or for a longer time period. So, they went on to produce stable transgenic mouse lines responding to functional calcium indicators; (including 'inverse pericam' and 'camgaroo-2') using viral vectors. These transgenic mouse lines were under TET inducible promoter (tetracycline, a broad-spectrum antibiotic) control. The TET system offered the advantage of targeting combination of different neuronal cell assemblies. The other side of the Ptetbi (bidirectional promoter tetracycline) promoter was attached to the firefly luciferase gene. They were also sensitive to doxicline (another antibiotic belonging to the same category as tetracycline) in terms of regulation of luciferase, as well.

They then used a heteromeric sensor protein called D3cpv, which was made to produce in the nerve cells of the transgenic mice. Two subunits of this protein reacted to the binding of calcium ions in a way that when the yellow-fluorescent protein (YFP) lit up and the cyan-fluorescent protein (CFP) intensity diminished. When calcium was bound to the D3cpv complex; CFP (cyan fluorescent protein) and YFP (yellow fluorescent protein) came closer together bringing about FRET, in such a way that there was a visible color change, 'visually' or optically indicating the progression of action potential in real time. CFP and YFP are spectral variants of GFP linked together by a Ca++ sensitive linker.

They used 'two-photon imaging microscopy' to study this phenomenon. They excited thinned out rat skulls using two-photons simultaneously using 'mode-locked' Titanium-sapphire laser. They then amplified the signal using photomultipliers and analyzed them.

The resolution of the experiment was limited to less than 1 Hz (frequency of action potentials). They conferred that human thought processes might be mapped in much the same 'opto-physiologic way', in contrast to the usual electrophysiologic approach. Not only does the experiment throw light on the thought processes in real-time, but also, it is expected that it will be useful in the pathophysiology and treatment of Alzheimer's disease, Parkinson's disease and Huntington's chorea.

FCIP-positive cells were found in the hippocampal CA1 and CA3 regions, mossy fiber areas of the dentate gyrus, neocortical pyramidal cells and olfactory receptor neurons, they remarked. They studied cortical pyramidal cell, olfactory and optical responses in the mice in their experiment.

Hasan, M., Friedrich, R., Euler, T., Larkum, M., Giese, G., Both, M., Duebel, J., Waters, J., Bujard, H., Griesbeck, O., Tsien, R., Nagai, T., Miyawaki, A., & Denk, W. (2004). Functional Fluorescent Ca2+ Indicator Proteins in Transgenic Mice under TET Control PLoS Biology, 2 (6) DOI: 10.1371/journal.pbio.0020163
Last modified: never
Reference: Damian J Wallace, Stephan Meyer zum Alten Borgloh, Simone Astori, Ying Yang, Melanie Bausen, Sebastian Kügler, Amy E Palmer, Roger Y Tsien, Rolf Sprengel, Jason N D Kerr, Winfried Denk & Mazahir T Hasan. doi:10.1038/nmeth.1242

Duroquinone: A Parallelly Processing Chemical Computer

Dr Anirban Bandyopadhyay of the National Institute for Materials Science, Tsukuba, Japan, have developed a tiny chemical nano-brain, that could one day be guided by remote control. These machines could make surgery on human bodies easier and help revolutionize the computing power of future computers.

Scientists have built nanobots (nanoscale robots; nano means a billionth of a metre) previously but these bots could not be controlled by outside means. Dr. Bandyopadhyay has now devised a nanobot, a chemical one and not mechanical or electronic one, that can be controlled from outside.

This promising nanomachine, just 2 billionths of a meter across, consists of a molecule called duroquinone. A single nanomachine comprises of 17 duroquinone molecules; with one molecule at the center and remaining 16 surrounding it. All these molecules are connected by hydrogen bonding. As is shown in the figure, each duroquinone molecule has four spoke like arms jutting out from it, which can be independently rotated to represent four different states. Thus they can be made to represent four different 'logic states', bits: 0,1,2,3. While ordinary computers work on binary logic (0,1), computers using this technology would have four billion possible combinations with this chemical brain.

The molecule at the center, to which the rest are connected, can be controlled by a scanning tunneling microscope (STM). This machine is not only capable of 'manipulating/directing' their (nanobots') orientations, it is also capable of 'reading' the states they are in. They act rather like both a transducer and a receiver. By tweaking the central molecule, one could switch the nanobot's configurations. Comparable switches in electronic circuits include CD4066, a quad bilateral switch, electrical relays, transistors and others. But here, we are controlling a chemical device by using STMs. In future, we may be able to operate the duroquinone machinery by using the conformational properties of proteins, by optical devices like lasers and may be other electromagnetic devices too.

The researchers were inspired by the parallel processing circuitry of the glial cells in the brain.
Said Dr. Bandyopadhayay, "Doctors will inject molecular machines attached to similar control unit, the assembly will go to the target part inside our body through veins, and carry out bloodless surgery. Till now several molecular machines have been built, prior to this work, but there were no machine that could control them."

Aspirin and Ion Trapping

The property of cell membranes or biological membranes that cover the cells all around, is an important deciding factor in permitting or denying entry of molecules to and fro. Any drug or molecule has to have an aqueous phase (water soluble) in order to dissolve in the surrounding water molecules and negotiate further. At the same time, it has to be lipid soluble, to pass through the hydrophobic domain of the cell membrane. Some peculiar instances arise from these effects.

Aspirin, a non steroidal anti inflammatory drug (NSAID), is used to treat fever, pain, coagulation disorders and various other ailments. Chemically it is a weak acid, acetyl-salicylic acid, a semi synthetic derivative of salicin, a chemical extracted from the willow bark, which was seen to be of use in curing fever and pain. When aspirin is ingested, it goes inside the stomach where the pH is in the acidic range (pH is low). Aspirin being a weak acid, can not ionize in the acidic pH of the stomach, according to Le Chatelier's principle. Thus, it behaves like a non-polar compound in the gastric lumen. Therefore, it hardly faces any difficulty to enter inside the epithelial cells, as non-polar compounds behave as lipophilic (hydrophobic) compounds. But once inside the cell, they come across an entirely different situation. The pH is high (alkaline) here. Aspirin ionizes as a result. The problem starts. Ionized aspirin now behaves as a polar compound. What a volte face! Being polar, it now can not diffuse back, as it can not cross the lipid barrier in the cell membrane. Aspirin is now trapped inside, to the detriment of the patient, as the likelihood of peptic ulceration increase. This phenomenon is known as 'ion trapping'. Thus, aspirin and other inhibitors of the cyclooxygenase pathway like ibuprofen or acetaminophen (US) [= paracetamol (UK)], plays a very important part in ulcer causation. COX enzymes are in charge of producing chemicals called prostaglandins and other bioactive molecules. Prostaglandins (PG) have a varied role spanning from fever and inflammation to pain. They also ensure the vitality and vascularity of the gastric epithelium, in addition to having an ulcer prevention role in the stomach and duodenum. Hence, pathways interfering with PG synthesis will likely cause gastric ulcers too, along with the desired objective of analgesia or antipyresis.

Another fine example of ion trapping is that of the anti ulcer drug omeprazole. The acidity of the stomach is due to the secretion of hydrogen ions (H+) by the parietal cells (oxyntic cells) of the stomach. This secretion is helped by an energy-driven pump, called the proton pump (H+/K+ ATPase), since H+ ion is same as a proton. Drugs such as omeprazole, pantoprazole, rabeprazole, esomeprazole and other such drugs inhibit this pump; and hence grouped under proton pump inhibitors (PPI).

Omeprazole, for example is a prodrug (has to be converted in the body to be activated). It is alkaline in nature and has to be given in an enteric coated form so that it can not be degraded by the acidity of the stomach. It dissolves in the alkaline environment of the small intestine, and as expected, it does not ionize. By not ionizing, it behaves as lipophilic and gets absorbed across biological membranes; is transported by blood to be secreted in the parietal cells. There, in the apical canaliculus, where the pH is very low (acidic), it dissociates into the active sulfonamide cations and consequently gets trapped (cations are positively charged ions, so named because they are attracted towards the cathode), which then cause disulfide linkages within the H+/K+ ATPase molecular structure to occur. The proton pumps get blocked. Acidity of stomach decreases. Ulcer healing is facilitated. Physics, physiology, chemistry, medicine are all inter related. United we stand.

Last Modified: Mar10,2014

Aging, Immunity, Inflammation and Glycation

It has long been known that the level of proinflammatoy cytokines such as interleukins 1,6 and tumor necrosis factor-alpha rise with age, so does inflammatory diseases like cancer, arthritis, with age. Sleep, exercise and other healthy lifestyles lead to a decrease in the level of these substances. For example sleep reduces TNF-alpha, IL1 and IL6, whereas exercise causes a decrease in the acute phase reactant, c-reactive protein (CRP), a substance typically associated with inflammation.

While immunity plays a vital role in protecting our bodies against foreign invaders, excess of it can damage us. There are even some situations where our bodies are unable to distinguish between self and non-self (foreign) proteins, due to a defect in immunity. It then turns itself on against our own proteins. Some researchers argue that this might play a role in aging. Indeed, autoimmune diseases become more frequent with age.

Another contributing factor in aging is glycation. Glucose can bind with non-glucose molecules to form different molecules, this reaction is called glycosylation. Enzymes, catalytic substances, can facilitate this reaction. However, glycosylation can also occur non-enzymatically, it is then known as glycation. In diabetes, we measure the glycated hemoglobin content (HbA1c) to have an overall (and integrated) view of blood sugar control, for the preceding 2-3 months. This is because of two reasons: since the red blood corpuscles (RBC) live for about 120 days, the hemoglobin (Hb) can also be thought of for living as many days; and that glycation reactions being independent of enzymatic activity, will thus reflect the blood sugar concentration. Glycated end products (AGE or advanced glycosylation end products) are frequently referred to as Amadori products, Maillard reactions or Schiff bases; though minute differences exist among them. It is expected that in diabetes, where the blood glucose levels remain elevated, the glycated products will be more. These are responsible for microvascular complications of diabetes such as diabetic nephropathy (kidney/renal failure) and diabetic retinopathy (may lead to blindness). These damages result from AGEs and glucose combining with protein molecules in such a way that these protein molecules become extensively cross-linked. As a result, the protein shape (conformation) changes: they may clump together or their functions may reduce, as a result. Diminution of function is due to its change in structure, both secondary and tertiary (folding), as protein function depends not only on the sequence of its constituent amino acids, but also the way the are arranged in space. Aspirin, carnosine, alpha lipoic acid and some other substances inhibit glycation. On the other hand, synthetic molecules, such as Alt711 can break the cross-links which have already formed. These agents may help us combat aging by interfering with glycation. Thus it is evident that glycation will leave its imprint on aging, by interfering with cell function.

Related posts: Aging: From a General and Evolutionary Perspective; Aging, Mitochondria and Free Radicals; Hayflick limit, Telomere and Aging

To add Spice: Don't "Bend it like Beckham"

In my previous article, On her majesty's service..., I wrote about how the sperms 'sniffed' and chased their way to the ovum till it nailed her down. But for the sperms to reach it's destination, it has to be deposited in the right place. Thats where this organ comes into functioning. Its name is penis. It is a very interesting organ. Just like the states of matter (solid, liquid, gas and plasma), it can be soft, rubbery, and small or it can be hard and long. It not only injects (ejaculates) sperms, but also it acts as a conduit for urine to flow out of our system. Hence it has been christened as the genitourinary organ.

When mosquitoes bite us, their proboscis get hard, for a soft one can not penetrate our skin. Likewise, it needs a hard (erect) penis to enter the vulva. You would say, its nothing great; the muscles there would do this job. Here, we have no skeletal muscles, only smooth muscles are there. When we are stimulated erotically, say by seeing an erogenic picture/video or in our vivid REM sleep dreams, the brain sends the corresponding electrical impulses through the nerves (nervi erigentes). These nerves secrete (neurotransmitter), neither nor-adrenaline, nor acetyl choline and hence are classified into a separate group called the NANC fibers. They secrete a chemical substance called nitric oxide (NO). (Nitrogen has five valence states and thus forms 5 different compounds with oxygen; nitrous oxide, N2O, is another compound that is used in medicine, as an anesthetic). This gas, previously called EDRF or the endothelium-derived relaxing factor, relaxes non-vascular smooth muscles in the corpora cavernosa of the penis, so that more blood can rush through it. The penis gets tough, as a result. Nitrous oxide stimulates/activates an enzyme called guanylyl cyclase to form cyclic GMP (guanosine mono phosphate). It is cGMP which brings about erection. Well, this (cGMP) is finally broken down by an enzyme, called phosphodiesterase and the erection ends. Sildenafil (the popular drug viagra), tadalafil etc inhibit phosphodiesterase, making the staff stay erected longer. It can act only if the nerve supply is intact. It also causes visual disturbances (impaired blue-green discrimination) as phosphodiesterase also plays a role in vision. Viagra can add vigor to the diabetics suffering erectile dysfunction. Bear in mind, erection for too long a duration can be hazardous, a condition known as priaprism. The penis may slough out! Viagra, can also be used to treat spasmodic arterial diseases such as Raynauds phenomenon (blanching, bluish and cold fingers;- in a nutshell), refractory pulmonary hypertension (raised blood pressure within the lungs resulting from vasospasm) and other diseases. However, since it dilates arterioles, there is a chance of hypotension, due to diminution in the resistance in the vascular bed, especially in persons taking concomitant drugs, such as nitroglycerin (used for the treatment of cardiac pain or angina) and antihypertensives (blood pressure lowering drugs). A few cases of myocardial infarction or heart attack have been reported. Prostaglandins such as alprostadil; phentolamine and apomorphine can help us add spice to our lives.

I would do injustice, if I did not mention how the testicles are kept in an air-conditioned chamber called scrotum, in this context. There is a heat radiator system that operate in the scrotum which keeps the temperature 2 degree Celsius (centigrade) lower than the core body temperature. It is effected by the position of the testicles (which is not in direct contact/apposed with the body) and the radiator fins just mentioned (the pampiniform venous plexus). This is necessary for effective spermatogenesis to occur. Persons who wear tight pants, works in hot environment (furnace workers, vehicle drivers exposed to engine heat) have impaired spermatogenesis and the chance of infertility (NOT impotence) is great in them.

Lastly, about the nomenclature of this post. 'Bend it like Beckham' is a movie about the legendary football player David Beckham and Victoria (of Spice Girls fame) is her wife. How Beckham makes the ball bend in 'mid air' can be explained by Magnus effect, which I have discussed in my previous post. I hope I have explained my stand.

Cell Membranes: Smart Wrappers

The cells in our bodies are covered by a coat called the cell membrane, which is also known as plasma membrane. This membrane is bi-layered, and is composed of phospholipids, among other things such as proteins. The interior of the cells contain water and the cells themselves bathe in an ocean of saline water (a legacy from our marine ancestors). Hence, the bilayer is fashioned in such a way that the water loving (hydrophilic/polar) portions of phospholipid molecules are in contact with water lying external and internal to it. The structure of phospholipids resemble matchsticks; the tips representing hydrophilic phosphate parts while the shafts represent lipid portions, hydrocarbon chains. Thus, it can be very clearly comprehended that the tips of these matchsticks will be oriented exteriorly and inwardly (as is seen in the picture), while the hydrocarbon ends (non polar/hydrophobic), lie buried deep within the membranes' middle portion.

This membrane is in no way static, as the picture might convey. It is highly dynamic and this gives rise to membrane fluidity, which is contributed largely by cholesterol. Imagine a pond with numerous soccer balls floating on the water. You throw a heavy object, say a stone on them. The balls will make way for the stone to go through them before it sinks. Moments later the balls will again fill the gap, the stone created, thus realigning themselves. The cell membrane possesses this property, fluidity. This is essential for the cell to change shape (RBCs change shape while negotiating small capillaries), endocytosis (a process by which cells engulf external particles), receptor conformational changes and many others.

The protein molecules that are studded/embedded within the cell membrane serve various functions. They act as receptors (molecules that interact with various ligands), structural proteins, pumps, carrier proteins (helps in ferrying molecules by facilitated diffusion), ion channels (conduits for ions), enzymes and adhesion molecules (helps cells stick/adhere to themselves and to the underlying basal lamina or basement membrane), to name a few.

Cell membranes also help maintain the polarity of the cell, both by electrical (ionic) insulation and Na+/K+ ATPase pump activity. Membranes that cover intracellular bodies (organelles), also resemble cell membranes and they serve vital functions too. For example, mitochondria generate harmful free radicals, which could wreck havoc had it not been covered by this biological membrane. This intelligent mosaic carpet thus continue to amaze us.

Lithium: From Here To Eternity

The lightest metal on earth, Lithium, is an alkali metal. It is unique in many aspects. Like all alkali metals, it has a single electron in its outer shell and is highly reactive. It is one of the very few 'primordial elements', that were produced with in minutes after the Big Bang. It has given new life to the patients of manic depressive psychosis (MDP), while giving cosmologists a nightmare.

Australian psychiatrist, Cade has been credited with its pharmacotherapeutic application in MDP (bipolar illness), after he attributed its calming (tranquilizing) effect in his patients, to lithium. (Lithium salts were used for various purposes in the past). Since then, it is used to treat various illnesses including depression, cluster headaches, neutropenia and various other ailments apart from mania. The exact mechanism of its action is yet unknown, though many possible ways through which it may act, has been postulated. It has a narrow therapeutic index, meaning a slight excess of this drug could be fatal, necessitating its frequent blood level estimation in patients.

Cosmologists, on the other hand, were foxed about its discrepancy in its celestial distribution. They seem to find less of it, than they should, based on theoretical predictions. As has already been stated, it is one of the 'primordial elements' which was created in the dawn of creation of the universe. Big Bang Nucleosynthesis (BBN), as this process of synthesis of elements from subatomic particles called, is in practice a lot different from the nucleosynthesis that occurs in our bodies. (Apart from lithium; hydrogen, deuterium and helium were also produced. Almost all other elements we see, or even have in our bodies, were created in the stars.) Recently, Andreas Korn of Uppsala University in Sweden and colleagues have discovered that stars gobble up lithium, which diffuses from its surface into its interior, where it is burnt up. Their discovery also confirmed theoretical cosmologists' predictions about this, long time ago. It also strengthened the BBN. Thus it seems, not only humans, but also stars ingest lithium alike.

Cell Voltage In Biology

The vibrations of the Big bang, which occurred billions of years ago, can still be found in the form of CBR (cosmic background radiation). They envelop the universe even today. Similarly, our cells continue to bathe in the salinity, as we are said to have evolved from our marine ancestors. Hence the concentration of Sodium and Chloride(ions, Na+, Cl-) in the outside of the cells are more than that of the interior. Naturally, Na+ would tend to diffuse to the interior, down the concentration gradient. Again, Na+ being a positively charged ion (cation), is also attracted by the negative charges in the inside of the cell. Thus there must be a mechanism to expel the intracelluar Sodium to the exterior. Here comes the enzyme Na+K+ATPase. It does its job at the expense of energy in the form of ATP (adenosine tri phosphate), a high energy phosphate compound. While it drives out 3 Na+, it lets 2 Potassium ions (K+) in, building up electronegativity in the process, as there is a 'net loss' of one positive charge from the interior of the cell. Thus the inside is negative with respect to the outside. Other factors like the negative charges of intracellular proteins also contribute to the intracellular negativity.

The electrical cells (dry cells, lead acid, nickel cadmium, lithium ion etc.), also produce/store electricity in the form of ions. But in addition to the above generalization, biological cell voltages may vary rhythmically (pacemaker cells), in response to a stimulus (action potential, generator potential) etc.. Not only that, the polarity of the cell (inside +ve; outside -ve), may even reverse (depolarization), which most commonly occurs due to influx of Na+ into the cell. Similarly, entry of chloride ions inside the cell or efflux of K+ (potassium ions) to the outside will lead to more negativity inside. This is called hyperpolarization.

Depolarized nerve fibers (depolarization occurs in other tissues too) carry spreading impulses along its axons just as electricity is carried by wires. Thus cells are not just batteries, they have wires fitted with them. The myelin sheath, its (axon's) covering, acts as the insulator while the interior (of axons, broadly speaking) acts as the ionic conductor.

When this insulation is breached, current leaks and demyelinating diseases like multiple sclerosis result.

Related Links: Cell voltage animation, shockwave flash
Pacemaker potential generation
Last updated: Aug 19, 2008
References: Hyperlinks provided

Sleep to Dream and Dream to Discover

Imagine this. You are trying to solve a problem for the last few days. You are too tired to concentrate any more. You go to bed and sleep like a log, just as The Beatles sang. All of a sudden you find the "key" that leads to the solution you wanted, in a dream.

Things like that do happen in real life. Many a inventions in the past were directly or indirectly inspired by dreams. Elias Howe was toiling his brains out trying to figure out how he would make a needle stitch clothes, so that it could be operated by a machine. He was dog tired and went to bed. He had a good night's sleep that day only to be taken prisoner, in his dream, by fierce tribals wielding bizarre lances with holes at the tips. He immediately understood the dream's implication and the sewing machine was born.

Otto Loewi's discoveries about chemical neurotransmitter won him the Nobel Prize in Physiology or Medicine. The discovery appeared in a dream. He immediately jotted it down. But he couldn't decipher his own handwriting the next day. Loewi, disappointed, spent his 'longest day' in his life and went to sleep again. He got another dream. This time he went straight to his laboratory and performed the test according to the dream on a frog. This dream led to the discovery of neurotransmitters, chemicals through which neurons communicate. Acetylcholine was discovered and Loewi became known as the father of Neuroscience.

Kekule, the German chemist, was doubly fortunate for he was rewarded twice in dreams. Firstly, he got the structural formula and valencies of carbon atoms in a dream and secondly he propounded the ring structure of benzene ring, after having dreamed of a snake fidgeting with it's tail and putting it into it's mouth. His dream, while he was traveling in a London bus is well recorded. Serendipity in dreams doesn't end here, for there are many more examples. That is why Kekule once said, 'lets learn to dream'.

The whys and hows of dreams are not clearly understood but it is known that the brain does some housekeeping tasks (consolidation of semantic memories) while we are asleep. Also, it is the dreams in REM sleep that are vivid and remembered upon waking. It (REM or rapid eye movement) is a paradoxical sleep phase since, although the person is sleeping there is increased heart rate, brain activity and breathing. So, we need to sleep tight if we are to stay ahead in the race, and right now I feel I should do justice to myself by giving my fatigued brain it's due. Zzzzzzz....