The multi-dimensional integrated approach for medicine - Practice by outstanding people overwhelms notation -

  The inside of the human body, particularly vital organs and tissues such as the heart and brain, is protected in a multilayered manner starting from the epidermis of the skin so as not to be highly sensitive to the effects not only of chemical substances and microorganisms but also of physical stimuli such as electromagnetic waves and matter waves. Therefore, the human body is structured in such a way that it cannot be easily or artificially manipulated from the outside. This is an essential condition for protecting both mind and body from the various stimuli and stresses present in the Earth’s environment and for humans to establish homeostasis and live in good health; however, at the same time, it is also the reason why medical interventions—including the examination, diagnosis, and treatment of various diseases arising from distortions of modern life, including genetic factors—are difficult. Conversely, it can be said that in examinations, diagnoses, treatments, and prognostic management required for medical care, skillfully overcoming these multilayered barriers inherent to the human body, or more broadly to living organisms, through biological, chemical, and physical approaches, and arbitrarily manipulating or, in a more "ethical and protective" sense, "adjusting, controlling" them, can be defined as the ultimate goal of medicine. Treatments that utilize biology include those that make use of microorganisms, including viruses, and cells. Treatments that use chemistry refer broadly to widely practiced pharmacological therapies. A typical form of physical treatment, from the perspective of physical invasiveness, can be described as surgical treatment. Not only in treatment but also in examination and diagnosis, biological, chemical, and physical approaches have become widespread. For example, MRI systems and ultrasound echo systems, which are closely related to the main content of this article, excel at analyzing the inside of the body in a non-invasive and relatively safe manner using physical methods based on magnetic fields, electromagnetic waves, and matter waves (sound waves), respectively. Ultrasound echo systems, due to their relatively high level of safety, are widely used in obstetrics and gynecology, where the growth of a fetus inside the uterus of a pregnant woman is regularly observed. Although, at present, this device has limited resolution and a small number of information dimensions as visual imagery, it is, in principle, excellent at capturing spatiotemporal information over a wide range, that is, video imaging. However, at present, examinations, diagnoses, treatments, prognostic management, and/or biology, chemistry, physics, and/or the various clinical departments within hospitals are, in many cases, separated and functionally divided, and integrative approaches across these dimensions are still in their nascent and early stages. The integration of diagnosis and treatment is referred to as theranostics, and for example, methods have been developed in which high-energy electromagnetic radiation emitted during nuclear decay at lesion sites is analyzed using PET and related techniques. On the other hand, the integration of treatment and prognostic management is referred to as survivorship, as typified by cancer. In particular, in treatments targeting minors and young people, which are the focus of this article, because the remaining lifespan is long, it is necessary to conduct research and development for examination, diagnosis, and treatment while comprehensively considering the benefits to the patient over their entire life, to implement these interventions, and, furthermore, in prognostic management, to integratively address various issues that arise from having a history of overt disease, including physical and mental health, social, economic, employment, and marital issues. This extends beyond medicine and must also be addressed as welfare. As an example of a therapeutic approach integrating biology and chemistry, CAR immune cell therapy can be cited. This involves chemically modifying proteins on the surface of immune cells to confer specific functions on living biological materials, namely cells. As for treatments integrating chemistry and physics, a representative example is therapy that combines anticancer drugs and radiation therapy, which are procedurally independent. However, from the perspective of an integrative approach across at least the three dimensions described above, the current state of medicine has not yet reached the level demanded by modern medical needs. Not only does the integrative approach itself require improvements in medical examinations, diagnoses, treatments, and prognostic management, as well as improvements in teamwork as an organization that transcends the boundaries of clinical departments as comprehensive medical care, but there also remains substantial room for improvement in medical practice within each independent domain. The reason for this is self-evident, obvious: even in various contemporary overt diseases—likewise in typical malignant tumors and neurodegenerative diseases that are prevalent in old age—the goal of eradication remains far from being achieved. To move even slightly closer to that goal, for the sake of basically improvement of each individual’s physical and mental health, it is necessary to establish, publish, disseminate, and promote health guidelines that extend into daily life, such as walking, running, other exercise, proper nutrition, weight and oral management, continuous nasal breath, and, in parallel with such efforts, to strongly pursue more integrative approaches in medicine itself, while fully considering their relationship with existing medical practices. This articles aim to pursue integrated (as much as possible) approach for medicine in addtion to Health guideline that has already published. 
  As described above, the means that can currently be conceived for medical use—by delivering physical stimuli into the interior of the body, enabling spatiotemporally (location- and time-) specific control, and applying them to examination, diagnosis, treatment, and prognostic management—are either to focus a single signal or to combine two or more signals, to introduce biologically or chemically specific substances and make them act, or to increase the dimensionality of each individual signal by incorporating factors such as its waveform, polarity, rotation(chirality), energy, duty cycle, and so on. When physical signals are used, it is fundamentally important to select transmission media that are highly safe for the living body and have high penetrability. Representative examples include magnetic fields, matter waves, and low-energy electromagnetic waves (radio waves). With regard to these, the discussion is developed starting from very basic physical principles. The types of motion of matter can be divided into motion that involves a change in position in spacetime and rotational motion that is independent of such displacement. Rotational motion is a state; macroscopically, it represents order or bias in states, and because it does not itself involve displacement, it does not transport energy through displacement. However, rotation includes the collective propertie such as spin currents (looks like moving,but), which have bosonic-like properties closely related to magnons and phonons and represent flows of order in a field. Therefore, in principle, even if the magnetic field becomes strong, it does not by itself violently displace matter within the body in energetic terms, and the associated destruction of genes, tissues, or organs is unlikely to occur if the interactions are properly adjusted. By applying a sufficiently strong magnetic field to space, it is possible to provide a uniform magnetic field to the entire body, and in such cases the energetic burden on the living body is extremely small. However, in order to form such a main magnetic field over the entire body, electromagnetic induction is required, and large-scale, highly regular currents surrounding the body—implemented using hardware such as superconductors that do not generate Joule heat—are necessary. By imposing higher-order gradients on this magnetic field, it becomes possible to construct specific coordinates within the body using magnetic force as an index; that is, magnetic field strength and gradients can be used as “tags.” This is generally utilized in MRI and constitutes one of its fundamental principles. Another important factor is matter waves. Matter waves can be broadly divided into signals in which the directions of vibration are aligned, such as ultrasound, and heat, in which the direction of each individual vibration is random; heat flow indicates that, as a collective, these random motions have a direction. However, heat is characterized by thermal diffusion—namely, large thermal resistance in the human body—and because it is a collective behavior, it has low focusability; moreover, it inevitably involves heat generation, leading to a high risk of burns, and its utility for organs far from the body surface is low, making its application difficult. Nevertheless, temperature micro-increments (ΔT) can potentially be used not as a primary signal but as a secondary signal, including as a “temporal tag.”
　On the other hand, matter waves arising from vibrations of ordered matter, in terms of the degree of freedom along the propagation direction, exhibit two modes in ordered materials such as crystal lattices: the optical phonon mode, in which neighboring particles vibrate in opposite phases, and the acoustic phonon mode, in which the phases are identical. Sound waves, including ultrasound, correspond to the acoustic phonon mode. Therefore, in principle, when applying matter waves to integrative medicine, it is possible to utilize optical phonons in addition to ultrasound. However, as described above, optical phonons have opposite phases between neighboring particles, resulting in low propagation efficiency and a tendency toward random vibrations; in other words, they are easily converted into heat. To induce such phenomena, electromagnetic fields are often required. For example, radio waves, which are low-energy electromagnetic waves capable of penetrating the body and are used in MRI, are absolutely insufficient in energy to generate even a single optical phonon and therefore cannot induce optical phonons. Consequently, even as temporary signal tags, the application of optical phonon modes to integrative medicine requires considerable ingenuity. For instance, MRI employs not only radio waves but also a main magnetic field. As mentioned above, although direct energy transfer is difficult to achieve, energy that exists as potential energy during rotational motion can be excited by radio-wave induction, and when this energy relaxes, specific optical phonon modes may appear. Optical phonons involve neighboring positive and negative charges (ions or polarized functional groups) vibrating in opposite directions, thereby causing the local electromagnetic field at that location to oscillate at extremely high frequencies in the terahertz (THz) range.　This, in turn, exerts the following effects on radio-frequency signals through spin behavior: what occurs as a result of radio-frequency excitation in MRI is an energetically gentle stimulation synchronized with the periodicity of the rotational axis, which acts not on the principal quantum number but on the magnetic quantum number, and since the magnetic quantum number corresponds to the direction of rotation, excitation by this radio wave in practice results in the alignment of the rotational directions of hydrogen nuclei; at this stage, by skillfully manipulating the rotational axis using radio-frequency pulses, it becomes possible to induce motions of the rotational axis that appear through optical phonon modes.　The Z-axis, which is ordinarily aligned, is ordered by a strong main magnetic field, and when the conditions are satisfied such that this axis is tilted laterally by radio-frequency stimulation, together with temporal modulation and the structural fixation of hydrogen molecules (conditions close to those of a solid), optical phonon modes may appear locally and transiently via spin–lattice interactions. Although the rotational axis of a hydrogen nucleus itself possesses a Larmor frequency at which it precesses under a specific radio-frequency, the precessing rotational axis itself, at a more macroscopic hierarchical level, begins to rotate slowly under the influence of optical phonon modes. By applying another radio-frequency corresponding to this slower rotational rate that exists at a higher hierarchical level above the ordinary precessional motion of the rotational axis, it becomes possible to induce specific degrees of freedom based on optical phonons. As a result, changes arise in the relaxation time required for the rotational order associated with the magnetic quantum number, established by radio-frequency excitation matched to the original Larmor frequency, to return to a random state, and due to the anti-phase nature of the motion, this relaxation time becomes faster. This speeding up phenomenon could be also ulitized to "confirm" whether optical phonon mode is stimulated or not. When vibrations of optical phonons (beating in the kHz to MHz range) shake the second rotational axis, small signal peaks known as “sidebands” appear on both sides of the main Larmor frequency, and by analyzing the frequencies at which these sidebands emerge, specific molecules (for example, collagen, elastin, or particular receptor proteins) can be identified in a fingerprint-like manner. This corresponds not to observing the “amount of water,” but to directly observing the “type of molecule and its activity state.” Optical phonon modes vibrate with spatially specific directions, that is, with anisotropy, and by performing measurements while varying the direction and strength of the second radio-frequency field, it is possible to examine how the signal intensity changes depending on direction, with this information indicating the “orientation and degree of order (regularity of alignment)” of the material. Although it is fundamentally difficult to induce optical phonons using radio-frequency energy alone, in situations where constraints are imposed by strong magnetic fields such as those used in MRI, radio-frequency stimulation applied relative to the potential energy associated with those fields can locally and transiently induce optical phonon modes. It is called "phonon-MRI".
　The sidebands mentioned above are phenomena analogous to the sideband peaks observed in X-ray diffraction when a crystal is engineered to have a superlattice or other periodic structure whose period is　significantly longer than the fundamental lattice constant of the crystal. In such cases, the main precessional motion produces diffraction peaks at its integer multiples, while the optical phonons corresponding to the sidebands have much shorter periods at those integer-multiple frequencies. In other words, because the frequency of the optical phonons is higher than that of the precessional motion, multiple sidebands appear around the main peak. With respect to the discussion above, a "correction" is required. The statement that “the rotation axis undergoing precession itself exists at a more macroscopic hierarchical level and slowly rotates under the influence of optical phonon modes, and that by applying another radio-frequency field matched to the period of this slow rotation existing at a higher hierarchical level than the ordinary precession, one can induce specific degrees of freedom based on optical phonons” needs to be revised. In reality, the frequency of optical phonons lies in the terahertz range, whereas the frequency of hydrogen nuclear spins lies in the megahertz range, differing by approximately six orders of magnitude. Therefore, when optical phonon modes coexist with actual hydrogen nuclear spins, the resulting rotational mode is such that, during one complete rotation of the nuclear spin, a much smaller rotation occurs at a speed roughly six orders of magnitude higher. Consequently, the description “slowly rotating under the influence of optical phonon modes at a macroscopic hierarchical level” must be corrected to “rotating at extremely high speed under the influence of optical phonon modes at a microscopic hierarchical level.” Under this corrected view, while the precessional frequency of nuclear spins corresponds to radio-frequency electromagnetic waves, applying the same approach would require electromagnetic waves with wavelengths differing by about six orders of magnitude. This would introduce serious drawbacks, such as reduced penetration into the body and increased complexity of the experimental apparatus. For this reason, synchronization with optical phonon modes is instead attempted by matching the timing through on–off control rather than by using continuous electromagnetic waves.In the terahertz frequency range, the required time accuracy is on the order of picoseconds, which makes control with radio-frequency signals impractical. From here, the discussion becomes somewhat more complex. Essentially, the on-off logic control is implemented using semiconductors, and the elements that determine the temporal precision of square pulses include the rise and fall time constants (that is, the slopes) as well as the time constants during the steady on or off states. The rise and fall time constants are limited by the speed of electrons during the transition across the semiconductor threshold band, and depending on the channel length, time resolutions on the order of several picoseconds are achievable. Therefore, creating a 1 ps period on-off signal is more demanding than creating a 1.000001 μs on-off signal, since in the latter case, the device performance requirement is limited only by the rise and fall time constants at the picosecond level, making the demand on the device smaller. Considering whether a 1.000001 μs period on-off pulse signal can capture a 1 ps optical phonon signal, the 1 ps vibration corresponds to 1,000,000 cycles per microsecond. Consequently, a nanosecond-order pulse signal averages over one million waves. In contrast, if there are 1,000,001 cycles per 1.000001 μs, then by allowing these pulse signals to coexist and taking their difference, it becomes possible to detect the net signal corresponding to a single cycle. While extremely high detector precision is required, this suggests that, physically, it might be possible to excite the optical phonon mode in MRI using radio-frequency waves and detect the signal corresponding to that phenomenon. If one wanted to synchronize and capture the signal at exactly the same timing, femtosecond-level time accuracy would be required, so optical phonon characteristics under conditions that do not require temporal synchronization are needed: the frequency must be stable, the coherence time must exceed the observation window (μs), and the amplitude statistics must be reproducible. Therefore, various constraints must be satisfied for realization. However, the challenge of how to excite the optical phonon mode remains unresolved.
 On the other hand, acoustic phonons are matter waves in material systems that possess a lattice state and a certain degree of binding, in which the phases of vibration of neighboring constituents are aligned. They are what is generally called sound, that is, sound waves. Ultrasound, which is used to detect information from matter inside living organisms, including animals and especially the human body, and to visualize it as images, employs frequencies higher than those audible to the human cochlea. There are several reasons for this. First, audible frequencies are mixed with various kinds of environmental noise. In addition, strong sound waves cause audible noise. Ultrasound has high directionality, and because its wavelength is short, it is excellent for obtaining fine (high-spatiotemporal resolution) images within living tissue. This point is extremely important, as ultrasound will hold the key in next-generation medicine, and therefore it should be discussed in somewhat greater detail. Without a solid foundation, outstanding applications will never be realized. Do those who work with ultrasound as expertise, or medical professionals, truly understand matter waves related to sound waves? Let us confirm this together using my own cross-disciplinary intellect and investigative ability. Matter waves related to sound waves are classified as “longitudinal density waves(compression wave).” That is, in the motion of particles in a state where there is collective, fixed regularity—namely, a state constrained by spatial forces—there exist regions where the particle density is small (that is, “rarefied”) and regions where it is large (that is, “compressed”) with a certain periodicity. ・　・・　・・　・・　・. It looks something like this. On the other hand, the origin of the wave that generates sound waves is a phonon mode in which neighboring particles vibrate with phases that are identically “close,” namely, an acoustic phonon. In a longitudinal density wave, the rarefied and compressed regions move, appearing macroscopically as oscillation. This is what is called the propagation of sound. It is useful to search for videos using keywords such as “Acoustic wave propagation animation.” In other words, sound involves at least two hierarchical levels of vibration and waves. On the microscopic level, there are vibrations of neighboring particles with nearly identical phases, called acoustic phonons. The other is the macroscopic collective vibration defined as a longitudinal density wave. The wavelength of this longitudinal density wave corresponds to the pitch of the sound, that is, its frequency. Why does this happen? Earlier, acoustic phonons were described as vibrations in which the phases of neighboring particles are identically “close.” This means they are not exactly identical but are slightly phase-shifted. As the phase changes little by little in this way, particles at a certain separation will appear whose phases are opposite, that is, shifted by 180°. When a particle at the starting point is positioned to the “right” relative to the direction of propagation to the right, a distant particle that is shifted by 180° will be positioned to the “left.” In other words, it is like “→” “←”.Conversely, a distant particle that is shifted by 180° away from a particle on the “left” will be on the “right.” That is, it is like “←” “→.” Because this occurs periodically, it becomes “→” “←” “→” “←,” and as a result, a longitudinal density wave is formed. Do not think you fully understand it at this point??, but let us dig a little deeper. What kind of question would you have here? Then, why does the phase shift little by little? The reason is that the transmission of forces between particles, and the oscillation of the particles themselves, have finite speeds. Each individual particle has a characteristic time associated with oscillating at a certain frequency. In addition, there is a transmission time, based on the speed of light, required to convey force from one particle to a neighboring particle via bosons, which serve as the mediators of force transmission. Furthermore, there is a relaxation time required for the energy of the transmitted boson to relax and be converted into the kinetic energy of the neighboring particle. Ultimately, what is the fundamental answer to the question of why the phase shifts little by little? It leads to the physical law that the speed of transmission in matter cannot exceed the speed of light, and that “there is no information in the universe that is transmitted instantaneously.” This is also related to the law of conservation of energy. If information were transmitted instantaneously, light would end up transmitting force to an infinite number of massive substances through field interactions, causing energy to diverge. Because of this absolute constraint, spatially separated matter based on acoustic phonons has a limitation in the propagation of its vibrations, namely the speed of sound, and its origin lies in the fact that each individual force transmission time is finite and that the vibration propagates with a gradual phase shift. This phase shift produces a fixed spacing of rarefaction and compression as a property of matter. When the period of this rarefaction and compression is short, it is ultrasound. Then, what does it mean for the period of rarefaction and compression to be short? In the oscillatory motion of each individually constrained particle, phase differences arise due to differences in motion and force transmission, and if this phase difference becomes larger, the spacing of rarefaction and compression becomes, in principle, shorter. That phase difference increases because, when the vibration period of each particle becomes shorter, a larger amount of phase (in radians) progresses in a shorter time; as a result, in principle, the phase difference between neighboring particles becomes larger, and the period of the longitudinal density wave becomes shorter.
  Although this paragraph becomes a bit difficult, it is an extremely important element even when focused ultrasound devices are used not only transcranially but throughout the entire body, so I will not cut corners and will seriously and carefully think through the details. This is a discussion of the resolution of focused ultrasound. Although the order of explaining some important physical constituent elements will be reversed to some extent, I will explain that later as well. Transcranial means that, in principle, ultrasound transducers, which are the ultrasound sources, can be arranged over nearly 180° in two axial directions, so the aperture diameter when focusing ultrasound can, in principle, be made infinitely large. In reality, this does not happen because issues such as the spatial synchronization of a very large number of phased-array transducers, and the complex interplay of scattering and reflection along the propagation paths, are intricately intertwined. In terms of the theoretical limit, it becomes possible to focus down to half the wavelength of the ultrasound frequency. This is called the diffraction limit. Writing this in my own way based on AI explanations, what we mean by “resolving” is to distinguish reflected waves from two separate points as separate entities. However, because waves have the property of spreading out radially (diffraction), reflected waves from two points overlap in space and cause interference. In order to distinguish and image reflected waves, at a minimum, in order to separate them, it is necessary to secure the minimum and maximum distances of separation as waves, and if we consider them as compression–rarefaction waves, this means securing the minimum and maximum spacing of compression and rarefaction; as a result, in order to distinguish and detect, as information, the properties of reflected waves from a substance that corresponds to one pixel, at least a spatial extent of half the wavelength of the detected wave is required. Now, on the other hand, I will explain based on my own way of thinking. Ultimately, what are we actually observing in ultrasound detection? As described in the previous paragraph, ultrasound is a compression–rarefaction wave, so compression and rarefaction propagate along the direction of travel. They scatter and reflect at various points, but a “single” such wave cannot, by itself, produce a physical distinction along the depth direction, so in principle it is not possible to specify “where?” along the propagation direction is being observed. In order to determine that “where?”, it is necessary to “gather” multiple waves at a specific depth. At that point, it is necessary to concretely describe what is actually happening at the focal region. This is a spatial extraction, and for temporal extraction, pulses (wave packets) are used. By doing this, spatiotemporal tags are assigned. So then, what is a focus? Only there is physical differentiation required. The waves emitted from each transducer are controlled so that their phases perfectly coincide only at the focal point. As a result, the pressure amplitude increases sharply, and the energy density is concentrated at that point. Because the phases coincide, the waves are amplified. At this time, the information such as the amplitude and phase of the ultrasound waves captured by each detector, as manifested through reflection, scattering, transmission, and so on, together with the directional information indicating which detector captures them, represents the physical properties of the material at the focal position. For example, if there is a state like a “bubble” inside the body and it is located at the focal position, it strongly scatters in all directions with respect to direction. Because there is a clear interface, the amplitude, as well as the reflection and scattering intensity, is extremely strong. Since gas has no molecular binding, the phase is inverted and returns. In such cases, the minimum necessary conditions to obtain such information must be related to the diffraction limit. In order to obtain information, at least the phase coincidence of two waves is required. To explain this using the simplest constraint, draw semicircular arcs expanding from two dots · · with a constant period, and mark with dots · the points where those arcs intersect. The spacing between those marks must be at least the spacing of each arc. These points are points of phase coincidence, that is, points of wave amplification. In order to make waves interfere and amplify them to form a focus, at least the distance from crest to crest is required, and when considering opposite-direction crests as well, a minimum of Π rad, 180°, that is, half a wavelength, is required. When synthesizing waves to create a specific spatiotemporal tag, this interference problem arises, and at least a half-wavelength distance is required. Then, why is it that, when there is an aperture diameter as in a handheld transducer, this diffraction limit cannot, in principle, be achieved? That is because, in principle, a focal point at which the phases coincide to amplify waves at a single point cannot be geometrically defined based on the wave properties. In other words, points that satisfy the same phase-matching condition exist continuously in space. Ultimately, what is important is how sharply the spatiotemporal tags can be defined, namely, the range of spatiotemporal positions where the phases of a very large number of sound sources coincide in a highly specific manner. Therefore, if the spatial resolution of ultrasound is expressed by representing intensity as color, it is gradual. For example, there may be a phase-coincidence point of “100,” and there are also intermediate phase-coincidence points of “50.” These numbers change gradually. It is not a situation with sharply defined thresholds, but rather a blurred one.