Molecular Imaging of the Brain

The human brain has evolved over many millenniums. But over the last three centuries or so the analytical power of mind has accelerated many fold and at a much faster rate. There is a gradual increase in the desire to understand the science of the human mind and of the brain. The brain science in action we need to know has to be experienced at the miniaturized the atomic and molecular level. Newton around three centuries ago was amazed to see that an apple from a tree falls to the ground and not the other way around. Our earth is like a sphere hanging (due to gravitational forces among our star the Sun and other planets revolving round it) in space. All points on earth are equally exposed to the space around it and yet the apple is attracted toward the earth. This is despite apple’s density is higher than the density of air space surrounding it. This thought about the act of science was just a curiosity in Newton’s mind. Science is curiosity and curiosity is science. The science in its mathematical analytical aspect was little developed in Newton’s time. Soon the art of thinking became the art of scientific creation. The science became a tool, of production of technologies those followed. It changed the humanity forever. This was the beginning of the discovery of the forces of gravity which keep the sun, earth, moon, the galaxies, etc. in a dynamic equilibrium. In fact the universe we live in makes the human mind create science all the time.

One should realize that the quantum science is not as much a common knowledge as the Newtonian Science is. It thus becomes a formidable task, to propagate further about the new developments in the brain science. The neuroscience audience who this work should attract the most would normally have little and basically no exposure to the basics of the quantum physic so deeply rooted in the dynamics of the atoms, molecules, tissues, etc., in the brain. However an effort at grass roots level is made in this work in that direction. To keep it simple explanation is made by reference to diagrams drawn. It is a rough spin model picture of the brain MRI that is exposed here. It is as if it were a collection of ordered spins in an ensemble of molecules in the direction of the static magnetic field naturally present around the nucleus. Spins in molecules are surrounded by smeared out orbital electron cloud of the molecules, fluids, tissue, etc. There are as many electrons in the orbital state as there are the protons in the nuclei in a small region consisting of several molecules.

The neurodegenerative Wilson disease (NWD) is a genetic disease. It is caused by mutations in the P-type ATPase. The defect leads to abnormal copper transport and metabolism in mitochondria and causes apoptotic and necrotic cell death due to oxidative damage after excess accumulation of intercellular copper. MRI shows T₂ hyper intense lesions involving mostly the putamina and less frequently the thalamic brain stem cerebellar dentate regions and cerebral white matter. The diffusion weighted imaging (DWI) and proton magnetic resonance spectroscopy (PMRS) are very useful techniques to shed light on the pathogenesis of NWD by inspecting the microscopic water diffusion and cellular metabolism in vivo. The T₁-weighted imaging (T₁WI) shows low signal intensity and markedly high intensity on T₂-weighted imaging (T₂WI) on asymmetrical basal ganglionic lesions. Moreover there is seen increased intensity on T₂WI, of the occipital, peri-ventricular and subcortical white matter bilaterally without mass effect, suggestive of demyelination. Single voxel PMRS with voxel placed in the right putaminal lesion shows a low N-acetylaspartate/creatine ratio and a high lactate/Cr ratio, in contrast to those of bilateral occipital lobes. It is seen that impairment of copper transport across membranes leads to accumulation of copper in the liver, brain, cornea and kidney, and causes toxicity to those regions.

There are no short cuts to science and development. The quantum nature of matter is learnt through the basics of the quantum mechanics (QM). Quantum science education unfortunately at present does not form part of the curriculum at secondary level of education. It is the situation all over the world. Learning QM is no more difficult than learning the Newtonian Mechanics (NM). In NM we are dealing with large rigid bodies; the dynamics is macroscopic in nature and the object’s position, velocity, acceleration etc. can be accurately determined. Further in NM the large objects e.g. planets do not react chemically. The only interaction they have is through the gravitational forces and is very weak. It has little affect on the human life visually to any degree of significance known. Planets in our solar system interact through gravitational forces among each other and with the sun in space and time and keep their dynamics of motion in equilibrium. The forces which make them move and remain in balance are well understood. The motion of the moon under the influence of gravitational forces around earth does however control to some extent the tidal effects and probably the climate on earth as well.

One naturally asks a question what is this density matrix and why do we need it. The answer is that the density matrix (DM) is a physical representation of an ensemble of atoms, molecules in a matrix format, whose elements tell us at any point in space and time what is the status of the spins and the spin system as a whole. In the absence of any external field the spins distribute themselves in a random manner in the brain. The net magnetism is thus zero. The magnitude of the magnetization (magnetic moment per unit volume) at any point in space and time is not constant in an ensemble like the brain. It is measured through the number of spins per unit volume N₀. One basically measures the susceptibility variation which is the same thing as the magnetization variation in space and time in the MRI mapping of the brain. The spin distribution overall can be assumed to be in equilibrium (though not uniform in space) in an ensemble like our brain. The equilibrium is due to the internal fields e.g. the magnetic fields of the nuclei, various metabolic activities etc.

In the presence of an external static magnetic field H₀ say applied in the Z-direction the isolated non-interacting (no quantum correlation) spins will try to align themselves along the field. The spins do not stay stationary along the Z-direction. Instead they precess (rotate) randomly at a resonance frequency of ω₀ around the field H₀. Here ω₀ = γ H₀, γ being the gyromagnetic ratio (GMR) = (μ_b/ђ), ђ is the angular Planck’s constant and μ_b is the fundamental dipole magnetic moment moment of an atom called as the Bohr magneton. The frequency ω₀ is referred to as the Larmor frequency. Now if an additional RF electromagnetic field say H₁ in the form of a pulse is applied along a perpendicular direction to H₀, say in the X-direction the angle of precession around the Z-direction of the spins acquires new angle α = (γH₁ τ). This angle α is called as the flip angle and the time τ is called as the pulse time. This simplified picture is true if the applied RF signal has a single frequency and is in exact resonance with the natural frequency of vibration of a single spin i.e. the Larmor frequency. But the pulse has a bandwidth of frequencies Ω_i. Further a single spin is not in vacuum and is surrounded by many others of varied nuclear structure. The angle α should thus be α = (Ω_i − ω₀) τ, different angle for each frequency. In fact it should be α = (Ω_i − ω₀) T, where T is the time when signal is measured and the time T ≫ τ. The response of the pulse is measured as a decay of the maximum amplitude with time. The rate of decay will be different in different directions. In the X–Z and Y–Z planes it is taken as T₁ and in X–Y plane it is T₂. The mapping of the anisotropic structure of T₁ and T₂ in different directions (X, Y, Z) leads to T₁ and T₂ weighted images.

MRI is a valuable tool to explore and understand the human brain science. It provides a scientist with a bundle of knowledge about the static and dynamic status of the brain. The information collected can be due to the collective echoes from a region on a mms to cms scale due to the incident RF radiation. There is a broadly referred to in MRI the technique of echo planar imaging (EPI). The technique analyzes echo signals received back by an RF receiver in space an time. In its simplest form it treats all the spins as identical. One collects the variant signals from the brain by virtue of the spins being present in a gradual change of their environment. The imaging with treatment of the spins as being identical is referred to as the single quantum magnetic resonance imaging (SQ-MRI). Recently NMR (nuclear magnetic resonance) has entered into the field of medical imaging. Over the years reference to MRI as single quantum MRI was dropped. It has been simply called as the MRI. In the last decade the discovery of the multi-quantum spin–spin interactions and their use in imaging, has changed the situation. The imaging can be the result of quantum coherent interactions between individual macro-molecules and also within the molecule itself. The heteronuclear atoms and molecules retain their individual identities due to their individual electronic orbits structure as well as their nuclear structure. The dynamics of the electrons around the nucleus and of the protons and the neutrons inside the nucleus is a quantum one. What it means is that when the atoms and molecules are excited by the RF radiation the electrons, protons and neutrons occupy only quantized higher energy states due to the absorbed extra energy. They interact quantum mechanically to create local coherence transfer pathways (CTPs) and present information in a coherent manner.

The quantum science (QS) of the brain needs to be developed right from the grass roots. It would be an ideal thing to build it as a formal source of learning for medical professionals. The newly emerging QMRI (muti-quantum magnetic resonance imaging) technology is based on QS. It is not easy to present that kind of knowledge via a work like this. What this work has done is, that it has made a beginning. It is hoped that later this will be followed by a more comprehensive work. It would be worth taking up the venture of writing a text book in this field at the undergraduate level and even at the secondary level of education. This would require tremendous amount of time and resources at one’s disposal. It is not easy to obtain that unfortunately in the present state of environment of the science. The status of science and opportunities to participate in the research and development in the field of QMRI and neuroscience is very limited for scientists at large. It is available only at limited number of places in the world and to limited number of people, unfortunately. Availability of wider research participation in the field is only a part of the problem. Transmission of the newly emerging knowledge by research, to a wider community is very crucial and quicker the better. This aspect is not easy to fulfill. As the gap between the known and the unknown, keeps on becoming wider the chance of catching up becomes even slower.

Nature has played a very clever role in the evolution of higher life forms such as animal and human. There are many chemical elements which are involved as integrated part of enzymes and proteins in electron charge and energy transport in our body. They are at the centre of action and are directly engaged in biological actions of life. The physiological processes in our body takes place using major simple ions e.g., Na⁺, K⁺, Mg^2+, Ca^2+, Cl⁻, etc. These act through being in a bound state of a tissue and or of the free state in the mainstream of the fluids present in our body system. An optimum dynamic balance of the concentration of the ions in the tissue-cell-fluid pump is worked out by the life maintaining mechanisms. We need to understand the physics, chemistry and mathematics (PCM) of the electronic charge and the energy transfer of the life giving processes happening in our body. The PCM processes evolved by nature give us a healthy normal active life. Any abuse from the nature’s chosen dynamic balance leads to diseases and ultimately death. It is thus time to learn in detail about the basics dynamics of the life maintaining processes happening in our body.

It seems nature has evolved as an interplay between a great many organic and inorganic compounds. The result is there is a considerable number of elements essential for higher life forms i.e. animals and humans. Many elements are cofactors of rather integrated parts of, enzyme and of proteins involved in electron transfer and oxygen transport. The physiological processes commonly involve an electrolyte solution containing as the major ions Na⁺, K⁺, Mg²⁺, Ca²⁺, and Cl⁻. Many important biopolymers like DNA, RNA and ionic mucopolysaccharides and also the aggregates of charged monomers like biological membranes, are highly charged and interact strongly with these ions. in higher organisms. Most of these are also unevenly distributed between intracellular and extra cellular spaces with the concentration gradients maintained through energy consuming active transport. Temporary changes in these ion gradients are used in nature as means of signal transmission.

A valid distinction between cytotoxic and vasogenic edema is based mainly on the differences in blood–brain barmier permeability. Vasogenic edema fluid develops in association with a variety of pathologic conditions such as brain tumors, brain abscesses hypertension or areas of infarction. In cases of brain tumor edema fluid leaks from the tumor vessels and spreads into the surrounding white matter. Similarly, cryogenic injury of the cerebral cortex causes a transient breakdown of the blood–brain barrier in the zone bordering the necrotic region allowing edema fluid to spread into the white matter. The regions in which the blood–brain barrier is defective and those in which the edema accumulates do not necessarily correspond. MRI has a proved to be a valuable and sensitive method by which to detect vasogenic edema. Multinuclear MR imaging (proton and sodium) permits in vivo assessment of the relative distributions of water and sodium within the brain. One can define the sodium signal associated with edema fluid as well as investigate the relaxation characteristics of extra-cellular sodium, for properties that may be specific to sodium in the extra-cellular compartment. A model of vasogenic edema can thus be developed. Previously models have relied on local injury to the brain by either cold or chemical insult. The resulting region of necrotic brain has a defective blood–brain barrier and vasogenic edema forms adjacent to the injured tissue. One can avoid a mixture of necrotic and edematous brain tissue by the use of a non traumatic mode of vasogenic edema in mongrel dogs.

Animal and plant life to some extent is replica of the life inside earth itself. Earth lives and so do we. Inside earth’s crust there are elements like iron, copper, silicon, sodium, magnesium, uranium, etc., etc. in the form of stable and not so stable compounds. We mine them, process them and use them, in various technologies, including nuclear energy for peaceful, and sometimes not so peaceful purposes. There are circulating molten solid currents, due to high pressures and temperatures, inside earth’s crust, which give rise to the magnetism inside and outside earth. We are quite familiar with the N–S poles of the giant magnet, in the core of the earth. It provided the source of navigation and discovery of unknown places on the surface of earth, for centuries, to some clever people. The N–S magnetic axis of the earth is not along the geographic N–S poles of the earth. The N–S magnetic axis of the earth is not fixed in time either. It reorients itself on daily, monthly and yearly basis. Why it does so? One scientific reason we know of is that the earth is bombarded by heavy mass of charged particles, on regular basis, from Sun. The mother nature’s magnetic field on the surface of earth which is of the order of only milli to micro Tesla, protects our body from harmful effects of the radiation, we receive on earth on daily basis from the surrounding universe. The radiation e.g., the solar radiation, provides us life on earth, as well, on daily basis. The magnetic field on the surface of earth, changes in a systematic manner, with distance. One can see magnetic field gradient present on the earth and it varies slowly, and is stronger in one direction than the other. Our body is exposed to it all the time. Is it shear coincidence that we use magnetic field gradients of the order mT/meter, close to present on earth, to produce MRI pictures in human body? May be. May be not. Some researchers have used earth’s field as the source of magnetic field to perform MRI experiments. This curiosity has produced some interesting results. That is how the development of the MRI technology we use today was stated half a century ago and is still evolving. This applies to every science-based technology we use.

The resonance phenomenae are in common use in many technologies, we enjoy today. Use of RF (radio frequency) electromagnetic radiation, magnetic resonance of molecules, for the human body, to produce an image, deserves special recognition. MRI is a non invasive application of science, to the diagnostics of various diseases and disorders in human body and is particularly challenging, in the human brain arena. The renounce phenomena used in MRI is little different in principle from other applications. The well known applications are the radio broadcast, the production of television picture, Laser, etc. The subtle difference lies in the selection of the frequency band of radiation, out of the very wide electromagnetic radiation band. TV broadcast uses the visible (light) part of the electromagnetic, radiation spectrum, to produce pictures, and the microwaves are used, to carry it and broadcast over large distances. On the receiving end, electrical resonance phenomena, in the electrical circuits, is used to produce the picture. This picture is about the movement of the external parts of an object or of a living body. The TV picture is clearly visible to the naked eye. MRI uses the dark (invisible) RF radiation. It brings out the behavior of internal molecular movements which are not visible to the naked eye.

The Appendices A, B and A1 [1–35] included here cover a brief exposition of the basic physics principles and the relevant terminologies arising in MRI.