\r\n\tThis book will describe the self-assembly of materials and supramolecular chemistry design principles for a broad spectrum of materials, including bio-inspired amphiphiles, metal oxides, metal nanoparticles, and organic-inorganic hybrid materials. It will provide fundamental concepts of self-assembly design approaches and supramolecular chemistry principles for research ideas in nanotechnology applications. The book will focus on three main themes, which include: the self-assembly and supramolecular chemistry of amphiplies by coordination programming, the supramolecular structures and devices of inorganic materials, and the assembly-disassembly of organic-inorganic hybrid materials. The contributing chapters will be written by leading scientists in their field, with the hope that this book will provide a foundation on supramolecular chemistry principles to students and active researchers who are interested in nanoscience and nanoengineering fields.
",isbn:"978-1-83969-702-9",printIsbn:"978-1-83969-701-2",pdfIsbn:"978-1-83969-703-6",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,hash:"e9cc643ae0a219e91e445a1e61b33a22",bookSignature:"Prof. Hemali Rathnayake and Dr. Gayani Pathiraja",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11908.jpg",keywords:"Amphiphiles, Artificial Siderophores, Coordination Chemistry, Self-Assembly Design, Supramolecular Structures, Metal Oxides, Metal Particles, 2D Inorganic Materials, Supramolecular Devices, Stimuli-Responsive Materials, Assembly-Disassembly Design, Superstructures",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"April 27th 2022",dateEndSecondStepPublish:"May 25th 2022",dateEndThirdStepPublish:"July 24th 2022",dateEndFourthStepPublish:"October 12th 2022",dateEndFifthStepPublish:"December 11th 2022",remainingDaysToSecondStep:"5 days",secondStepPassed:!1,currentStepOfPublishingProcess:2,editedByType:null,kuFlag:!1,biosketch:"Dr. Rathnayake is a pioneering researcher in self-assembly and supramolecular chemistry, with a Ph.D. from the University of Massachusetts Amherst, US. She is an inventor of three innovative technologies, including the Bioinspried Sub-7 nm self-assembled structures for patterning, and holder of multiple registered patents.",coeditorOneBiosketch:"Dr. Gayani Pathiraja is a Postdoctoral Research Scholar at the Joint School of Nanoscience and Nanoengineering (JSNN). She received her Ph.D. in Nanoscience from the University of North Carolina at Greensboro in 2021. Her research interests focus on the crystal growth mechanism and kinetics of metal oxide nanostructure formation via self-assembly.",coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"323782",title:"Prof.",name:"Hemali",middleName:null,surname:"Rathnayake",slug:"hemali-rathnayake",fullName:"Hemali Rathnayake",profilePictureURL:"https://mts.intechopen.com/storage/users/323782/images/system/323782.jpg",biography:"Dr. Hemali Rathnayake, Associate Professor in the Department of Nanoscience at the Joint School of Nanoscience and Nanoengineering, the University of North Carolina at Greensboro, USA, obtained her B.S. in Chemistry from the University of Peradeniya in Sri Lanka. She obtained her Ph.D. from the University of Massachusetts Amherst (UMass), Department of Chemistry in 2007. She was a Postdoctoral research fellow at Polymer Science & Engineering, UMass Amherst. \r\nDr. Rathnayake is a pioneer scientist and a chemist in the field of Nanomaterials Chemistry, with a focus on the interfacial interaction of nanomaterials, molecules, macromolecules, and polymers in homogeneous and heterogeneous media. Her research on the design, synthesis, self-assembly, and application of well-defined superstructures in nanoelectronics, environmental remediation, and sustainable energy has impacted the scientific community with highly rated peer-reviewed journals publications, and more than 80 invited talks to scientific and non-scientific communities including colleges and high schools.",institutionString:"University of North Carolina at Greensboro",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"University of North Carolina at Greensboro",institutionURL:null,country:{name:"United States of America"}}}],coeditorOne:{id:"427650",title:"Dr.",name:"Gayani",middleName:null,surname:"Pathiraja",slug:"gayani-pathiraja",fullName:"Gayani Pathiraja",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003CCSN2QAP/Profile_Picture_1644217020559",biography:"Dr. Gayani Pathiraja is a Postdoctoral Research Scholar at the Joint School of Nanoscience and Nanoengineering (JSNN). She received her Ph.D. in Nanoscience from the University of North Carolina at Greensboro (UNCG) in 2021. Her expertise area of focus is investigating the crystal growth mechanism and kinetics of metal oxide nanostructure formation via in-situ self-assembly design principles. \r\nDr. Pathiraja earned her master’s degree in electrochemistry/Environmental Engineering from the University of Peradeniya, Sri Lanka, and her Bachelor’s degree in Materials Science and Technology from Uva Wellassa University, Sri Lanka. Dr. Pathiraja started her academic career as a lecturer at the Department of Engineering Technology, University of Ruhuna, Sri Lanka in 2016. She is a co-author of several peer-reviewed journal publications and a book chapter, and she has presented her work at several regional, international, and national conferences.",institutionString:"University of North Carolina at Greensboro",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"University of North Carolina at Greensboro",institutionURL:null,country:{name:"United States of America"}}},coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"8",title:"Chemistry",slug:"chemistry"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"466998",firstName:"Dragan",lastName:"Miljak",middleName:"Anton",title:"Mr.",imageUrl:"https://mts.intechopen.com/storage/users/466998/images/21564_n.jpg",email:"dragan@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. 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1. Introduction
In silicon (Si) complementary metal-oxide-semiconductor (CMOS) chip technology, silicon oxycarbide (SiCxOy) materials have been extensively employed to serve multiple purposes. For example, SiCxOy materials have been the focus of extensive study due to their applicability as low-k dielectrics, passivation layers, and etch-stop layers to name a few [1, 2]. SiCxOy materials have also been the focus of studies due to their potential application in a plethora of other technological applications (e.g. light emission, energy, and bioapplications). In particular, they have been proposed as candidates for white light-emitting materials [3–5], filters, porous adsorbents, and catalytic supports [6, 7], as hydrogen storage materials [8], gas sensors [9], negative electrode materials for lithium batteries [10, 11], and in biomedical devices [12]. Additionally, it has been also shown that SiCxOy can be utilized as a host material to optically active impurities (rare earth ions). To this end, europium (Eu2+)-doped SiCxOy thin films synthetized by RF magnetron sputtering [13] as well as erbium (Er3+)-doped SiCxOy thin films for near-infrared (IR) emission at the commercially useful telecommunication wavelength of 1540 nm have been recently reported [14–16].
The fabrication of luminescent Si-based nanostructured materials for light emission applications is highly desirable, similarly to how Si-based nanophotonics has undergone great advancements in recent years [17, 18]. Due to the seamless integration of Si-based materials with process protocols and technologies developed for semiconductor CMOS technology, manufacturing costs and process complexity could be also reduced. Furthermore, the extreme down-scaling methods achieved by CMOS technology offer the opportunity to study new compelling properties owing to possible confinement effects in one (1D) or two (2D) dimensions (e.g., the reduction of exciton-phonon interactions, the increase of extraction efficiency of spontaneous emission, and suppression of Auger recombination) [19, 20]. Therefore, the functionality of such nanostructured materials and their devices can be employed in a ubiquitous way in light emission applications [21]. To this extent, SiCxOy nanowires (NWs) have been recently shown to exhibit strong room-temperature visible luminescence [22–24].
In parallel, the identification and elimination of potential obstacles that could deteriorate the luminescence efficiency of such materials (e.g., temperature and excitation power density) needs to be taken into consideration. Indeed, the luminescence efficiency is known to be influenced by environmental fluctuations in temperature and pump-power-density changes [25, 26]. These fluctuations can become critical in luminescence applications such as light-emitting diodes (LEDs). In these applications, the operating temperature and power density can reach respectively ~150°C and ~200 W/cm2, thus greatly influencing the light output and color chromaticity.
Silicon oxycarbide films have been grown predominantly through low-temperature plasma-enhanced chemical vapor deposition (PECVD) using an array of silane-based precursors for the needs of semiconductor industry [27–30]. However, the incorporation of source precursor fragments and decomposition byproducts in the resulting films has led to the observation of enhanced stress levels and increased defect density, both of which have detrimental effects on the optical performance of resulting materials and device structures. Recently, Lin et al. prepared amorphous SiCxOy using a very high-frequency plasma-enhanced chemical vapor deposition (VHF-PECVD) technique [31]. The resulting films exhibited intense room-temperature blue luminescence, characteristic of Si-related neutral oxygen vacancy defect centers. Ryan et al. and Vasin et al. showed that a wide variety of SiCxOy with a continuous range of compositions could be produced by reactive RF-magnetron sputtering [32, 33]. Karakuscu et al. and Abbass et al. have reported sol-gel-prepared SiCxOy thin films [34, 35], while Vasin et al. have reported a-SiCxOy:H thin films growth by low-temperature oxidation of carbon-rich a-SixCy:H thin films [36].
Nevertheless, it is desirable to identify alternative deposition methods, which can inhibit or minimize processing induced structural and/or compositional damage to SiCxOy materials due to phase separation owing to the non-stoichiometric composition. Herein, key findings are summarized pertaining to the development of a thermal chemical vapor deposition (TCVD) strategy for the growth of SiCxOy thin films approximating the SiCxO2(1−x) (0 < x < 1) stoichiometry for light emission applications [37, 38]. These studies led to the identification of a deposition process window for the growth of SiCxOy thin films with strong room-temperature light emission [3]. Additionally, we present the findings pertaining to room-temperature visible photoluminescence (PL) from SiCxOy sub-100-nm nanowire materials fabricated by electron beam lithography (EBL) and reactive ion etching (RIE). These metal-free non-toxic Si-based nanostructured materials may offer an alternative and environmentally friendly pathway toward efficient visible light-emitting materials and devices.
2. Synthesis and fabrication of silicon oxycarbide thin films and nanostructures
2.1. SiCxOy materials grown by thermal chemical vapor deposition: composition control
SiCxOy thin films and their nanostructures are deposited on Si(100) or SiO2 substrates in a hot-wall quartz tube reactor by thermal CVD at 800°C. A single source oligomer (2,4,6-trimethyl-2,4,6-trisila-heptane (C7H22Si3)) is utilized as the source precursor for silicon and carbon atoms and ultra-high purity oxygen (O2) and argon (Ar)/nitrogen (N2) are also employed as co-reactant and dilution gases. The composition of the resulting amorphous SiCxOy≤1.73 (0.11 < x < 0.65) thin films is regulated by modifying the oxygen flow rate and, hence, the oxygen partial pressure in the reaction zone. The films are deposited onto three types of substrates: single-crystal silicon (c-Si) (100), for composition, structural and optical analysis; double-polished intrinsic Si and high-quality UV transparent fused silica, for infrared and optical studies. A subset of the as-deposited SiCxOy films was annealed for 1 h in different ambient (e.g., O2, Ar, N2, or forming gas (FG, 5% H2 and 95% N2)) at temperatures in the range from 500 to 1100°C. Detailed description of the deposition and annealing processes can be found elsewhere [37, 38]. The resulting samples were subsequently employed in a comparative analysis of as-deposited and post-annealed films to determine the effects of thermal treatment on film structural and optical properties as well as their photoluminescence performance.
Rutherford backscattering spectroscopy (RBS) and X-ray photoelectron spectroscopy (XPS) were employed to determine the Si, C, and O content in the SiCxOy materials and they were separated in three different classes, defined by their composition: SiC-like ([O] < 5 at.%), Si‐C‐O, and SiO2-like ([C] < 5 at.%). The compositional evolution of the SiCxOy thin films was plotted in the Si‐C‐O ternary diagram of Figure 1a along with the SiCxO2(1−x) (0 < x < 1) line, with the latter representing stoichiometric silicon oxycarbide without any excess of carbon. The upper and lower limits in SiCxO2(1−x) correspond to SiC and SiO2, for, respectively, x = 1 and 0 [39, 40].
Figure 1.
(a) Si‐C‐O ternary diagram with the compositions of as-deposited (AD) silicon oxycarbide (SiCxOy) materials, (b) NRA hydrogen depth profiles of the as-deposited SiCxOy and (c) mass density of SiCxOyHz films [22, 37].
As is shown in Figure 1a, the composition of the thermal CVD-grown SiCxOy was properly tailored to closely follow the pure stoichiometric oxycarbide formula over the whole range of the synthesis process parameters. The SiCxO2(1−x) behavior observed in the samples produced herein suggests the substitution of two divalent oxygen atoms by one tetravalent carbon atom as the C concentration in the SiCxOy materials increases. The latter will be further discussed in Section 3.1. Furthermore, the observed small deviation from the stoichiometric SiCxO2(1−x) trend suggests that there is much less excess of C compared to non-stoichiometric compositions reported for SiCxOy with SiC/SiO2 phases and free carbon, as it is shown in Figure 1 of reference [39].
Due to the presence of methyl groups in the CVD reactants, it is expected to have hydrogen atoms in the grown silicon oxycarbide thin films whose concentration cannot be quantified by the RBS or XPS techniques. Instead, the nuclear reaction analysis (NRA) was conducted by using the 15N + 1H → 12C + 4He + γ-ray resonant nuclear reaction at 6.835 MeV [41]. Figure 1b shows the NRA-derived hydrogen concentration measurements of the silicon oxycarbide films as a function of post-deposition annealing temperature Ta [37]. After the 900°C annealing step, the hydrogen content is significantly reduced to 5, 2.2, and 4.5 at.%, respectively, for the SiC-like, Si‐C‐O, and SiO2-like samples. For annealing temperatures above 1000°C, the hydrogen content was not detectable (>1 at.%) in all three different types of samples.
The mass density ρ (g/cm3) of thin films was calculated using the elemental compositions determined by RBS and XPS and the thicknesses measured by scanning electron microscope (SEM) by employing the following equation:
where D is the thickness in rump units, which is related to the planar density, d is the film thickness, ASi, AC, AO, and AH are the atomic weights of Si, C, O, and H, respectively, and x, y, and z are the normalized fractional contents, respectively, of C, O, and H.
The density of the silicon oxycarbide films was observed to increase with higher annealing temperature, due at least partly to the reduction in hydrogen concentration, as shown in Figure 1c. More specifically, the densities of the as-deposited films are 2.8, 2.2, and 2.1 for, respectively, SiC-like, Si‐C‐O, and SiO2-like films. After annealing at 1100°C, the densities were measured to be significantly higher, with values of 3.3, 2.6, and 2.4 g/cm3 for, respectively, SiC-like, Si‐C‐O, and SiO2-like films.
2.2. Nanofabrication of silicon oxycarbide nanostructures
SiCxOy nanostructured systems were fabricated by electron beam lithography and reactive ion etching, namely periodically ordered sub-100-nm nanowire arrays. A representation of the baseline nanofabrication scheme of the SiCxOy NW arrays is schematically depicted in Figure 2. Following the synthesis of SiCxOy thin films, negative hydrogen silsesquioxane (HSQ) (6% HSQ in methyl-isobutyl-ketone solvent) resist is spun onto SiCxOy wafer pieces—deposited on Si (100)—at 1000 rpm, followed by a bake procedure for 4 min at 80°C. Line patterns are exposed using electron beam lithography and then the resulting wafer piece is developed in a chemical solution bath (low concentration (2.38%) of tetramethylammonium hydroxide (TMAH) developer), yielding 2D-nanowire HSQ patterns. The HSQ patterns then underwent a hardening annealing process in Ar/N2 ambient at 500°C, followed by a fluorine-based (e.g., combination of CHF3 and CF4 gases) anisotropic RIE to transfer the pattern into the SiCxOy thin films. The HSQ residue is then removed by wet etching in buffered hydrofluoric (BHF) acid, resulting in periodically well-defined NWs [22].
Figure 2.
(a–d) Fabrication steps of the SiCxOy nanowires (NW) using lithography and RIE. The final NW arrays are shown in SEM image 1 and (e–h) fabrication steps of the SiCxOy nanowire (NW) arrays using the SIT method by SiC conformal deposition on the resist followed by RIE to open the SiC top layer, wet etch to remove the resist, and RIE. The final NW arrays made by SIT are shown in SEM image 2.
Pertaining to the NW fabrication, certain samples underwent a sidewall image transfer (SIT) process which was performed by conformal deposition of a thin silicon carbide (SiC) hard mask (sidewall layer) on the patterned photoresist followed by anisotropic RIE [23]. This allowed for a significant reduction of the critical dimensions as, during the SIT process, the NW width is defined by the thickness of the SiC layer rather than the resolution of the lithography step. The SiCxOy NWs underwent different post-fabrication thermal treatments for up to 2 h at annealing temperatures in the range of 50–700°C in Ar, O2, or forming gas (5% H2 and 95% N2) atmospheres.
3. Bonding configuration of silicon oxycarbide materials and nanowires
3.1. Fourier transform infrared spectroscopy (FTIR) characterization of silicon oxycarbide thin films
Figure 3a shows the Fourier transform infrared spectroscopy (FTIR) data of SiCxOy thin films in the 400–1700-cm−1 range. The spectra are characterized by three absorption bands and a shoulder assigned to the Si‐O‐C rocking, Si‐C stretching, and Si‐O transverse and longitudinal-stretching vibration modes, centered at, respectively, ~440, ~800, ~1000, and ~1150 cm−1 [22, 37, 38].
Figure 3.
(a) The FTIR absorption spectra of the AD SiCxOy and SiO2 control in the 400–1700 cm−1 range. The peak positions of the AD SiCxOy appear red-shifted compared to the SiO2 control, due to the incorporation of less electronegative C, (b) the [Si‐C]/[Si‐O] bond-area ratio plotted as a function of the C/O content ratio showing a linear increase with increasing C/O and (c) the Si‐O‐Si bond angle of the bridging O atom in the SiCxOy [22].
More specifically, the Si‐O‐C vibration mode (~440 cm−1) is caused by the ≡Si‐O‐Si≡ rocking mode due to out-of-plane motion of O in O(3−x)Cx≡Si‐O‐Si≡CyO(3-y) and is unaffected by the Si‐O‐Si-bridging bond-angle variation [42–45]. For samples with C content higher than 20 at.%, the density of ≡Si‐O‐Si≡-bonding groups decreased significantly, as dictated by the SiCxO2(1−x) stoichiometry, suggesting that the backbone-bonding network related to the SiO4 tetrahedral in SiCxOy changed toward SiC-like structures with significant presence of SiC4 tetrahedral. The replacement of O atoms by C atoms with increasing C content in films is reflected in the monotonic increase of the bond area ratio of [Si‐C] and [Si‐O] as clearly depicted in Figure 3b.
Additionally, incorporation of the less electronegative C atoms leads to a reduced Si‐O‐Si bond angle between tetrahedral (see Figure 3c) [30, 44]. As a result, the density of the as-grown films is expected to increase with increasing C content, which is in agreement with the density values shown in Section 2.
Figure 4 displays the FTIR spectra collected in the range from 400 to 2300 cm−1 for the three classes of as-deposited silicon oxycarbide materials and for their annealed counterparts at 900 and 1100°C [37].
Figure 4.
IR absorption spectra for the as-deposited, 900°C-, and 1100°C- annealed (a) SiC-like, (b) Si‐C‐O, and (c) SiO2-like samples [37].
Deconvolution of the FTIR spectra reveals several bonding components in the as-deposited SiCxOy material systems [30, 37, 45, 46]. In particular, the deconvolution of the absorption bands in the range of 400–1400 cm−1 for the SiC-like film indicates the presence of a weak C‐H mode at ~530 cm−1, a major Si‐C-stretching absorption mode at ~764 cm−1, and a shoulder assigned to the Si‐O-stretching mode at ~960 cm−1. The hydrogen-related absorption bands (Si‐H and C‐H) are located at ~2100 and 2900 cm−1, respectively. Finally, the absorption observed at ~1846 cm−1 is attributed to a C‐O-stretching mode.
As seen in Figure 4b, the IR spectrum of Si‐C‐O film has three characteristic absorption band regions, originating from the Si‐C and Si‐O functional groups [37]. In comparison to the SiC-like matrix films, a new absorption peak is seen at ~440 cm−1, attributed to the Si‐O‐C vibration mode discussed above. The IR region from 600 to 1300 cm−1 is broader compared to that in the SiC-like films, and its deconvolution shows the presence of four peaks centered at 663, 816, 1002, and 1114 cm−1 attributed to Si‐C‐H, Si‐C stretching, and to the transverse optical (TO) and longitudinal optical (LO) asymmetric Si‐O-stretching modes, respectively. Compared to the SiC-like films, the position of the Si‐C absorption peak shifted from 764 to 816 cm−1, owing to the addition of more electronegative O atoms in the network [47].
The FTIR absorption spectrum of the SiO2-like film is characterized by an intense Si‐O‐Si mode (rocking), centered at ~440 cm−1: a Si‐O mode (bending) located at ~815 cm−1, and an intense Si‐O vibration mode (stretching) at ~1100 cm−1. The hydrogen-related vibration modes for C‐H and O‐H are observed at, respectively, ~2900 cm−1 and in the 3100–3700-cm−1 range.
The findings outlined above describe the evolution of the as-deposited films from silicon carbide-like to silicon dioxide-like films as the amount of C decreases. Regarding the annealed samples up to 700°C, the IR absorption behavior remains similar to the case of their as-deposited counterparts, and it is worth mentioning that changes took place at annealing temperatures beyond 900°C [44−46].
In the case of the SiC-like sample annealed at 900°C (Figure 4a), the Si‐C- and Si‐O-stretching modes show minor changes. However, both hydrogen-related modes appear with reduced intensities, as expected from the NRA results shown in Figure 1b. After the 1100°C annealing, the Si‐C absorption band increased drastically in intensity and its line shape changed from Gaussian to mix of Gaussian and Lorentzian, suggesting the presence of longer-range order (Lorentzian). Additionally, all hydrogen-related vibration modes are no longer present in the films owing to hydrogen desorption.
Similarly, for the 900°C-annealed Si‐C‐O a small intensity increase of the Si‐C-stretching mode was observed, while further annealing at 1100°C led to an overall absorption intensity increase accompanied with a blue shift of the Si‐O stretching (Figure 4b). Finally, the annealing studies on the SiO2-like material (Figure 4c) revealed a significant intensity increase of the Si‐O‐Si-rocking and the Si‐O-stretching modes.
The bond density is directly proportional to the area of the IR band absorption, and can be estimated as in reference [37] using the inverse absorption cross section found in literature (3 × 1019 cm−2 for Si‐C [48], 1.4 × 1020 cm−2 for Si‐H [49], and 1.35 × 1021 cm−2 for C‐H [50, 51]). The Si‐C bond density for the as-deposited SiC-like sample is ~2.2 × 1023 cm−3 while for the as-deposited Si‐C‐O sample is ~5.5 × 1022 cm−3. The dependence of Si‐C bond density with annealing temperature for both SiC-like and Si‐C‐O is presented in Figure 5a. It shows a constant concentration up to 700°C annealing temperature. At higher temperatures, the Si‐C bond concentration increases owing to the densification of the materials and hydrogen desorption, which contributes to the increased availability of Si and C atoms formerly bonded to hydrogen. Indeed, as seen in Figure 5b, the bond density of the Si‐H and C‐H bonds decreases with annealing temperature Ta ≥ 900°C for both classes of materials.
Figure 5.
(a) Bond density of Si‐C, Si‐H, and C‐H bonds as a function of annealing temperature for the SiC-like films, (b) bond density of Si‐C and C‐H bonds as a function of annealing temperature for the Si‐C‐O films and (c) total atomic concentration of H, as obtained by means of NRA and FTIR for the SiC-like and Si‐C‐O samples [37].
As shown in Figure 5c, the total concentration of hydrogen atoms as determined by the NRA measurements is greater than the total content of hydrogen as calculated by FTIR. Each H-related bond corresponds to one H atom; therefore, the H-related bond density corresponds to the H atomic density. The total atomic density is determined by RBS measurements. This finding suggests that some H atoms are incorporated during CVD growth and are not chemically bound to other elements. These non-bonded H atoms may be present in the form of molecular hydrogen formed during the decomposition of the precursor [37].
3.2. FTIR characterization of silicon oxycarbide nanowires
Large SiCxOy NW structures were fabricated on intrinsic Si substrates in order to perform bonding configuration analysis [22]. The normalized absorbance FTIR spectra of both the as-deposited SiC0.34O1.52 thin film and the as-fabricated NWs are shown in Figure 6. It was found that the bonding configuration of the SiC0.34O1.52 NW system was maintained after nanofabrication as the relative intensities of Si‐C and Si‐O absorption bands remained the same with respect to the as-deposited thin film. A slight absorption increase of the Si‐O shoulder at ~1200 cm−1 may be due to surface oxidation induced on the as-synthesized NWs.
Figure 6.
FTIR absorbance spectra of SiC0.34O1.52 thin film and its 70-nm-width NW array counterpart. Upper inset: SEM image of the NW array used for FTIR measurements (36 blocks of 490 × 490 μm2 NW arrays). Lower inset: The conservation of the structural characteristics is also observed in the C=O vibration mode at ~1900 cm−1, which remained unchanged [22].
3.3. XPS characterization of silicon oxycarbide thin films
The information about the bonding configuration in silicon oxycarbide thin films extracted by the means of FTIR analysis was also independently assessed by XPS studies [37]. The XPS analysis focused on examining the electronic environment (chemical bonding) of the Si 2p, C 1s, and O 1s core energy.
In the case of the as-deposited samples, the Si 2p spectrum of the SiC-like matrix (Figure 7) is composed of a center peak at 100.3 eV assigned to Si‐C bonds and two shoulders centered at 99.2 and 101.2 eV assigned to Si‐H- and Si‐C‐O-type bonding [37, 52]. In the case of the Si‐C‐O material, the Si 2p peak broadened and shifted to higher binding energies. The peak deconvolution showed the presence of three components centered at 100.8, 102.1, and 103.2 eV which are attributed to the Si‐C, Si‐C‐O, and Si‐O bonds, respectively [37, 46, 52]. This result agrees with the FTIR findings where, for both Si‐C- and Si‐O-stretching modes, the vibration frequencies increased with increasing O content (incorporation of more electronegative atom).
Figure 7.
XPS spectra of the Si 2p peaks for the as-deposited SiC-like, Si‐C‐O and SiO2-like samples [37].
In the case of the as-deposited SiO2-like material, the Si 2p spectrum shifted to even higher binding energy and yielded two peaks centered at 102.3 and 103.5 eV which are related to two different Si‐O electronic configurations [37, 53, 54].
4. Optical properties of silicon oxycarbide materials
The structural evolution of the as-deposited silicon oxycarbide materials along the SiCxO2(1−x) stoichiometry was also reflected in their optical properties. The evolution of the index of refraction and the optical gap as a function of the C content of the materials and upon annealing treatments will be addressed in the following subsections.
4.1. Refractive index
The refractive index (n) of SiCxOy is found to exhibit a linear relationship with increasing the [Si‐C]/[Si‐O] bond area ratio (Figure 8a). The linear increase of n versus [Si‐C]/[Si‐O] over the range analyzed is found to be partly associated with an increase of mass density in SiCxOy with increasing [Si‐C]/[Si‐O] [37]. To understand this behavior, someone can correlate the refractive index (n) or the dielectric constant (ε = n2) with the structural parameters through the Lorentz-Lorenz (L-L) equation [55].
Figure 8.
(a) The index of refraction at 800 nm of different SiCxOy given as a function of the [Si‐C]/[Si‐O] bond-area ratio. The solid line is the linear fit of the displayed data and (b) plot of index of refraction (n) at 800 nm as a function of annealing temperature [22, 37].
The FTIR measurements in Figure 3 show a decrease in the Si‐O‐Si bond angle with C addition, which is expected considering the difference in the electronegativity between C and O. The mass density and Si atomic content (Si atoms possess higher electronic polarizability than O) of samples with higher carbon concentration is larger as opposed to SiO2-like samples [56]. It is therefore suggested that the increased index of refraction with increasing [Si‐C]/[Si‐O] ratio is due to the variations in bond angles, larger mass density, and higher Si content. Further increase of the refractive index of all three classes of silicon oxycarbide materials is also observed upon post-deposition annealing beyond 900°C (Figure 8b). This behavior is expected considering the densification of SiCxOy materials upon annealing as shown in Figure 1c [22, 37].
4.2. Optical gap
The observed increase in the refractive index n, as C concentration increases along the SiCxO2(1−x) stoichiometry, correlates well with the decrease in the optical gap of the films. For example, the E04 gap, which corresponds to the energy where the absorption coefficient (α) is equal to 104 cm−1 (α(E04)= 104 cm−1), is found to decrease with increasing [Si‐C]/[Si‐O] ratio (Figure 9a). The Tauc optical gaps, Eg, were also calculated from the optical absorption measurements using Tauc’s law, (αhν)1/2 = B1/2(hv-Eg), where α is the absorption coefficient and hν is the photon energy [38].
Figure 9.
(a) E04 and Eg energy values for different SiCxOy materials versus the [Si‐C]/[Si‐O] bond-area ratio, (b) E04 (spheres) and Eg (circles) values with annealing temperature and (c) E04 values as a function of H content in the films [22, 37].
Similar to E04, the Eg values decrease with increasing [Si‐C]/[Si‐O]. This behavior can be explained by considering the larger splitting energy difference between the bonding and anti-bonding electronic states in Si‐O bonds in comparison to Si‐C bonds [22, 38, 57].
In addition, as seen in Figure 9a, E04 values are generally higher than their Eg counterparts, similar to other hydrogenated disordered systems [58]. This could be explained by taking into account that Tauc’s optical gap refers to the optical transitions between extended states close to the band edge, while E04 is related to transitions of the extended states away from the band edge [38, 58].
As seen in Figure 9b, both the E04 and Eg gaps decrease with increasing annealing temperature. It is worth mentioning that the decrease in the optical gap is more pronounced in the films with higher O concentration. For example, the decrease of the Tauc gap values between the as-deposited and post-1100°C annealed films are ~0.5, ~0.6, and ~1.4 eV for, respectively, the SiC-like, Si‐C‐O, and SiO2-like classes of SiCxOy. It is suspected that the possible precipitation of carbon in the high O-containing systems could be responsible for this phenomenon at high annealing temperatures. The Si‐C bond length (~1.88 Å) is longer than the Si‐O bond length (~1.63 Å). Consequently, a high degree of strain may accumulate in the Si‐C sites within the SiO2 network (e.g., in the SiO2-like sample with <5 at.% C). Thermal annealing may result in strain relaxation, with the subsequent structural rearrangements perhaps favoring the formation of carbon clusters, as reported in a previous study [59]. Their optical gap values may vary between ~0.6 and 3 eV, depending on the cluster size [58, 60]. Consequently, it would be expected that the precipitation of carbon in O-rich samples (e.g., SiO2-like) could be relatively facile, with the optical gap in these samples decreasing more rapidly with increased annealing temperatures.
Furthermore, the decrease in optical gap with increased annealing temperatures seems to correlate well with the loss of hydrogen. As seen in Figure 9c, hydrogen reduction is accompanied by a decrease in the energy band gap in the annealed SiCxOy films. The presence of Si‐H bonds (~2000 cm−1) can be an indication of dangling-bond passivation in the material, while the presence of other hydrogen-bonding configurations may be responsible for forming recombination centers and increasing the degree of structural disorder [61, 62].
In the as-deposited high C content samples, the Si‐Hn stretching mode is found at ~2100 cm−1 (insets of Figure 4(a–c)). These peaks are attributed to Si‐H-related bonds [63, 64]. Considering the absence of any Si‐Hn bonding (2000–2200 cm−1) in the Si‐C‐O- and SiO2-like samples, it is suggested that any dangling bonds in the films remained unsaturated, resulting in enhanced structural disorder. Furthermore, hydrogen desorption upon annealing would likely contribute to the formation of additional dangling bonds and defect states, which lead to the increased density of localized states below the mobility edge, thereby decreasing the optical gap. This mechanism seems to be taking place in all thermally grown CVD SiCxOy films in this study.
4.3. Structural disorder and dangling bonds
Regarding the electronic structure of amorphous materials, it is common to expect the presence of band-tail states and localized defect states. These states exist due to the structural disorder in materials and may have a significant effect on the material’s performance even at low concentrations. Therefore, it is important to elaborate on the degree and impact of structural disorder in the CVD-grown SiCxOy systems.
As it was discussed earlier, thermal annealing causes lowering of the optical gap owing to the increased optical absorption observed in the SiCxOy materials grown by CVD. The latter is true even at photon energies well below the optical gaps. The enhanced sub-band-gap absorption is a result of an increased density of band-tail states and localized defect states [31]. One of the proposed mechanisms responsible for the increased density of band-tail states upon annealing is the annealing-induced enhanced bond-angle disorder due to structural reconfiguration and/or strain relaxation [65]. In this context, the FTIR full-width half maximum (FWHM) values for both the Si‐O- and Si‐C-stretching modes in the TCVD SiCxOy films, with the exception of the 1100°C-annealed SiC-like sample, increased after annealing, suggesting that thermal treatments indeed enhance bond-angle distortion (see Figure 4(b and c)).
In the case of SiC-like material annealed at 1100°C, the FTIR spectrum shown in Figure 4a suggests that a significant amount of crystallization takes place resulting in the Lorentzian line shape of the infrared absorption band. This suggests that the bond-angle disorder is dramatically reduced. However, the optical absorption for the SiC-like films annealed at 1100°C is further increased compared to its as-deposited counterparts [38]. This suggests that, in addition to bond-angle variation, a different type of disorder is also present. Such behavior is known for amorphous covalent materials where both topological and compositional disorders are present simultaneously [66].
Furthermore, the deviation of the CVD-grown SiCxOy films from the purely stoichiometric SiCxO2(1−x) shown in the ternary diagram of Figure 1 suggests that there is a small excess of carbon that can form homonuclear bonds upon annealing. Also, this deviation increases for high C concentration materials, toward the SiC-like class regime. The electronic states associated with the homonuclear bonds would exist as localized states within the gap due to their relatively weak bond strength [67, 68].
In this context, electron paramagnetic resonance (EPR) studies on SiCxOy materials, grown by CVD, showed the presence of unpaired electrons (dangling bonds) [5]. The same study proposed that one of the major EPR signals may be originated from (≡Si-)3C• radicals or associated defects with different backbone atoms bonded to C atom, such as in C‐Si‐O configuration [69]. The SiCxO2(1−x) stoichiometry trend of SiCxOy (SiCxO2(1−x)) suggests that two divalent oxygen atoms are replaced by one tetravalent C, further supporting the presence of (≡Si-)3C• radicals in our films, originating from oxygen incorporation into (≡Si-)4C structures. Consequently, the density of such radicals is expected to increase following thermal oxidation of (≡Si-)4−nCHn groups, as it was observed, which have not been completely dehydrated during the film deposition [70]. Similarly, the oxidation of (≡Si-)4−nCHn groups with one or two back-bonded C atoms to Si may also lead to an increased density of Si-dangling bonds in SiCxOy. Such dangling bonds may also contribute to the formation of band-tail states in SiCxOy [5].
5. Photoluminescence properties of silicon oxycarbide thin films and nanowires
5.1. Visible luminescence emission from SiCxOy thin films
The room-temperature photoluminescence spectra for SiCxOy samples with different C concentrations under excitation at 300 nm are shown in Figure 10a. The spectra are characterized by a broad emission in the whole visible range (350–800 nm). The photoluminescence excitation (PLE) intensity (Figure 10b) shows the presence of a shoulder at low excitation energies (<3.5 eV) and a steep increase at high excitation energies (>~3.7 eV). This was fit linearly and the intercept of the fitted line at the photon energy abscissa was taken as the PLE edge. As shown in Figure 10c, a strong correlation was observed between the values of E04 and the PLE edge, suggesting that the PL emission energy in the SiCxOy samples may be related to their optical gap [5].
Figure 10.
(a) PL emission spectra from as-deposited (AD) SiCxOy thin films (4.13 eV excitation, ~300 μW), (b) normalized PLE spectra of the AD SiCxOy samples at the PL maxima. The linear fits (dashed lines) of the steep increase of the PLE intensities are shown along with the intercept of these straight lines at the excitation energy (PLE-edge values), and (c) E04 and PLE-edge energy values of SiCxOy thin films versus C [5].
Based on optical, FTIR characterizations, passivation experiments and electron paramagnetic resonance measurements, defect-related mechanisms and small sp2-carbon clusters that could be attributed to white luminescence from SiCxOy thin films were excluded [3, 5]. For example, structural defects typical seen with EPR measurements in silicon oxides, which cannot be explicitly controlled by material processing and are not directly related to the stoichiometry and material characteristics, such as Si-related neutral oxygen vacancies or non-bridging oxygen-hole centers, were ruled out. Instead, the observed intense white luminescence originates from the recombination of photogenerated carriers between the energy bands and at their tail states associated with the Si‐O‐C/Si‐C bonds, as indicated by the direct correlation between the integrated luminescence intensity and the Si‐O‐C bond density (see Figure 11) [3].
Figure 11.
Normalized integrated red and green PL emission bands and the integrated FTIR absorption of Si‐O‐C functional group at ~440 cm−1. Inset: FTIR absorptions of the Si‐O‐C-rocking mode in film [5].
On this, the integrated red and green PL emission bands were added and their normalized integrated values were plotted along with the intensity of the red-shifted Si‐O-rocking (related to Si‐O‐C bond density) mode as a function of C content (Figure 11) [3]. A strong correlation between the emitted luminescence and the Si‐O‐C bond density in SiCxOy was revealed. This suggests that the emitted luminescence can be directly associated with the Si‐O‐C structure in the materials [5]. Additionally, the PL/PLE analysis revealed a strong similarity in the PLE behavior for the green/blue band emissions between the SiC control and SiCxOy, suggesting that C‐Si/C‐Si‐O bonding may be also responsible for the excitation path of the observed luminescence in SiCxOy.
5.2. Band-tail recombination model
Representative forming gas-annealed SiCxOy samples were additionally studied with means of PL and PLE analyses as presented in Figure 12 [22].
Figure 12.
(a) Steady-state PL of the FG-annealed SiCxOy with 12 at.% C content (SiC0.34O1.52) under varying excitation photon energies (Eexc). The PL intensity increased monotonically by two orders of magnitude with Eexc, suggesting that the efficiency of photo-carrier generation increases with Eexc, (b) room-temperature steady-state PL peak position dependence on excitation energy of SiCxOy thin films of varying carbon concentrations. With increase in excitation energy, the PL peak-emission-position blue-shifts until ~Eexc,on (red-dotted line is used as a guide to the eye). Hopping edges are indicated by horizontal black dotted lines and (c) Eg calculated from Tauc’s law and Eexc,on values as a function of [Si‐C]/[Si‐O] bond ratio [23].
The evolution of the PL peak position in SiCxOy was supported by the band-tail states recombination model, typical of amorphous materials [71]. Upon excitation, the photogenerated carriers thermalized to lower energies associated with band edges (hopping edge) before they recombined radiatively (energy plateau in Figure 12b). The PL peak position increased with the excitation energy up to the Eexc,on value, as the electron population at high-lying band-tail levels of the conduction band increasing with higher excitation energy. The red shift of Eexc,on seen with increasing C content in SiCxOy can be ascribed to the observed linear decrease of the optical gap (Eg) with increasing [Si‐C]/[Si‐O] and their values almost coincide with the Eg values of the films [22].
PL dynamics experiments showed a fast decrease of the PL intensity, suggesting the existence of fast recombination mechanisms in SiCxOy, and the PL decay spectra followed a stretched exponential law [23]. These findings further support a band-tail states recombination model, in which carriers recombine by tunneling between spatially separated conduction and valence band-tail states. Due to the diffusivity/tunneling of the photogenerated carriers during thermalization in the band-tail states before they recombine and the inhomogeneous constitution of the band-tail states related to C‐Si/Si‐O‐C bonding, where each state contributes with a slightly different PL lifetime, a distribution of lifetimes is expected, hence the stretched exponential behavior. This is inherent in disordered semiconductors, such as amorphous Si:H, C:H, SiCx, and SiNx, due to the broad and variable spatial density of these states [72–74].
To further elucidate on the band-tail states recombination model in SiCxOy, the PL luminescence decay at different emission energies was additionally investigated. The time evolution of the PL line shape is presented in Figure 13a. It can be seen that during the first 1 ns of the luminescence decay, the integrated intensity substantially decreased and a red shift, equal to ΔE = 0.31 eV, in the PL emission peaks occurs for the SiCxOy thin film with 12 at.% C. This red shift is found to be less for samples with higher C concentration [23].
Figure 13.
(a) Time evolution of PL spectrum of SiC0.34O1.52 (Eexc = 3.06 eV). The number associated with each spectrum indicates the elapsed time (in nanoseconds) after excitation. (b) Raw data of PL decay transients of SiC0.34O1.52 film at different emission energies (IRF in black). (c) Average lifetimes of FG-annealed SiCxOy films with different C contents at different emission energies. The average lifetimes of the as-deposited (AD) SiCxOy films with 12 at.% C and 21 at.% C are also shown (gray symbols) [23].
Furthermore, the PL lifetimes increased as the emission energy was decreased, in agreement with electron-hole (e-h) hopping within lower-energy tail states, as the rate of thermalization decreases significantly due to the rapidly decreasing density of band-tail states [75]. Similar behavior was observed in amorphous semiconductors where the luminescence lifetime increase is attributed to e-h hopping [74]. Upon FG annealing, the average lifetimes exhibited higher values compared to their as-deposited counterparts (Figure 13c). Furthermore, the integrated PL intensity of the FG-annealed films increased significantly along with a blue shift in peak position (e.g., six times for the sample with 21 at.% C with 0.2 eV blue shift). This change in lifetimes and PL intensity can be attributed primarily to the passivation of non-radiative recombination centers present in lower-energy portion of the band-tail states of the as-deposited films.
The increase in the luminescence lifetime in SiCxOy with low C content can be attributed to the decrease of non-radiative recombination paths compared to their high C content counterparts. As the SiCxOy composition evolves from SiC-like to SiO2-like, a decrease of the local disorder is expected. As presented above herein FTIR measurements suggest that the degree of bond-angle disorder decreases with decreasing C content in the chemically grown SiCxOy films.
Additionally, it is expected that in the case of high C content samples, the density of band-tail states should increase as indicated by their increased sub-bandgap absorption [15, 76]. Therefore, for SiCxOy films with higher C content (C >14 at.%), a higher density of band-tail states and enhanced disorder is expected, which results in faster thermalization of the photogenerated carriers yielding higher decay rates and a tighter lifetime distribution (Figure 13b) [23].
5.3. Visible luminescence from SiCxOy nanowires
Figure 14a and b shows the normalized room-temperature PLE and PL emission spectra of SiC0.34O1.52 nanowire arrays. To better understand the visible light emission in SiCxOy NWs, their PL and PLE properties were explored in conjunction with data from the thin film of the same composition. The PL emission spectrum of SiC0.34O1.52 NWs exhibits broadband characteristics ranging from blue to deep red, while the PLE spectrum monitored at the peak luminescence emission (~550-nm) spans from near-UV to blue/green regions of the spectrum.
Figure 14.
(a) Room-temperature PLE spectra of 120-nm-thick SiC0.34O1.52 thin film and its corresponding NWs measured at its emission peak. Almost identical PLE emission spectra between NWs and thin films were observed, suggesting that there is no change in the excitation path and emission origin of the observed luminescence in SiC0.34O1.52 nanowires, (b) ensemble steady-state normalized PL spectrum of the SiCxOy NWs array along with the normalized PL spectrum of its thin film analog (Eexc = 4.1 eV) and (c) average lifetimes of the SiCxOy NW array with 12 at.% C and its thin film analog at different PL emission energies [22, 23].
PLE analysis suggested that the observed luminescence from SiCxOy NWs is related to radiative recombination of photo-excited carriers in band-tail states associated with C‐Si/Si‐O‐C-bonding groups [5, 22]. Furthermore, a supplementary mechanism, in addition to the proposed band-tail states recombination process, may be needed in order to take into account the reduced dimensionality of SiCxOy NW. In the case of the NW structure with spatially confined volume, the statistics of the lowest energy states due to Si‐C bonds may be excluded [77]. Furthermore, by nanostructuring the recombination volume is reduced, thus, the tunneling probability of a carrier between adjacent states at similar energy is expected to decrease. Consequently, the carriers will be exposed to a smaller number of non-radiative sites [23, 77, 78], resulting in enhanced PL efficiency, PL blue shift, and faster lifetimes with a tighter distribution as observed in SiC0.34O1.52 (12 at.% C) (Figure 14c). However, it is important to emphasize that the effects of NW-related surface recombination and optical scattering may not be ruled out.
5.4. Photo-stability upon thermal oxidation and excitation power density
In addition to PL and PLE studies, the luminescence performance of the SiC0.34O1.52 NW arrays was investigated as a function of oxidation temperature and excitation power density [22].
The oxidation treatments up to 250°C (Figure 15a) did not cause any change in the composition and bonding configuration of the SiC0.34O1.52 material. Consequently, the emission intensity and line shape, from SiC0.34O1.52 nanostructured arrays, did not reveal any changes, suggesting the absence of luminescence degradation due to thermal oxidation. This stability can be attributed to the similarity of the oxidation rates and activation energies of SiCxOy materials to those of SiC [79]. Hence, SiCxOy materials (with higher carbon content) appear to be significantly more resistant to oxidation annealing, compared to its SiO2-like counterparts (with very low carbon content) [3].
Figure 15.
(a) PL spectra of the AD and 2-h-oxygen-annealed SiC0.34O1.52 NW at various temperatures (excitation wavelength λexc = 457 nm). The inset shows the integrated PL intensity versus annealing temperature and (b) room-temperature PL spectra of the 70-nm-width SiC0.34O1.52 NWs for different CW excitation probing power densities (excited at the λexc = 457.9 nm of an Ar ion laser). The inset shows the linear behavior of the integrated PL intensity as a function of the excitation power density [22].
The excitation power dependence study (Figure 15b) showed a linear behavior in the integrated PL with respect to the power density (up to ~800 W/cm2). Similar to the thermal-oxidation study, the peak position and the line shape of the PL in the nanowires remained unchanged, suggesting good emission stability at high excitation intensity [22]. The latter is more supporting evidence suggesting the absence of defect-related localized emission in the proposed origin of the visible luminescence from SiCxOy nanowires, as no PL saturation at high powers was observed (e.g., due to state filling of the localized states) [80, 81].
6. Concluding remarks
The optical and luminescence properties of silicon oxycarbide thin films and nanostructured (e.g., NW) arrays are correlated to their synthesis routes, structural properties, and bonding configuration. The composition of the chemically CVD-grown SiCxOy thin films approximate the SiCxO2(1−x) (0 < x < 1) stoichiometry. The index of refraction increases linearly as the [Si–C]/[Si–O] bond-area ratio increases, accompanied by a linear decrease of the optical gap. The white (red, green, and blue) emission can be achieved simultaneously from the same SiCxOy film following a single-deposition process, without the complications encountered in the case of using nanocrystals (e.g., Si, SiC). In particular, it was determined that the white PL emission of SiCxOy thin films is strong enough to be seen with the naked eye under bright room conditions. Based on the PL, FTIR, and EPR analyses, typical structural defects in oxides were ruled out as the mechanism for white luminescence from SiCxOy. Instead, the observed intense visible luminescence originates from the recombination of photo-generated carriers between the energy bands and at their tail states associated with Si‐O‐C/Si‐C bonds. In this regard, the potential advantages offered by our proposed approach of SiCxOy thin films and NWs range from color tunability, thermal/photo-stability to enhanced light extraction efficiency and from cost reduction to environmental considerations. To this end, these compelling behaviors may provide a pathway for further controlling and enhancing the thermal stability and PL yield of white light emission from such films and nanostructured materials through optimal engineering of Si‐O‐C/Si‐C bonds in the matrix.
Acknowledgments
The authors would like to thank Dr. Mengbing Huang, of the Colleges of Nanoscale Sciences and Engineering at SUNY POLY, for his contribution to the work presented herein.
\n',keywords:"silicon oxycarbide, SiCxOy, Si‐O‐C, Si‐C‐O, nanowires, thin films, luminescence, CVD, e-beam lithography, structural properties, optical properties, band tails, disorder",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/53903.pdf",chapterXML:"https://mts.intechopen.com/source/xml/53903.xml",downloadPdfUrl:"/chapter/pdf-download/53903",previewPdfUrl:"/chapter/pdf-preview/53903",totalDownloads:2642,totalViews:472,totalCrossrefCites:3,totalDimensionsCites:9,totalAltmetricsMentions:0,impactScore:3,impactScorePercentile:84,impactScoreQuartile:4,hasAltmetrics:0,dateSubmitted:"June 2nd 2016",dateReviewed:"November 21st 2016",datePrePublished:null,datePublished:"March 8th 2017",dateFinished:"January 17th 2017",readingETA:"0",abstract:"Silicon oxycarbide (SiCxOy) has been extensively investigated due to its wide use in the Si semiconductor industry in applications that include low-k dielectrics, passivation layers, and etch-stop layers. Furthermore, SiCxOy research has been exploring its prospective use in numerous other technological usages, such as lighting, energy, and biological applications. The latter include white light-emitting materials, hydrogen storage materials, gas sensors, anode materials for lithium batteries, and biomedical devices. SiCxOy materials can intensively luminescence in a broad emission spectral range that spans the ultraviolet, the visible, and even the near-infrared spectrum, when doped with erbium. Herein, we present pertinent results on the material behaviors from chemically synthesized SiCxOy thin films and nanowires. Moreover, their light-emitting properties and underlying mechanisms for light emission are explored in conjunction with data from their thin film counterparts, which are also employed as baseline comparison metric. We further highlight major challenges and promises of such materials.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/53903",risUrl:"/chapter/ris/53903",book:{id:"5541",slug:"modern-technologies-for-creating-the-thin-film-systems-and-coatings"},signatures:"Spyros Gallis, Vasileios Nikas and Alain E. Kaloyeros",authors:[{id:"193036",title:"Dr.",name:"Spyros",middleName:null,surname:"Gallis",fullName:"Spyros Gallis",slug:"spyros-gallis",email:"sgalis@sunypoly.edu",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"200997",title:"Dr.",name:"Vasileios",middleName:null,surname:"Nikas",fullName:"Vasileios Nikas",slug:"vasileios-nikas",email:"vnikas@sunypoly.edu",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"200998",title:"Dr.",name:"Alain E.",middleName:null,surname:"Kaloyeros",fullName:"Alain E. Kaloyeros",slug:"alain-e.-kaloyeros",email:"akaloyeros@sunypoly.edu",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Synthesis and fabrication of silicon oxycarbide thin films and nanostructures",level:"1"},{id:"sec_2_2",title:"2.1. SiCxOy materials grown by thermal chemical vapor deposition: composition control",level:"2"},{id:"sec_3_2",title:"2.2. Nanofabrication of silicon oxycarbide nanostructures",level:"2"},{id:"sec_5",title:"3. Bonding configuration of silicon oxycarbide materials and nanowires",level:"1"},{id:"sec_5_2",title:"3.1. Fourier transform infrared spectroscopy (FTIR) characterization of silicon oxycarbide thin films",level:"2"},{id:"sec_6_2",title:"3.2. FTIR characterization of silicon oxycarbide nanowires",level:"2"},{id:"sec_7_2",title:"3.3. XPS characterization of silicon oxycarbide thin films",level:"2"},{id:"sec_9",title:"4. Optical properties of silicon oxycarbide materials",level:"1"},{id:"sec_9_2",title:"4.1. Refractive index",level:"2"},{id:"sec_10_2",title:"4.2. Optical gap",level:"2"},{id:"sec_11_2",title:"4.3. Structural disorder and dangling bonds",level:"2"},{id:"sec_13",title:"5. Photoluminescence properties of silicon oxycarbide thin films and nanowires",level:"1"},{id:"sec_13_2",title:"5.1. Visible luminescence emission from SiCxOy thin films",level:"2"},{id:"sec_14_2",title:"5.2. Band-tail recombination model",level:"2"},{id:"sec_15_2",title:"5.3. Visible luminescence from SiCxOy nanowires",level:"2"},{id:"sec_16_2",title:"5.4. Photo-stability upon thermal oxidation and excitation power density",level:"2"},{id:"sec_18",title:"6. Concluding remarks",level:"1"},{id:"sec_19",title:"Acknowledgments",level:"1"}],chapterReferences:[{id:"B1",body:'Grill A., Gates S. M., Ryan T. E., Nguyen S. V., and Priyadarshini D. 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Colleges of Nanoscale Sciences and Engineering, SUNY Polytechnic Institute, Albany, NY, USA
Colleges of Nanoscale Sciences and Engineering, SUNY Polytechnic Institute, Albany, NY, USA
'},{corresp:null,contributorFullName:"Alain E. Kaloyeros",address:null,affiliation:'
Colleges of Nanoscale Sciences and Engineering, SUNY Polytechnic Institute, Albany, NY, USA
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Dávila Rodríguez",authors:[{id:"12709",title:"Dr.",name:"Jose Rene",middleName:null,surname:"Rangel-Mendez",fullName:"Jose Rene Rangel-Mendez",slug:"jose-rene-rangel-mendez"},{id:"12711",title:"Dr.",name:"Vladimir Alonso",middleName:null,surname:"Escobar Barrios",fullName:"Vladimir Alonso Escobar Barrios",slug:"vladimir-alonso-escobar-barrios"},{id:"112164",title:"Dr",name:"Guillermo",middleName:null,surname:"Andrade-Espinosa",fullName:"Guillermo Andrade-Espinosa",slug:"guillermo-andrade-espinosa"},{id:"112165",title:"Dr.",name:"José Luis",middleName:null,surname:"Dávila-Rodríguez",fullName:"José Luis Dávila-Rodríguez",slug:"jose-luis-davila-rodriguez"},{id:"112167",title:"Dr.",name:"Nancy Verónica",middleName:null,surname:"Pérez-Aguilar",fullName:"Nancy Verónica Pérez-Aguilar",slug:"nancy-veronica-perez-aguilar"}]},{id:"36175",title:"Preparation and Characterization of PVDF/PMMA/Graphene Polymer Blend Nanocomposites by Using ATR-FTIR Technique",slug:"preparation-and-characterization-of-pvdf-pmma-graphene-polymer-blend-nanocomposites-by-using-ft-ir-t",signatures:"Somayeh Mohamadi",authors:[{id:"108556",title:"Dr.",name:"Somayeh",middleName:null,surname:"Mohamadi",fullName:"Somayeh Mohamadi",slug:"somayeh-mohamadi"}]},{id:"36176",title:"Reflectance IR Spectroscopy",slug:"fundamental-of-reflectance-ir-spectroscopy",signatures:"Zahra Monsef Khoshhesab",authors:[{id:"111629",title:"Dr.",name:"Zahra",middleName:null,surname:"Monsef Khoshhesab",fullName:"Zahra Monsef Khoshhesab",slug:"zahra-monsef-khoshhesab"}]},{id:"36177",title:"Evaluation of Graft Copolymerization of Acrylic Monomers Onto Natural Polymers by Means Infrared Spectroscopy",slug:"evaluation-of-graft-copolymerization-of-acrylic-monomers-onto-natural-polymers-by-means-infrared-spe",signatures:"José Luis Rivera-Armenta, Cynthia Graciela Flores-Hernández, Ruth Zurisadai Del Angel-Aldana, Ana María Mendoza-Martínez, Carlos Velasco-Santos and Ana Laura Martínez-Hernández",authors:[{id:"37761",title:"Prof.",name:"Ana Laura",middleName:null,surname:"Martinez-Hernandez",fullName:"Ana Laura Martinez-Hernandez",slug:"ana-laura-martinez-hernandez"},{id:"107855",title:"Dr.",name:"Jose Luis",middleName:null,surname:"Rivera Armenta",fullName:"Jose Luis Rivera Armenta",slug:"jose-luis-rivera-armenta"},{id:"108894",title:"MSc.",name:"Cynthia Graciela",middleName:null,surname:"Flores-Hernández",fullName:"Cynthia Graciela Flores-Hernández",slug:"cynthia-graciela-flores-hernandez"},{id:"108896",title:"MSc.",name:"Ruth Zurisadai",middleName:null,surname:"Del Angel Aldana",fullName:"Ruth Zurisadai Del Angel Aldana",slug:"ruth-zurisadai-del-angel-aldana"},{id:"108898",title:"Dr.",name:"Carlos",middleName:null,surname:"Velasco-Santos",fullName:"Carlos Velasco-Santos",slug:"carlos-velasco-santos"},{id:"108905",title:"Dr.",name:"Ana Maria",middleName:null,surname:"Mendoza-Martínez",fullName:"Ana Maria Mendoza-Martínez",slug:"ana-maria-mendoza-martinez"}]},{id:"36178",title:"Applications of FTIR on Epoxy Resins - Identification, Monitoring the Curing Process, Phase Separation and Water Uptake",slug:"applications-of-ftir-on-epoxy-resins-identification-monitoring-the-curing-process-phase-separatio",signatures:"María González González, Juan Carlos Cabanelas and Juan Baselga",authors:[{id:"107857",title:"Prof.",name:"Juan",middleName:null,surname:"Baselga",fullName:"Juan Baselga",slug:"juan-baselga"},{id:"138113",title:"Dr.",name:"María",middleName:null,surname:"González",fullName:"María González",slug:"maria-gonzalez"},{id:"138114",title:"Dr.",name:"Juan C.",middleName:null,surname:"Cabanelas",fullName:"Juan C. Cabanelas",slug:"juan-c.-cabanelas"}]},{id:"36179",title:"Use of FTIR Analysis to Control the Self-Healing Functionality of Epoxy Resins",slug:"use-of-ft-ir-analysis-to-control-the-self-healing-functionality-of-epoxy-resins",signatures:"Liberata Guadagno and Marialuigia Raimondo",authors:[{id:"106836",title:"Prof.",name:"Liberata",middleName:null,surname:"Guadagno",fullName:"Liberata Guadagno",slug:"liberata-guadagno"}]},{id:"36180",title:"Infrared Analysis of Electrostatic Layer-By-Layer Polymer Membranes Having Characteristics of Heavy Metal Ion Desalination",slug:"infrared-analysis-of-electrostatic-layer-by-layer-polymer-membranes-having-characteristics-of-heavy",signatures:"Weimin Zhou, Huitan Fu and Takaomi Kobayashi",authors:[{id:"110384",title:"Dr.",name:"Takaomi",middleName:null,surname:"Kobayashi",fullName:"Takaomi Kobayashi",slug:"takaomi-kobayashi"}]},{id:"36181",title:"Infrared Spectroscopy as a Tool to Monitor Radiation Curing",slug:"infrared-spectroscopy-as-a-tool-to-monitor-radiation-curing",signatures:"Marco Sangermano, Patrick Meier and Spiros Tzavalas",authors:[{id:"112286",title:"Dr.",name:"Spiros",middleName:null,surname:"Tzavalas",fullName:"Spiros Tzavalas",slug:"spiros-tzavalas"},{id:"114382",title:"Prof.",name:"Marco",middleName:null,surname:"Sangermano",fullName:"Marco Sangermano",slug:"marco-sangermano"},{id:"114384",title:"Dr",name:"Patrick",middleName:null,surname:"Meier",fullName:"Patrick Meier",slug:"patrick-meier"}]},{id:"36182",title:"Characterization of Compositional Gradient Structure of Polymeric Materials by FTIR Technology",slug:"characterization-of-compositional-gradient-structure-of-polymeric-materials-by-ft-ir-technology",signatures:"Alata Hexig and Bayar Hexig",authors:[{id:"20867",title:"Dr.",name:"Bayar",middleName:null,surname:"Hexig",fullName:"Bayar Hexig",slug:"bayar-hexig"},{id:"111986",title:"Dr.",name:"Alata",middleName:null,surname:"Hexig",fullName:"Alata Hexig",slug:"alata-hexig"}]},{id:"36183",title:"Fourier Transform Infrared Spectroscopy - Useful Analytical Tool for Non-Destructive Analysis",slug:"fourier-trasform-infrared-spectroscopy-useful-analytical-tool-for-non-destructive-analysis",signatures:"Simona-Carmen Litescu, Eugenia D. Teodor, Georgiana-Ileana Truica, Andreia Tache and Gabriel-Lucian Radu",authors:[{id:"24425",title:"Dr.",name:"Simona Carmen",middleName:null,surname:"Litescu",fullName:"Simona Carmen Litescu",slug:"simona-carmen-litescu"},{id:"24429",title:"Prof.",name:"Gabriel-Lucian",middleName:null,surname:"Radu",fullName:"Gabriel-Lucian Radu",slug:"gabriel-lucian-radu"},{id:"108318",title:"Dr.",name:"Eugenia D.",middleName:null,surname:"Teodor",fullName:"Eugenia D. Teodor",slug:"eugenia-d.-teodor"},{id:"108323",title:"Dr.",name:"Georgiana-Ileana",middleName:null,surname:"Badea",fullName:"Georgiana-Ileana Badea",slug:"georgiana-ileana-badea"},{id:"136337",title:"Ms.",name:"Andreia",middleName:null,surname:"Tache",fullName:"Andreia Tache",slug:"andreia-tache"}]},{id:"36184",title:"Infrared Spectroscopy in the Analysis of Building and Construction Materials",slug:"infrared-spectroscopy-of-cementitious-materials",signatures:"Lucia Fernández-Carrasco, D. Torrens-Martín, L.M. Morales and Sagrario Martínez-Ramírez",authors:[{id:"107401",title:"Dr.",name:"Lucia J",middleName:null,surname:"Fernández",fullName:"Lucia J Fernández",slug:"lucia-j-fernandez"}]},{id:"36185",title:"Infrared Spectroscopy Techniques in the Characterization of SOFC Functional Ceramics",slug:"infrared-spectroscopy-techniques-in-the-characterization-of-sofc-functional-ceramics",signatures:"Daniel A. Macedo, Moisés R. Cesário, Graziele L. Souza, Beatriz Cela, Carlos A. Paskocimas, Antonio E. Martinelli, Dulce M. A. Melo and Rubens M. Nascimento",authors:[{id:"102015",title:"MSc.",name:"Daniel",middleName:null,surname:"Macedo",fullName:"Daniel Macedo",slug:"daniel-macedo"},{id:"112309",title:"MSc",name:"Moisés",middleName:"Romolos",surname:"Cesário",fullName:"Moisés Cesário",slug:"moises-cesario"},{id:"112310",title:"Ms.",name:"Graziele",middleName:null,surname:"Souza",fullName:"Graziele Souza",slug:"graziele-souza"},{id:"112311",title:"MSc.",name:"Beatriz",middleName:null,surname:"Cela",fullName:"Beatriz Cela",slug:"beatriz-cela"},{id:"112312",title:"Prof.",name:"Carlos",middleName:null,surname:"Paskocimas",fullName:"Carlos Paskocimas",slug:"carlos-paskocimas"},{id:"112314",title:"Prof.",name:"Antonio",middleName:null,surname:"Martinelli",fullName:"Antonio Martinelli",slug:"antonio-martinelli"},{id:"112315",title:"Prof.",name:"Dulce",middleName:null,surname:"Melo",fullName:"Dulce Melo",slug:"dulce-melo"},{id:"112316",title:"Dr.",name:"Rubens",middleName:"Maribondo Do",surname:"Nascimento",fullName:"Rubens Nascimento",slug:"rubens-nascimento"}]},{id:"36186",title:"Infrared Spectroscopy of Functionalized Magnetic Nanoparticles",slug:"infrared-spectroscopy-of-functionalized-magnetic-nanoparticles",signatures:"Perla E. García Casillas, Claudia A. Rodriguez Gonzalez and Carlos A. Martínez Pérez",authors:[{id:"104636",title:"Dr.",name:"Perla E.",middleName:null,surname:"García Casillas",fullName:"Perla E. García Casillas",slug:"perla-e.-garcia-casillas"},{id:"112440",title:"Dr.",name:"Carlos A.",middleName:null,surname:"Martínez Pérez",fullName:"Carlos A. Martínez Pérez",slug:"carlos-a.-martinez-perez"},{id:"112441",title:"Dr.",name:"Claudia A.",middleName:null,surname:"Rodriguez Gonzalez",fullName:"Claudia A. Rodriguez Gonzalez",slug:"claudia-a.-rodriguez-gonzalez"}]},{id:"36187",title:"Determination of Adsorption Characteristics of Volatile Organic Compounds Using Gas Phase FTIR Spectroscopy Flow Analysis",slug:"determination-of-adsorption-characteristics-of-volatile-organic-compounds-using-gas-phase-ftir-spect",signatures:"Tarik Chafik",authors:[{id:"107310",title:"Prof.",name:"Tarik",middleName:null,surname:"Chafik",fullName:"Tarik Chafik",slug:"tarik-chafik"}]},{id:"36188",title:"Identification of Rocket Motor Characteristics from Infrared Emission Spectra",slug:"identification-of-rocket-motor-characteristics-from-infrared-emission-spectra",signatures:"N. Hamp, J.H. Knoetze, C. Aldrich and C. Marais",authors:[{id:"112229",title:"Prof.",name:"Chris",middleName:null,surname:"Aldrich",fullName:"Chris Aldrich",slug:"chris-aldrich"},{id:"112232",title:"Prof.",name:"Hansie",middleName:null,surname:"Knoetze",fullName:"Hansie Knoetze",slug:"hansie-knoetze"},{id:"135327",title:"Ms.",name:"Corne",middleName:null,surname:"Marais",fullName:"Corne Marais",slug:"corne-marais"}]},{id:"36189",title:"Optical Technologies for Determination of Pesticide Residue",slug:"optical-technology-for-determination-of-pesticide-residue",signatures:"Yankun Peng, Yongyu Li and Jingjing Chen",authors:[{id:"113343",title:"Prof.",name:"Yankun",middleName:null,surname:"Peng",fullName:"Yankun Peng",slug:"yankun-peng"},{id:"116636",title:"Dr.",name:"Yongyu",middleName:null,surname:"Li",fullName:"Yongyu Li",slug:"yongyu-li"},{id:"116637",title:"Dr.",name:"Jingjing",middleName:null,surname:"Chen",fullName:"Jingjing Chen",slug:"jingjing-chen"}]},{id:"36190",title:"High Resolution Far Infrared Spectra of the Semiconductor Alloys Obtained Using the Synchrotron Radiation as Source",slug:"high-resolution-spectra-of-semiconductor-s-alloys-obtained-using-the-far-infrared-synchrotron-radi",signatures:"E.M. Sheregii",authors:[{id:"102655",title:"Prof.",name:"Eugen",middleName:null,surname:"Sheregii",fullName:"Eugen Sheregii",slug:"eugen-sheregii"}]},{id:"36191",title:"Effective Reaction Monitoring of Intermediates by ATR-IR Spectroscopy Utilizing Fibre Optic Probes",slug:"effective-reaction-monitoring-of-intermediates-by-atr-ir-spectroscopy-utilizing-fibre-optic-probes",signatures:"Daniel Lumpi and Christian Braunshier",authors:[{id:"109019",title:"Dr.",name:"Christian",middleName:null,surname:"Braunshier",fullName:"Christian Braunshier",slug:"christian-braunshier"},{id:"111798",title:"MSc.",name:"Daniel",middleName:null,surname:"Lumpi",fullName:"Daniel Lumpi",slug:"daniel-lumpi"}]}]}],publishedBooks:[{type:"book",id:"6083",title:"Semiconductors",subtitle:"Growth and Characterization",isOpenForSubmission:!1,hash:"53bed47ef5d839f8d10d5f1a3b050c49",slug:"semiconductors-growth-and-characterization",bookSignature:"Rosalinda Inguanta and Carmelo Sunseri",coverURL:"https://cdn.intechopen.com/books/images_new/6083.jpg",editedByType:"Edited by",editors:[{id:"174858",title:"Prof.",name:"Rosalinda",surname:"Inguanta",slug:"rosalinda-inguanta",fullName:"Rosalinda Inguanta"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6845",title:"Graphene and Its Derivatives",subtitle:"Synthesis and Applications",isOpenForSubmission:!1,hash:"63a9783e678fc42ce981efb35be02096",slug:"graphene-and-its-derivatives-synthesis-and-applications",bookSignature:"Ishaq Ahmad and Fabian I. 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\n
1. Introduction
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Functional connectivity based on MRI (fcMRI) measures simultaneous and synchronous neuronal activities at various regions connected intrinsically in brain with functional MRI time courses. In our recent study, we reported lower functional connectivity in posterior cingulate and temporal regions with aging within the default mode network (DMN) [1]. We also found higher fcMRI in the dorso-attentional network (DAN) (including in the dorso-lateral prefrontal cortex) at age, which could be due to the negative connectivity with DMN. Furthermore longitudinal changes in fcMRI occurred in regions similar to those demonstrating cross-sectional effects of age, with only a few small brain areas showing significant age by interval or gender by interval effects. The rate of fcMRI longitudinal change, however, was not influenced significantly by baseline age or gender, after adjusting for baseline age and gender modulation effects in majority of brain regions, suggesting moderate linear interval effects of fcMRI longitudinal changes in brain. Our results from this relatively large cohort suggest that fcMRI variability from various networks in different scales might be useful to monitor brain changes in normal aging and preclinical stages of Alzheimer’s disease [1]. As for diffusion tensor imaging (DTI), we used both voxel-wise four DTI metrics and tract-specific ROI analysis to investigate myelin and axonal integrity differences with age, gender and APOE genotype with four DTI metrics at baseline [2, 3, 4, 5]. One of the main findings was the decreased fractional anisotropy (FA) but increased radial diffusivity (RD) with age based on both voxel-wise and tract-specific analyses indicating both axonal degeneration and demyelination [6, 7]. Dramatic decreases of FA with age, especially in participants over 50 years old, accompanied by increased RD suggest that white matter (WM) integrity declines with age. In contrast, changes in axial diffusivity (AX) and mean diffusivity (MD) with age are in two-way: higher AX and MD in some tracts and cortical regions including bilateral thalamic radiation and cingulum bundles, as well as decreased AX and MD in some long-distance fasciculus [8, 9, 10, 11].
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Regarding DTI and fMRI correlations, significant gray matter (GM) and WM correspondences based on GM atrophy and WM fractional anisotropy (FA) reductions in several brain regions were found in multiple sclerosis (MS) patients including primary visual cortex/optic radiation as well as somatosensory cortex/superior longitudinal fasciculus at baseline [12]. However, with disease progresses, these associations might be deteriorated and are not maintained [13, 14, 15], although each imaging feature at baseline and longitudinal time points remain consistent and highly correlated [16, 17]. The degree of change (or rate of change) of each metric is dependent on the sensitivity during the disease course [18, 19, 20]. For instance, GM atrophy and functional coordination decrement were found at follow-up visit in MS patients, in contrast to the usual observation of significant FA reductions and WM lesions predominantly in corpus callosum, periventricular areas, occipital horns and cingulum areas at baseline in MS compared to controls [12]. In mild traumatic brain injury (MTBI), 1 year after injury, there was measurable global brain atrophy, larger than that in control subjects. The anterior cingulate WM bilaterally and the left cingulate gyrus isthmus WM, as well as the right precuneal GM, showed significant decreases in regional volume in patients with MTBI over the 1st year after injury [21]. However at baseline, after normalization to supratentorial brain volume, there were no significant regional brain volume differences between patients with MTBI at the time of their initial visit and the control group. Our observations complement these findings and indicate that specific brain structure such as the cingulum and precuneus may be more vulnerable to long-term structural changes [22, 23].
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It had been reported that baseline imaging findings including micro-structure integrity measured with DTI can predict functional activation and coordination at follow-ups. We had reported that FA measure at baseline predicted follow-up functional coordination score from fMRI data (r = 0.68, P = 0.007), indicating a possible initial WM inflammatory factor to the subsequent neurodegenerative processes in MS patients [12]. We also found that baseline composite imaging metrics can predict cognitive function and neuropsychological scores. For instance, in MTBI, the clinical symptom at follow-up visit could be predicted with high accuracy from baseline imaging features with r = −0.82, P < 0.001 for depression; r = −0.65, P = 0.01 for anxiety; r = −0.71, P = 0.005 for fatigue; and r = −0.67, P = 0.008 for post-concussion syndrome (PCS) [23]. Revealing the brain micro-structural changes over a relatively short period at individual levels are especially important given that many risks associated with age including vascular and neuroinflammation increases and could confound the baseline parametric images of each individual. However, literatures related to longitudinal changes of neuroimaging data with age are still limited [24].
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The goals of this study were to assess baseline and longitudinal age and gender-related changes with neuroimaging and neurocognitive data from a large sample of healthy older adults, as well as apolipoprotein E (APOE) genotypic effects. The strengths of this study are the extensive and well-characterized large sample of older adults, and multiple imaging metrics including advanced fcMRI, four DTI (FA, MD, RD, AX) to capture extensive properties of functional connectivity and white matter myelination at both baseline and longitudinal follow-up time points. Both conventional whole brain voxel-wise analyses and fiber track-specific ROI quantification measures that are more robust and less prone to registration error were used to increase the white matter myelin detection specificity. Beside previous fcMRI findings [1], we also investigate longitudinal changes of multiple DTI and fMRI metrics as well as neurocognitive tests. The correlations among different imaging metrics as well as between neuroimaging findings and neurocognitive scores were quantified to better illustrate the full spectrum of multiple phenotypic data.
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2. Methods
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2.1 Participants
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We studied 572 cognitively normal participants in the neuroimaging substudy from the Baltimore Longitudinal Study of Aging (BLSA) who had DTI assessments. Exclusion criteria were as follows: subjects with excessive motions and unwanted imaging qualities (N = 17 and 30 scans); subjects with incidental findings of brain lesions or other central nervous diseases, such as, Parkinson’s disease (N = 4). Twenty individuals aged 24–39, 39 individuals aged 40–49, 51 aged 50–59, 137 aged 60–69, 186 aged 70–79, and 138 aged 80–89.
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Three hundred and eighty-seven participants (68%) had available APOE genotype information, 107 APOE ε4+ and 280 APOE ε4− participants were further divided into six sub-groups based on the APOE isoforms. These sample characteristics are shown in Table 1. Two hundred and forty-five subjects had longitudinal follow-up (interval range 0.9–3.5 years, mean interval of 1.9 ± 0.6 years) and were used to characterize aging effects at short interval. Neurocognitive data from 21 cognitive tests with 59 variables that measure multiple cognitive functionalities including visual perception and attention, learning and memory encoding and recall, language fluency, and executive function for each participant was collected at the same day of the MRI scan [25]. After post-processing with normalization, 52 test scores were used for further analysis including correlation tests.
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\n
\n
\n
\n
\n
\n
\n
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\n\n
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Characteristic
\n
All DTI baseline
\n
ε4/ε4
\n
ε3/ε4
\n
ε2/ε4
\n
ε3/ε3
\n
ε2/ε3
\n
ε2/ε2
\n
Both DTI and fMRI
\n
\n\n\n
\n
Total n
\n
572
\n
4
\n
95
\n
8
\n
219
\n
59
\n
2
\n
236
\n
\n
\n
Age, years; mean ± SD
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69.7 ± 13.4
\n
68.4 ± 16.8
\n
67.0 ± 12.1
\n
69.4 ± 12.6
\n
70.1 ± 11.3
\n
70.0 ± 10.1
\n
75.9 ± 16.4
\n
72.0 ± 12.2
\n
\n
\n
Gender n; women/men
\n
311/261
\n
3/1
\n
56/39
\n
7/1
\n
115/104
\n
30/29
\n
1/1
\n
135/101
\n
\n
\n
Education, years; mean ± SD
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17.1 ± 2.7
\n
17.5 ± 1.0
\n
17.4 ± 2.5
\n
17.1 ± 2.1
\n
16.9 ± 2.6
\n
17.6 ± 2.2
\n
16.0 ± 2.8
\n
17.0 ± 2.4
\n
\n
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MMSE at visit
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28.6 ± 1.5
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28.3 ± 1.5
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28.8 ± 1.4
\n
29.5 ± 0.6
\n
28.4 ± 1.6
\n
28.5 ± 1.4
\n
29.0 ± 1.4
\n
28.8 ± 1.3
\n
\n\n
Table 1.
Sample characteristics for the whole sample and six APOE genotypic sub-groups.
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\n
\n
2.2 Imaging parameters
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MRI imaging was obtained with a 3T whole-body scanner (Philips, Achieva) at National Institute of Aging, using an eight-channel head coil. The DTI sequence was evaluated previously and found to have good intra-site reliability and inter-section reproducibility [1]. Specifically, standard echo-planar imaging (EPI)-based DTI protocol was performed during the routine 45-min scan (TR/TE = 6801/75 msec, flip angle = 90°, FOV = 212 × 212 mm2, spatial resolution = 0.83 × 0.83 × 2.2 mm3, 65 slices to cover the whole cerebrum). Thirty-two diffusion gradient directions (diffusion gradient time Δ = 36.3 ms and pulse duration δ = 16 ms) with b-factor of 700 s/mm2 and a total of 3:58 min for each run as well as two identical runs were obtained for each subject.
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A standard echo-planar imaging (EPI) resting-state (RS)-fMRI protocol (TR/TE = 2000/30 msec, flip angle = 75°, FOV = 240 × 240 mm2, voxel size =3 × 3 × 4 mm3, 37 slices) was performed during an approximately 45-min brain MRI protocol. A total of 180 volumes were acquired during the 6-min RS-fMRI scan. Participants were instructed to remain still, with eyes open and focused on a cross fixation, and encouraged to relax during the scan. A 3-dimensional T1-weighted MPRAGE (magnetization prepared rapid gradient-echo imaging) sequence (TR/TE/TI = 6.8/3.2/849.2 msec, FA = 8°, FOV = 192 × 256 × 256 mm3, voxel size = 1.2 × 1 × 1 mm3) was acquired in sagittal-view for segmentation of tissue types and registration/normalization of EPI images to MNI space.
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2.3 Image processing
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DTI data were first pre-processed with the diffusion toolkit toolbox (http://trackvis.org) to obtain the FA/RD/AX/RD values in original b0 space. For the FA/RA/AX/RD quantification, the FMRIB, Software Library (FSL, http://fsl.fmrib.ox.ac.uk/fsl) tract-based spatial statistics toolbox steps 1–2 (i.e., preprocessing, brain mask extraction with FA > 0.2 and normalization) were used for registration of all participants’ FA into the FSL 1-mm white matter skeleton template. The transformation of the individual FA data to the FSL Montreal Neurological Institute (MNI) template with 1-mm isotropic voxel size, was implemented with the nonlinear registration tool FNIRT based on a b-spline representation of the registration warp field. After normalization of FA map to the MNI space, tract-specific mean FA values were obtained in 20 regions from the well-defined probabilistic tract template (FSL/JHU ICBM atlas). Quantitative MD/AX/RD values were obtained by applying the same transformation from individual FA to template space and computed with tract-specific values [1].
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The anatomic T1-MPRAGE and 4D EPI functional data were preprocessed using both FSL and Analysis of Functional NeuroImages (AFNI) programs (adapted scripts from http://www.nitrc.org/projects/fcon_1000 developed based on FSL and AFNI). For structural MPRAGE data used for fMRI data normalization, preprocessing included reorientation to the right-posterior-inferior convention and skull stripping, and segmentation into three tissue types: GM, WM, and cerebrospinal fluid (CSF). The segmental tissue masks were used to derive the nuisance fMRI signals in WM and CSF. Finally, the MPRAGE image was co-registered with the fMRI data and normalized to the Montreal Neurologic Institute (MNI) 152-brain template with 2-mm isotropic voxel size [1, 12].
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For fcMRI processing, the first four volumes of the RS-fMRI data of each subject were discarded for scanner and image stability. Preprocessing steps for RS-fMRI data included rigid alignment of the time frames using AFNI motion correction algorithms, spatial smoothing using a Gaussian kernel with 6 mm full-width-at-half-maximum (FWHM), and band-pass temporal filtering of 0.005–0.1 Hz to improve signal-to-noise ratio. Removal of nuisance signals was then performed using a Gaussian regression model after co-registration to MPRAGE data. Namely, motion parameters, global signal, and signals derived from CSF and WM based on the tissue masks were modeled in the Gaussian linear mixed model, and residual signal at each voxel was maintained for further analyses. Finally the residual 4D fMRI data after regression were transformed to MNI standard space [26]. A DMN seed including both medial prefrontal cortex (MED) (MNI center: 0, 48, 23 mm) and posterior cingulate cortex (PCC) (MNI center: 26, 248, 39 mm) with a combined volume of 4112 mm3 (each seed of 2056 mm3) was used. We refer to this seed as the combined core seed. We chose the combined core seed over separate PCC and MED seeds because the latter approach generates different and incomplete DMN connectivity patterns [27], whereas the combined core seed yields consistent and complete depictions of DMN [26]. Whole brain voxel-wise Pearson correlation coefficients were computed between the average time series within the seed and the time course of each fMRI voxel in the brain. Finally Z-statistics were derived voxel-wise. 2nd-level Gaussian random field (GRF) and family-wise corrections were applied to derive the functional connectivity (FC) map with FSL toolbox.
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In addition to the combined core seed, the fcMRI generated from other seeds were also evaluated to study the systematic-level fcMRI, with a total of 26 seeds [1]. The other 25 seeds included 12 conventional regions of different sub-areas of DMN (e.g., PCC and intra-parietal sulcus), three thalamic (left, right, and whole thalamus) and seven subthalamic seeds [28], and three subcortical seeds (caudate and putamen from the MNI template, and hypothalamus from an in-house developed probability map) [29]. The conventional 12 seeds were derived from the script seed library (http://www.nitrc.org/projects/fcon_1000), including the hippocampal formation and frontal eye field (FEF) seeds that generated the task-positive networks (i.e., these networks are more active at task-conditions, in contrast to resting state). All seeds were well-evaluated and validated previously [27, 28, 30]. The global mean Z-values were obtained from the fcMRI maps generated from each of 26 seeds to study age and gender effects as well, by averaging the fcMRI Z-maps over the whole brain with a threshold of GRF cluster-corrected P < 0.01.
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Meanwhile in the resting state, fractional amplitude of low-frequency fluctuations (fALFF) has been shown to be higher in the DMN regions that are active and it had also been reported that task-related (e.g., working memory, motor visual stimuli and cognitive tasks) alterations of low-frequency oscillations could reflect real-time neuronal activity [28]. The idea of fALFF method was to scale the summary of amplitude at low-frequency band (e.g., 0.01–0.08 Hz) to the summary of amplitude across whole band to remove white and physiological noise. In this study, the resting-state fALFF Z-value at baseline and longitudinal changes of fALFF, as well as correlations with the age and other fcMRI/DTI neuroimaging metrics were performed from 236 participants with available data resource.
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2.4 Statistical analyses
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For DTI, effects of age, gender and APOE genotype were studied at both whole-brain voxel-wise level and tract-specific ROI analyses using the four DTI metrics-FA, RD, AX and MD. Linear mixed effects (LME) model was applied to characterize both baseline and longitudinal effects of age, gender and age by gender interactions of the four metrics [1, 31]. We used the MATLAB Statistics toolbox (www.mathworks.com, R2015b) and in-house programs to perform model fitting as listed in Eq. (1). Longitudinal data were incorporated to characterize the longitudinal change of DTI metrics with interval as the prediction parameter as well. In order to account for within-individual correlations stemming from follow-up data, we included random intercept and random interval (i.e., random slope) terms per individual in LME.
For whole-brain analyses, voxel-wise linear regression with DTI metrics as the dependent variable and age as an independent variable using SPM12 software (Statistical Parametric Mapping, http://fil.ion.ucl.ac.uk/spm/software/spm12) was implemented. Gender term was included as a covariate. Then two-sample t-test comparison using baseline DTI data was also implemented to study gender differences between women and men, and age was used as a covariate [32].
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For tract-specific ROI-based analyses, the mean value of each regional FA and diffusivity (i.e., RD, AX and MD) analysis were quantified with FSL toolbox and in-house programs developed with MATLAB (www.mathematics.com). Both linear and quadratic fitting were used to examine white matter myelination along aging trajectories. Mean values of all six APOE genotypes were derived from each ROI to form the waveform and multiple-group comparisons of the four DTI metrics stratified by genotypic isoforms were performed in MATLAB toolbox.
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To characterize cross-sectional and longitudinal changes in fcMRI, we used a LME model, similar to DTI longitudinal data model with the same analyses algorithm as listed in Eq. (2). In order to account for cross-sectional differences across individuals, we included baseline age and gender as covariates. Baseline age was centered at group mean of 69.4 years. Men were coded as 0.5 and women as −0.5. Time interval in years between baseline and follow-up was included to capture longitudinal change in fcMRI. We also included interaction terms with interval, random intercept and interval terms to compute longitudinal rates of fcMRI change accounting for baseline age and gender interactions [1].
Conventional statistical comparison (with relatively smaller number of participants) using a two-sample t-test at baseline and 3 years follow-ups, adjusting for gender, with the same statistical threshold as used in LME model (P < 0.01 and cluster size ≥10 voxels) was used for longitudinal fALFF data quantification. To validate the age and gender effects observed in LME model, SPM-based conventional regression model including general linear correlational analysis between age and fcMRI adjusted for gender, and comparison between women and men group adjusted for age were performed as well.
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3. Results
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3.1 Age effects on DTI
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Whole brain DTI FA showed prominent aging effects (i.e., reduced FA with aging) in the main projections fibers including cingulum bundle and superior longitudinal fasciculus (P < 0.00001) (Figure 1a). The monotonically reduction of FA was observed in relatively older subject with age larger than 50 years old that construe the majority of the sample size. RD, on the other hand, showed only significantly higher RD values with age in bilateral thalamic radiations, bilateral somatosensory cortex, visual cortex, anterior and posterior cingulate gyri, middle temporal cortex including hippocampus, subcallosal cortex and posterior cerebellum (P < 0.01, cluster size = 10). Very small clusters and primarily in the cerebellum was found to have lower RD along the age (Figure 1b). Axial diffusivity showed significantly higher AX values with age in some similar regions to RD including bilateral thalamic radiations, bilateral somatosensory cortex, visual cortex, posterior cerebellum and superior corona radiata tract (P < 0.01, cluster size = 10). In contrast to RD and FA, AX was also significantly lower in white matter regions including bilateral cortico-spinal tract, inferior longitudinal fasciculus, optic radiation and cerebellum (Figure 1c). MD shows almost a similar aging pattern as of AX (Figure 1d) [1].
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Figure 1.
(a) Prominent aging effects were demonstrated with negative correlation between voxel-wise FA and age, i.e., decreased FA along the age (statistical T map, P < 0.01, cluster size = 10) for all brain regions. On the other hand, RD was increased along the age for some of the brain regions including somatosensory cortex and cingulum bundle (b). There are both increases and decreases of AX (c) and MD (d) in different brain regions along the age, and the changes of AX and MD have very similar patterns (all P < 0.01, cluster size = 10). Background image was derived from average of all subjects’ FA maps in MNI space.
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As expected, all the tract-based ROI showed significant aging effects (i.e., reduced FA with age) after adjustment for multiple comparisons (r = 0.3–0.7, mean r = 0.5, corrected P < 0.0001). Quadratic fitting of FA from 20 track-specific ROIs showed aging trajectories with maturation age (i.e., mean FA reaches maximum) falling between [24, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41] years. The relatively earlier maturation age was found in the major forceps and bilateral thalamic radiation (28–33 years) and later maturation age from bilateral hippocampal portion of the cingulum and corticospinal tracts (39–42 years) (Figure 2). The tract-based ROI that has the earliest maturation age with highest FA at 27.9 years is the major forceps. The left hippocampal portion of the cingulum bundle has the latest maturation age (42.1 years). While the diffusivity measures from tract-based ROIs showed mostly linearly increases of diffusivity along the age with RD, and some tracts showed no significant aging effects based on AX or MD [1].
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Figure 2.
Quadratic aging trajectories of two tract-specific ROIs. Star (cyan color) indicates maturation age when mean FA of the tract each tract-specific ROI reaches maximum. Major forceps has the earliest maturation age, with highest FA at 27.9 years (blue color). While the left hippocampal portion of the cingulum bundle has the latest maturation age, with highest FA at 42.1 years (red color).
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Using diffusion toolkit (http://www.nitre.org/projects/trackvis/) with an advanced tensorline propagation algorithm for fiber tracking, we found tracts that play important roles in memory and cognitive function also illustrated significant aging effects, including fiber tract numbers of the fornix that connects the hippocampus to the whole brain, and fibro bundles connecting bilateral parahippocampus to the whole brain were decreased significantly with aging (both P < 0.00001).
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3.2 Longitudinal change of FA
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Based on LME model, no significant age by gender interactions have been found to either FA or diffusivity metrics in the whole-brain voxel-wise analyses indicating aging and gender effects can be studied independently (Figure 3a). The interval effective regions estimated from LME model showed longitudinal change of FA and RD/AX values remained similar to the aging results found with cross-sectional data as in Figure 1 and gender effective brain regions (P < 0.01, cluster size = 10) (Figure 3b).
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Figure 3.
(a) Based on LME model, no significant age by gender interaction of DTI FA and diffusivity values across whole-brain with only a few outliers (P < 0.01). (b) The interval effect estimated from LME model using longitudinal data showed longitudinal change of FA, RD and AX values (MD is almost the same as AX) in brain regions similar to the baseline aging effects (1–3 years of interval of follow-up time; P < 0.01, cluster size = 10), suggesting an observable longitudinal change within a short time interval.
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3.3 Gender effects on DTI
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We found men had significantly higher FA in the hippocampal portion of the cingulum bundle, secondary somatosensory cortex, thalamus, cingulate and cerebellar regions compared to women, based on voxel-wise FA comparisons (P < 0.01). Lower FA in men than women in bilateral inferior longitudinal fasciculus, anterior thalamic radiation, frontal cortex and temporal part of the superior longitudinal fasciculus were also observed (P < 0.01, cluster size = 10). Scattered cortical regions including superior frontal, cerebellum and insular showed higher RD in men than women, and lower RD in men only with small clusters in cerebellum. Furthermore AX and MD values in most of brain regions were higher in men than women (P < 0.01, cluster size = 10).
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3.4 APOE genotype effects
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Voxel-wise FA and MD comparisons between different APOE genotypes showed differences in scattered brain clusters (P < 0.01, cluster size = 10). Scattered brain regions showed both higher FA and higher diffusivity in APOE ε2/ε3 compared to APOE ε3/ε3, as well as comparing APOE ε3/ε4 to APOE ε3/ε3. Only RD was decreased in small clusters in APOE ε3/ε4 compared to APOE ε3/ε3 (P < 0.01, cluster size = 10). And AX comparison between APOE ε2/ε3 vs. APOE ε3/ε3 showed more brain regions with higher AX in APOE ε2/ε3 carriers. MD showed similar pattern as of AX.
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Furthermore, track-based mean FA stratified by different APOE genotype in majority of fibers demonstrated an incremental consistent pattern (44-24-33-23-34-22 chain, lowest in APOE44 and highest in APOE22 carriers); especially in right cortico-spinal tract and bilateral uncinate fasciculus (Figure 4). RD waveforms of 20 ROIs stratified by APOE genotype showed different waveforms than FA, with highest RD in APOE ε2/ε3 isoforms, and lower in APOE ε4+ carriers in all 20 ROIs. Both MD and AX measures showed very similar waveforms as of RD in 20 ROIs.
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Figure 4.
Effects of APOE genotype on global fcMRI strength of task-positive networks seeding from intra-parietal sulcus (a), thalamus (b,c,d,e) and hypothalamus (f) demonstrated increasing patterns of fcMRI along with the 44-24-33-23-34-22 genotype. On the other hand, decreasing genotypic patterns of resting-state default mode networks (DMN) seeding from the posterior cingulum (g) and core seeds of DMN (h) were observed.
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In addition, 11 out of 26 seed-based fcMRI strength (mean Z-value, with P < 0.001) stratified by different APOE genotype follow an incremental pattern with the 44-24-33-23-34-22 isoform including mean fcMRI seeding from subcortical thalamus (b–e), hypothalamus (f), and task-positive intra-parietal sulcus (a) as well as ventral medial prefrontal cortex; especially the hypothalamus (f) and from the thalamus segment 3 (d) that projected to visual cortex. On the other hand, gradual decrement of fcMRI strength with the APOE 44-24-33-23-34-22 genotypic chain of the DMN connecting from the posterior cingulate cortex (PCC) seed (g) and DMN core seed (h) had been observed as well (Figure 5).
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Figure 5.
APOE genotypic effects on tract-specific DTI mean FA in 20 brain tracts. The mean FA of bilateral corticospinal, left cingulum and right superior longitudinal fasciculus tracts (marked with large **) follow the APOE 44-24-33-23-34 incremental pattern consistently. Inf = inferior; SLF = superior longitudinal fasciculus; L = left; R = right.
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3.5 fALFF and fcMRI results
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As of fALFF, group mean image demonstrated higher fALFF in cortical gray matter with only temporal cortex largely spared (Figure 6a). Baseline aging effects demonstrated decreased activity with age in the caudate, superior middle frontal and precuneus regions, but increased activity in the cerebellum and bilateral frontal white matter (P < 0.001) (Figure 6b and c). Average fALFF activity strength over the whole brain demonstrated magnificent aging effects (r = −0.28, P = 0.00001). Gender comparison showed slight difference with men had lower fALFF than women in small regions of caudate and frontal white matter clusters, but higher activity of men than women in the cerebellum (P < 0.001) (Figure 6d and e). Longitudinal comparison of baseline fALFF and 3 years later showed decreased functional activity in the right inferior parietal lobe and right occipital cortex; accompanied by increased activity in the front eye field region, left superior frontal and left temporal cortices (P < 0.01).
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Figure 6.
Functional activity measured with fALFF with group mean (a) (corrected P < 0.001) showing higher fALFF in cortical gray matter with only temporal cortex largely spared. Decreased activity with age in the superior middle frontal and precuneus as well as in the cortical caudate region (b), but increased activity in the cerebellum and bilateral frontal white matter (c) (both cluster corrected P < 0.001) were observed. Women group had higher fALFF Z values in frontal white matter area and small regions in caudate (d), while men group had higher fALFF in cerebellum (e) (both corrected P < 0.001).
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3.6 Correlations
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LME model performed to available 52 neurocognitive tests at baseline also found significant aging effects (P < 0.00001) in almost all tests with worsening cognitive function at age. And similar longitudinal interval effects were found with a smaller significance level for each cognitive test (most P < 0.001).
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Significant correlations between average Z-value of fcMRI strength in the DMN and neurocognitive tests were found as following: (1) between DMN Z and digital span test (DST) total score (r = 0.19, P < 0.00001); (2) between average DMN Z and Pegboard dominant (Dom) motor function score (r = 0.22, P < 0.00001); (3) between average DMN Z and Pegboard non-dominant (NonDom) mean score (r = 0.17, P = 0.00002); and (4) between average DMN Z and category fluency (FluenCat) test mean score (r = 0.12, P = 0.003). Interestingly, significant correlations between average DMN Z and graph-theory based resting-state functional network small-worldness properties were found as well, including: (1) between DMN Z and relative local efficiency (r = 0.15, P = 0.0002); (2) between DMN Z and absolute local efficiency (r = 0.17, P = 0.00002); (3) between DMN Z and relative global efficiency (r = 0.09, P = 0.02); (4) between DMN Z and absolute global efficiency (r = 0.1, P = 0.01); and (5) between DMN Z and small-worldness configuration (r = 0.15, P = 0.0001). Significant correlations between age and average DMN Z (r = −0.20, P < 0.00001; N = 608) are noted additionally.
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Significant correlations between four DTI metrics (FA/MD/AX/MD) and neurocognitive functions were found including California verbal learning test (CVLT), Fluencat, Benton visual retention total errors (BVTOT), Dom and NDom tests that measure visual perception and memory dysfunction, language fluency, communication and social function, speed and accuracy, cognitive flexibility, visual attention, spatial orientation, working memory and executive function, as well as movement speed and motor function domains (most P < 0.0001). And correlations were found in all 20 tracts that connect to the whole brain indicating regional and global-wise associations between brain structure connectivity and neurocognitive alterations.
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Significant correlations among imaging metrics were found as well including: (1) average whole-brain fALFF (a biomarker for functional activity) Z-value based on resting-state fMRI data and age (r = −0.28, P = 0.00002); (2) average fALFF Z and mean FA of whole brain (r = 0.26, P = 0.00007); (3) average DMN Z and mean FA of whole brain (r = 0.18, P = 0.007); and (4) average DMN Z and mean FA of DMN regions (r = 0.19, P = 0.004).
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4. Discussion and conclusion
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One of the main findings of DTI was the decreased FA but increased RD along the age based on both voxel-wise and track-specific analyses at both baseline and longitudinal follow-up visits. Longitudinal data revealed similar rate of change of DTI metrics associated with age and gender as to cross-sectional results, indicating these changes were observable over a very short period (e.g., longitudinal interval of 1–3 years). Especially the significant decreases of FA along the age in most of brain regions suggest that white matter integrity reduces with age. Radial diffusivity (RD) increased with age in the regions that play important roles in memory, visual and motor function such as bilateral thalamic radiations, bilateral somatosensory cortex, visual cortex, anterior and posterior cingulate gyri, middle temporal cortex and hippocampus (P < 0.01, cluster size = 10). This suggested that demyelination process that resulted in radial space increases occurred in these brain tracts with age, and was also confirmed with significant reduced fiber-bundles from fornix and parahippocampus, as well as the latest maturation age of the cingulum bundle that was more vulnerable to demyelination and retrograde degeneration [1]. While changes in AX and MD are in two-way: increased AX and MD in some tracts and cortical regions including bilateral thalamic radiation and cingulum bundles, together with decreased AX and MD in some long-distance fasciculus including bilateral corticospinal tract, inferior longitudinal fasciculus and optic radiation. Lower FA and higher RD indicating axonal degeneration have been found in a small sample with similar age range [24, 33]. A few long commissure and association fibers including corpus callosum, cortico-spinal tract, cingulum bundle and superior longitudinal fibers might also undergo Wallerian degeneration [34] with increased RD but decreased AX along the age [1].
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Consistent with the current view of neuroplasticity, neuroprotective and compensation roles of fMRI connectivity and activation [35, 36, 37], mean fcMRI values from DMN core and PCC core were lowest in the least risky APOE22 isoform, but highest in the most risky APOE44 isoform. And the waveforms of global DMN fcMRI strength decreases from the most to least risky genetic isoforms. However, for the subcortical regions including thalamus and hypothalamus seeds, the fcMRI increases from the expected most risky to least risky genetic isoforms. These changes of divergent waveforms of fcMRI from DMN and subcortical regions had also confirmed the opposite directions of resting-state DMN network and task-positive or attentional-recruitment networks, and might indicate less efficient or over-recruitment of neuronal source usage at most risky APOE44 carriers [38, 39, 40, 41]. On the other hand, the DTI metric of FA from majority of fibers demonstrated an incremental consistent pattern from APOE44 to APOE22 carriers, indicating micro-structural integrity was associated positively and tightly with the genotypic functional role of each APOE allele.
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Our results of significant imaging quantifications and neurocognitive tests indicate neuronal degeneration, functional disconnectivity as well as white matter deterioration (demyelination, Wallerian degeneration and structural connectivity) at age go parallel with each other, and present together with neurocognitive dysfunction (especially in the domains of memory, cognitive flexibility, visual perception and attention, and executive function). Similar correlation results were found between each tract-specific DTI metric and one-domain neurocognitive test suggest that regional correlations agree with each other, and significant structural connectivity-neurocognitive function correlations remain consistent across the whole brain. Associations between DMN functional connectivity and neurocognitive scores of memory, motor coordination and language social function are expected given the importance of DMN in these domains [42, 43, 44]. DMN also represents more global integration function based on the significant correlations between DMN fcMRI and local/global efficiencies of network analysis [45, 46]. Significant correlations were also found between global FA and global functional activity from fALFF; as well as between DMN fcMRI and DMN FA. Scattered longitudinal changes and gender differences of fALFF were found with different patterns from fcMRI (largely decreased DMN but increased DAN regions of fcMRI). However, the spatial distribution pattern of fALFF was mainly in cortical gray matter (significantly higher in occipital, parietal and frontal cortices but with relatively lower activation pattern in temporal cortex). Although fALFF is not a good biomarker due to lack of functional and spatial specialization, it might be used in epoch-related task fMRI study to reflect neuronal activation under task conditions [28].
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While our results are consistent with several published articles and are also in agreement with functional and structural connectivity findings [36, 47, 48, 49, 50], current study is still limited to the scope of conventional fMRI and DTI sequence with normal aging samples. Further improvement of the technique with acceleration-based fMRI acquisition and multi-shell and multi-b-value DTI [32] as well as validation of our observations using other molecular imaging findings such as amyloid and tau imaging that provide pathological evidence besides the current neuroimaging findings are expected [23, 32, 51, 52]. It had been reported that task-based fMRI data could reflect specific cognitive function such as executive function, high-level cognitive function and communication skill, we expect more correlations could be found between fMRI data and neurocognitive scores in other cognitive domains [53, 54].
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In conclusion, different sensitivities of DTI metrics in various brain regions have been observed of the age, gender and genotypic effects. For instance, FA measures showed age effects on white matter integrity across adulthood, with increases in FA through the 30’s and 40’s and subsequent decreases in middle-age and older adults. Accompanying the decreases of FA along the age in most of brain regions are the radial diffusivity increases that indicates demyelination process with age. AX and MD showed both lower and higher with age in different brain regions, suggesting possible axonal and Wallerian degenerations in these brain regions. We found longitudinal changes in both DTI and fcMRI in regions were similar to those demonstrating cross-sectional effects of age; for instance decreased fcMRI in DMN but increased fcMRI in anti-correlated DAN networks. The APOE genotypic signatures of FA and functional connectivity suggested possible tight associations between myelin/neuronal activation and APOE gene, indicating different roles of APOE alleles on brain structural conductivity, demyelination and neuroplasticity. Taken together, our neuroimaging and correlational neurocognitive results indicate significant and consistent age, gender and APOE genotypic effects on structural and functional connectivity at both baseline and longitudinal short-interval ranges.
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\n\n',keywords:"microstructure, function connectivity, DTI, longitudinal change, neurocognitive test, correlation, age, APOE gene",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/67361.pdf",chapterXML:"https://mts.intechopen.com/source/xml/67361.xml",downloadPdfUrl:"/chapter/pdf-download/67361",previewPdfUrl:"/chapter/pdf-preview/67361",totalDownloads:971,totalViews:0,totalCrossrefCites:0,dateSubmitted:"September 7th 2018",dateReviewed:"May 2nd 2019",datePrePublished:"May 29th 2019",datePublished:"November 27th 2019",dateFinished:"May 27th 2019",readingETA:"0",abstract:"Revealing brain functional and micro-structural changes over a relatively short period at individual levels are especially important given that many risks associated with age including vascular and neuroinflammation increases and could confound the baseline fMRI parametric images. Cellular-level axonal injury and/or demyelination as well as dispersed mesoscopic level substance abnormal aggregation and structural/functional abnormality could occur in short subacute/acute phases, while literatures related to longitudinal changes with age are limited with only our previous fMRI findings. Longitudinal data were used to characterize these multi-parameters including random intercept and interval per individual. No significant age by gender interactions have been found to either DTI fractional anisotropy (FA) or diffusivity metrics. The interval effective regions showed longitudinal change of FA and radial diffusivity (RD)/axial diffusivity (AX) values remained similar to the aging results found with cross-sectional data. Significant correlations between DTI and fMRI metrics as well as between imaging and neurocognitive data including speed and memory were found. Our results indicate significant and consistent age, gender and apolipoprotein E (APOE) genotypic effects on structural and functional connectivity at both short-interval and cross-sectional ranges, together with correlational neurocognitive functions.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/67361",risUrl:"/chapter/ris/67361",signatures:"Yongxia Zhou",book:{id:"8125",type:"book",title:"Medical Imaging",subtitle:"Principles and Applications",fullTitle:"Medical Imaging - Principles and Applications",slug:"medical-imaging-principles-and-applications",publishedDate:"November 27th 2019",bookSignature:"Yongxia Zhou",coverURL:"https://cdn.intechopen.com/books/images_new/8125.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",isbn:"978-1-78923-872-3",printIsbn:"978-1-78923-871-6",pdfIsbn:"978-1-78985-724-5",isAvailableForWebshopOrdering:!0,editors:[{id:"259308",title:"Dr.",name:"Yongxia",middleName:null,surname:"Zhou",slug:"yongxia-zhou",fullName:"Yongxia Zhou"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"259308",title:"Dr.",name:"Yongxia",middleName:null,surname:"Zhou",fullName:"Yongxia Zhou",slug:"yongxia-zhou",email:"yongxia.zhou@yahoo.com",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259308/images/system/259308.jpeg",institution:{name:"University of Southern California",institutionURL:null,country:{name:"United States of America"}}}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Methods",level:"1"},{id:"sec_2_2",title:"2.1 Participants",level:"2"},{id:"sec_3_2",title:"2.2 Imaging parameters",level:"2"},{id:"sec_4_2",title:"2.3 Image processing",level:"2"},{id:"sec_5_2",title:"2.4 Statistical analyses",level:"2"},{id:"sec_7",title:"3. Results",level:"1"},{id:"sec_7_2",title:"3.1 Age effects on DTI",level:"2"},{id:"sec_8_2",title:"3.2 Longitudinal change of FA",level:"2"},{id:"sec_9_2",title:"3.3 Gender effects on DTI",level:"2"},{id:"sec_10_2",title:"3.4 APOE genotype effects",level:"2"},{id:"sec_11_2",title:"3.5 fALFF and fcMRI results",level:"2"},{id:"sec_12_2",title:"3.6 Correlations",level:"2"},{id:"sec_14",title:"4. Discussion and conclusion",level:"1"}],chapterReferences:[{id:"B1",body:'Zhou Y. Functional Neuroimaging with Multiple Modalities. New York, USA: Nova Publishers; 2016\n'},{id:"B2",body:'Huster D, Yao X, Hong M. Membrane protein topology probed by (1) H spin diffusion from lipids using solid-state NMR spectroscopy. Journal of the American Chemical Society. 2002;124:874-883\n'},{id:"B3",body:'Basser PJ. Inferring microstructural features and the physiological state of tissues from diffusion-weighted images. NMR in Biomedicine. 1995;8:333-344\n'},{id:"B4",body:'Zhou XJ. Diffusion tensor imaging: Techniques and clinical applications. In: Conference Proceedings: Annual International Conference of the IEEE Engineering in Medicine and Biology Society IEEE Engineering in Medicine and Biology Society Annual Conference. Vol. 7. 2004. pp. 5223-5225\n'},{id:"B5",body:'Thiessen JD, Zhang Y, Zhang H, et al. Quantitative MRI and ultrastructural examination of the cuprizone mouse model of demyelination. NMR in Biomedicine. 2013;26:1562-1581\n'},{id:"B6",body:'Billiet T, Vandenbulcke M, Madler B, et al. Age-related microstructural differences quantified using myelin water imaging and advanced diffusion MRI. Neurobiology of Aging. 2015;36:2107-2121\n'},{id:"B7",body:'Gazes Y, Bowman FD, Razlighi QR, O’Shea D, Stern Y, Habeck C. White matter tract covariance patterns predict age-declining cognitive abilities. NeuroImage. 2016;125:53-60\n'},{id:"B8",body:'Sasson E, Doniger GM, Pasternak O, Tarrasch R, Assaf Y. Structural correlates of cognitive domains in normal aging with diffusion tensor imaging. Brain Structure and Function. 2012;217:503-515\n'},{id:"B9",body:'Agosta F, Dalla Libera D, Spinelli EG, et al. Myeloid microvesicles in cerebrospinal fluid are associated with myelin damage and neuronal loss in mild cognitive impairment and Alzheimer disease. Annals of Neurology. 2014;76:813-825\n'},{id:"B10",body:'Kochunov P, Glahn DC, Lancaster J, et al. Fractional anisotropy of cerebral white matter and thickness of cortical gray matter across the lifespan. NeuroImage. 2011;58:41-49\n'},{id:"B11",body:'Horch RA, Gore JC, Does MD. Origins of the ultrashort-T2 1H NMR signals in myelinated nerve: A direct measure of myelin content? Magnetic Resonance in Medicine. 2011;66:24-31\n'},{id:"B12",body:'Zhou Y. Neuroimaging in Multiple Sclerosis. New York, USA: Nova Publishers; 2017\n'},{id:"B13",body:'Bendfeldt K, Kuster P, Traud S, Egger H, Winklhofer S, Mueller-Lenke N, et al. Association of regional gray matter volume loss and progression of white matter lesions in multiple sclerosis—A longitudinal voxel-based morphometry study. NeuroImage. 2009;45:60-67\n'},{id:"B14",body:'Bjartmar C, Wujek JR, Trapp BD. Axonal loss in the pathology of MS: Consequences for understanding the progressive phase of the disease. Journal of the Neurological Sciences. 2003;206:165-171\n'},{id:"B15",body:'Bodini B, Khaleeli Z, Cercignani M, Miller DH, Thompson AJ, Ciccarelli O. Exploring the relationship between white matter and gray matter damage in early primary progressive multiple sclerosis: An in vivo study with TBSS and VBM. Human Brain Mapping. 2009;30:2852-2861\n'},{id:"B16",body:'Kolasa M, Hakulinen U, Helminen M, Hagman S, Raunio M, Rossi M, et al. Longitudinal assessment of clinically isolated syndrome with diffusion tensor imaging and volumetric MRI. Clinical Imaging. 2015;39:207-212\n'},{id:"B17",body:'Rocca MA, Preziosa P, Mesaros S, Pagani E, Dackovic J, Stosic-Opincal T, et al. Clinically isolated syndrome suggestive of multiple sclerosis: Dynamic patterns of gray and white matter changes—A 2-year MR imaging study. Radiology. 2016;278:841-853\n'},{id:"B18",body:'Forn C, Barros-Loscertales A, Escudero J, Benlloch V, Campos S, Antonia Parcet M, et al. Compensatory activations in patients with multiple sclerosis during preserved performance on the auditory N-back task. Human Brain Mapping. 2007;28:424-430\n'},{id:"B19",body:'Lowe MJ, Beall EB, Sakaie KE, Koenig KA, Stone L, Marrie RA, et al. Resting state sensorimotor functional connectivity in multiple sclerosis inversely correlates with transcallosal motor pathway transverse diffusivity. Human Brain Mapping. 2008;29:818-827\n'},{id:"B20",body:'Lisak RP. Neurodegeneration in multiple sclerosis: Defining the problem. Neurology. 2007;68:S5-S12, discussion S43-54\n'},{id:"B21",body:'Yount R, Raschke KA, Biru M, et al. Traumatic brain injury and atrophy of the cingulate gyrus. The Journal of Neuropsychiatry and Clinical Neurosciences. 2002;14(4):416-423\n'},{id:"B22",body:'Hudak A, Warner M, Marquez de la Plata C, Moore C, Harper C, Diaz-Arrastia R. Brain morphometry changes and depressive symptoms after traumatic brain injury. Psychiatry Research. 2011;191(3):160-165\n'},{id:"B23",body:'Zhou Y. Neuroimaging in Mild Traumatic Brain Injury. New York, USA: Nova Publishers; 2017\n'},{id:"B24",body:'Bender AR, Raz N. Normal-appearing cerebral white matter in healthy adults: Mean change over 2 years and individual differences in change. Neurobiology of Aging. 2015;36:1834-1848\n'},{id:"B25",body:'McCarrey AC, An Y, Kitner-Triolo MH,Ferrucci L, Resnick SM. Gender differences in cognitive trajectories in clinically normal older adults. Psychology and Aging. 2016;31:166-175\n'},{id:"B26",body:'Zhou Y, Milham MP, Lui YW, Miles L, Reaume J, Sodickson DK, et al. Default-mode network disruption in mild traumatic brain injury. Radiology. 2002;265:882-892\n'},{id:"B27",body:'Andrews-Hanna JR, Reidler JS, Sepulcre J, Poulin R, Buckner RL. Functional-anatomic fractionation of the brain’s default network. Neuron. 2010;65:550-562\n'},{id:"B28",body:'Zhou Y, Lui YW, Zuo XN, Milham MP, Reaume J, Grossman RI, et al. Characterization of thalamo-cortical association using amplitude and connectivity of functional MRI in mild traumatic brain injury. Journal of Magnetic Resonance Imaging. 2014;39:1558-1568\n'},{id:"B29",body:'Zhou Y. Abnormal structural and functional hypothalamic connectivity in mild traumatic brain injury. Journal of Magnetic Resonance Imaging. 2017;45:1105-1112\n'},{id:"B30",body:'Fox MD, Raichle ME. Spontaneous fluctuations in brain activity observed with functional magnetic resonance imaging. Nature Reviews. Neuroscience. 2007;8:700-711\n'},{id:"B31",body:'Goh JO, An Y, Resnick SM. Differential trajectories of age-related changes in components of executive and memory processes. Psychology and Aging. 2012;27:707-719\n'},{id:"B32",body:'Zhou Y. Functional Neuroimaging Methods and Frontiers. New York, USA: Nova Publishers; 2018\n'},{id:"B33",body:'Bartzokis G. Age-related myelin breakdown: A developmental model of cognitive decline and Alzheimer’s disease. Neurobiology of Aging. 2004;25:5-18. author reply 49-62\n'},{id:"B34",body:'Kodiweera C, Alexander AL, Harezlak J, McAllister TW, Wu YC. Age effects and gender differences in human brain white matter of young to middle-aged adults: A DTI, NODDI, and q-space study. NeuroImage. 2016;128:180-192\n'},{id:"B35",body:'Scheinost D, Finn ES, Tokoglu F, et al. Gender differences in normal age trajectories of functional brain networks. Human Brain Mapping. 2015;36:1524-1535\n'},{id:"B36",body:'Trachtenberg AJ, Filippini N, Ebmeier KP, Smith SM, Karpe F, Mackay CE. The effects of APOE on the functional architecture of the resting brain. NeuroImage. 2012;59:565-572\n'},{id:"B37",body:'Shu H et al. Opposite neural trajectories of apolipoprotein E 4 and 2 alleles with aging associated with different risks of Alzheimer’s disease. Cerebral Cortex. 2016;26:1421-1429\n'},{id:"B38",body:'Kennedy KM et al. Effects of beta-amyloid accumulation on neural function during encoding across the adult lifespan. NeuroImage. 2012;62:1-8. DOI: 10.1016/j.neuroimage\n'},{id:"B39",body:'Buckner RL. Memory and executive function in aging and AD: Multiple factors that cause decline and reserve factors that compensate. Neuron. 2004;44:195-208\n'},{id:"B40",body:'Sala-Llonch R, Bartres-Faz D, Junque C. Reorganization of brain networks in aging: A review of functional connectivity studies. Frontiers in Psychology. 2015;6:663\n'},{id:"B41",body:'Legon W, Punzell S, Dowlati E, Adams SE, Stiles AB, Moran RJ. Altered prefrontal excitation/inhibition balance and prefrontal output: Markers of aging in human memory networks. Cerebral Cortex. 2016;26(11):4315-4326\n'},{id:"B42",body:'Raichle ME, Mac Leod AM, Snyder AZ, Powers WJ, Gusnard DA, Shulman GL. A default mode of brain function. Proceedings of the National Academy of Sciences of the United States of America. 2001;98:676-682\n'},{id:"B43",body:'Buckner RL, Snyder AZ, Shannon BJ, LaRossa G, Sachs R, Fotenos AF, et al. Molecular, structural, and functional characterization of Alzheimer’s disease: Evidence for a relationship between default activity, amyloid, and memory. The Journal of Neuroscience. 2005;25:7709-7717\n'},{id:"B44",body:'Jones DT et al. Age-related changes in the default mode network are more advanced in Alzheimer disease. Neurology. 2011;77:1524-1531. DOI: 10.1212/WNL.0b013e318233b33d\n'},{id:"B45",body:'Fjell AM, Sneve MH, Storsve AB, Grydeland H, Yendiki A, Walhovd KB. Brain events underlying episodic memory changes in aging: A longitudinal investigation of structural and functional connectivity. Cerebral Cortex. 2016;26:1272-1286\n'},{id:"B46",body:'Kennedy KM, Rodrigue KM, Bischof GN, Hebrank AC, Reuter-Lorenz PA, Park DC. Age trajectories of functional activation under conditions of low and high processing demands: An adult lifespan fMRI study of the aging brain. NeuroImage. 2015;104:21-34\n'},{id:"B47",body:'Westlye LT, Reinvang I, Rootwelt H, Espeseth T. Effects of APOE on brain white matter microstructure in healthy adults. Neurology. 2012;79:1961-1969\n'},{id:"B48",body:'Ward AM, Mormino EC, Huijbers W, Schultz AP, Hedden T, Sperling RA. Relationships between default-mode network connectivity, medial temporal lobe structure, and age-related memory deficits. Neurobiology of Aging. 2015;36:265-272\n'},{id:"B49",body:'Zhou J, Greicius MD, Gennatas ED, et al. Divergent network connectivity changes in behavioural variant frontotemporal dementia and Alzheimer’s disease. Brain: A Journal of Neurology. 2010;133:1352-1367\n'},{id:"B50",body:'Bilgel M, An Y, Zhou Y, et al. Individual estimates of age at detectable amyloid onset for risk factor assessment. Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association. 2015;36(8):2333\n'},{id:"B51",body:'Scholl M, Lockhart SN, Schonhaut DR, et al. PET imaging of tau deposition in the aging human brain. Neuron. 2016;89(5):971-982\n'},{id:"B52",body:'Sheline YI, Raichle ME, Snyder AZ, et al. Amyloid plaques disrupt resting state default mode network connectivity in cognitively normal elderly. Biological Psychiatry. 2010;67:584-587\n'},{id:"B53",body:'Tsvetanov KA, Henson RN, Tyler LK, Razi A, Geerligs L, Ham TE, et al. Extrinsic and intrinsic brain network connectivity maintains cognition across the lifespan despite accelerated decay of regional brain activation. The Journal of Neuroscience. 2016;36:3115-3126\n'},{id:"B54",body:'Worthy DA, Davis T, Gorlick MA, Cooper JA, Bakkour A, Mumford JA, et al. Neural correlates of state-based decision-making in younger and older adults. NeuroImage. 2015;130:13-23\n'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Yongxia Zhou",address:"yongxia.zhou@yahoo.com",affiliation:'
Department of Radiology, Columbia University, USA
Department of Biomedical Engineering, University of Southern California, USA
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Her research interests include archaea metabolism, enzymes purification and characterization, gene regulation, carotenoids and bioplastics production, antioxidant\ncompounds, waste water treatments, and brines bioremediation.\nRosa María’s other roles include editorial board member for several journals related\nto biochemistry, reviewer for more than 60 journals (biochemistry, molecular biology, biotechnology, chemistry and microbiology) and president of several organizing committees in international meetings related to the N-cycle or respiratory processes.",institutionString:null,institution:{name:"University of Alicante",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"15",title:"Chemical Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/15.jpg",isOpenForSubmission:!0,editor:{id:"441442",title:"Dr.",name:"Şükrü",middleName:null,surname:"Beydemir",slug:"sukru-beydemir",fullName:"Şükrü Beydemir",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003GsUoIQAV/Profile_Picture_1634557147521",biography:"Dr. Şükrü Beydemir obtained a BSc in Chemistry in 1995 from Yüzüncü Yıl University, MSc in Biochemistry in 1998, and PhD in Biochemistry in 2002 from Atatürk University, Turkey. 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Dr. Beydemir is also Rector of Bilecik Şeyh Edebali University, Turkey.",institutionString:null,institution:{name:"Anadolu University",institutionURL:null,country:{name:"Turkey"}}},editorTwo:{id:"13652",title:"Prof.",name:"Deniz",middleName:null,surname:"Ekinci",slug:"deniz-ekinci",fullName:"Deniz Ekinci",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYLT1QAO/Profile_Picture_1634557223079",biography:"Dr. Deniz Ekinci obtained a BSc in Chemistry in 2004, MSc in Biochemistry in 2006, and PhD in Biochemistry in 2009 from Atatürk University, Turkey. He studied at Stetson University, USA, in 2007-2008 and at the Max Planck Institute of Molecular Cell Biology and Genetics, Germany, in 2009-2010. Dr. Ekinci currently works as a Full Professor of Biochemistry in the Faculty of Agriculture and is the Head of the Enzyme and Microbial Biotechnology Division, Ondokuz Mayıs University, Turkey. He is a member of the Turkish Biochemical Society, American Chemical Society, and German Genetics society. Dr. Ekinci published around ninety scientific papers, reviews and book chapters, and presented several conferences to scientists. He has received numerous publication awards from several scientific councils. Dr. Ekinci serves as the Editor in Chief of four international books and is involved in the Editorial Board of several international journals.",institutionString:null,institution:{name:"Ondokuz Mayıs University",institutionURL:null,country:{name:"Turkey"}}},editorThree:null},{id:"17",title:"Metabolism",coverUrl:"https://cdn.intechopen.com/series_topics/covers/17.jpg",isOpenForSubmission:!0,editor:{id:"138626",title:"Dr.",name:"Yannis",middleName:null,surname:"Karamanos",slug:"yannis-karamanos",fullName:"Yannis Karamanos",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002g6Jv2QAE/Profile_Picture_1629356660984",biography:"Yannis Karamanos, born in Greece in 1953, completed his pre-graduate studies at the Université Pierre et Marie Curie, Paris, then his Masters and Doctoral degree at the Université de Lille (1983). He was associate professor at the University of Limoges (1987) before becoming full professor of biochemistry at the Université d’Artois (1996). He worked on the structure-function relationships of glycoconjugates and his main project was the investigations on the biological roles of the de-N-glycosylation enzymes (Endo-N-acetyl-β-D-glucosaminidase and peptide-N4-(N-acetyl-β-glucosaminyl) asparagine amidase). From 2002 he contributes to the understanding of the Blood-brain barrier functioning using proteomics approaches. He has published more than 70 papers. His teaching areas are energy metabolism and regulation, integration and organ specialization and metabolic adaptation.",institutionString:null,institution:{name:"Artois University",institutionURL:null,country:{name:"France"}}},editorTwo:null,editorThree:null},{id:"18",title:"Proteomics",coverUrl:"https://cdn.intechopen.com/series_topics/covers/18.jpg",isOpenForSubmission:!0,editor:{id:"200689",title:"Prof.",name:"Paolo",middleName:null,surname:"Iadarola",slug:"paolo-iadarola",fullName:"Paolo Iadarola",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSCl8QAG/Profile_Picture_1623568118342",biography:"Paolo Iadarola graduated with a degree in Chemistry from the University of Pavia (Italy) in July 1972. He then worked as an Assistant Professor at the Faculty of Science of the same University until 1984. In 1985, Prof. Iadarola became Associate Professor at the Department of Biology and Biotechnologies of the University of Pavia and retired in October 2017. Since then, he has been working as an Adjunct Professor in the same Department at the University of Pavia. His research activity during the first years was primarily focused on the purification and structural characterization of enzymes from animal and plant sources. During this period, Prof. Iadarola familiarized himself with the conventional techniques used in column chromatography, spectrophotometry, manual Edman degradation, and electrophoresis). Since 1995, he has been working on: i) the determination in biological fluids (serum, urine, bronchoalveolar lavage, sputum) of proteolytic activities involved in the degradation processes of connective tissue matrix, and ii) on the identification of biological markers of lung diseases. In this context, he has developed and validated new methodologies (e.g., Capillary Electrophoresis coupled to Laser-Induced Fluorescence, CE-LIF) whose application enabled him to determine both the amounts of biochemical markers (Desmosines) in urine/serum of patients affected by Chronic Obstructive Pulmonary Disease (COPD) and the activity of proteolytic enzymes (Human Neutrophil Elastase, Cathepsin G, Pseudomonas aeruginosa elastase) in sputa of these patients. More recently, Prof. Iadarola was involved in developing techniques such as two-dimensional electrophoresis coupled to liquid chromatography/mass spectrometry (2DE-LC/MS) for the proteomic analysis of biological fluids aimed at the identification of potential biomarkers of different lung diseases. He is the author of about 150 publications (According to Scopus: H-Index: 23; Total citations: 1568- According to WOS: H-Index: 20; Total Citations: 1296) of peer-reviewed international journals. He is a Consultant Reviewer for several journals, including the Journal of Chromatography A, Journal of Chromatography B, Plos ONE, Proteomes, International Journal of Molecular Science, Biotech, Electrophoresis, and others. He is also Associate Editor of Biotech.",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorTwo:{id:"201414",title:"Dr.",name:"Simona",middleName:null,surname:"Viglio",slug:"simona-viglio",fullName:"Simona Viglio",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRKDHQA4/Profile_Picture_1630402531487",biography:"Simona Viglio is an Associate Professor of Biochemistry at the Department of Molecular Medicine at the University of Pavia. She has been working since 1995 on the determination of proteolytic enzymes involved in the degradation process of connective tissue matrix and on the identification of biological markers of lung diseases. She gained considerable experience in developing and validating new methodologies whose applications allowed her to determine both the amount of biomarkers (Desmosine and Isodesmosine) in the urine of patients affected by COPD, and the activity of proteolytic enzymes (HNE, Cathepsin G, Pseudomonas aeruginosa elastase) in the sputa of these patients. Simona Viglio was also involved in research dealing with the supplementation of amino acids in patients with brain injury and chronic heart failure. She is presently engaged in the development of 2-DE and LC-MS techniques for the study of proteomics in biological fluids. The aim of this research is the identification of potential biomarkers of lung diseases. She is an author of about 90 publications (According to Scopus: H-Index: 23; According to WOS: H-Index: 20) on peer-reviewed journals, a member of the “Società Italiana di Biochimica e Biologia Molecolare,“ and a Consultant Reviewer for International Journal of Molecular Science, Journal of Chromatography A, COPD, Plos ONE and Nutritional Neuroscience.",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorThree:null}]},overviewPageOFChapters:{paginationCount:49,paginationItems:[{id:"80495",title:"Iron in Cell Metabolism and Disease",doi:"10.5772/intechopen.101908",signatures:"Eeka Prabhakar",slug:"iron-in-cell-metabolism-and-disease",totalDownloads:1,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Iron Metabolism - Iron a Double‐Edged Sword",coverURL:"https://cdn.intechopen.com/books/images_new/10842.jpg",subseries:{id:"17",title:"Metabolism"}}},{id:"81799",title:"Cross Talk of Purinergic and Immune Signaling: Implication in Inflammatory and Pathogenic Diseases",doi:"10.5772/intechopen.104978",signatures:"Richa Rai",slug:"cross-talk-of-purinergic-and-immune-signaling-implication-in-inflammatory-and-pathogenic-diseases",totalDownloads:7,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Purinergic System",coverURL:"https://cdn.intechopen.com/books/images_new/10801.jpg",subseries:{id:"17",title:"Metabolism"}}},{id:"81764",title:"Involvement of the Purinergic System in Cell Death in Models of Retinopathies",doi:"10.5772/intechopen.103935",signatures:"Douglas Penaforte Cruz, Marinna Garcia Repossi and Lucianne Fragel Madeira",slug:"involvement-of-the-purinergic-system-in-cell-death-in-models-of-retinopathies",totalDownloads:4,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Purinergic System",coverURL:"https://cdn.intechopen.com/books/images_new/10801.jpg",subseries:{id:"17",title:"Metabolism"}}},{id:"81756",title:"Alteration of Cytokines Level and Oxidative Stress Parameters in COVID-19",doi:"10.5772/intechopen.104950",signatures:"Marija Petrusevska, Emilija Atanasovska, Dragica Zendelovska, Aleksandar Eftimov and Katerina Spasovska",slug:"alteration-of-cytokines-level-and-oxidative-stress-parameters-in-covid-19",totalDownloads:8,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Chemokines Updates",coverURL:"https://cdn.intechopen.com/books/images_new/11672.jpg",subseries:{id:"18",title:"Proteomics"}}}]},overviewPagePublishedBooks:{paginationCount:27,paginationItems:[{type:"book",id:"7006",title:"Biochemistry and Health Benefits of Fatty Acids",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7006.jpg",slug:"biochemistry-and-health-benefits-of-fatty-acids",publishedDate:"December 19th 2018",editedByType:"Edited by",bookSignature:"Viduranga Waisundara",hash:"c93a00abd68b5eba67e5e719f67fd20b",volumeInSeries:1,fullTitle:"Biochemistry and Health Benefits of Fatty Acids",editors:[{id:"194281",title:"Dr.",name:"Viduranga Y.",middleName:null,surname:"Waisundara",slug:"viduranga-y.-waisundara",fullName:"Viduranga Y. Waisundara",profilePictureURL:"https://mts.intechopen.com/storage/users/194281/images/system/194281.jpg",biography:"Dr. Viduranga Waisundara obtained her Ph.D. in Food Science and Technology from the Department of Chemistry, National University of Singapore, in 2010. She was a lecturer at Temasek Polytechnic, Singapore from July 2009 to March 2013. She relocated to her motherland of Sri Lanka and spearheaded the Functional Food Product Development Project at the National Institute of Fundamental Studies from April 2013 to October 2016. She was a senior lecturer on a temporary basis at the Department of Food Technology, Faculty of Technology, Rajarata University of Sri Lanka. She is currently Deputy Principal of the Australian College of Business and Technology – Kandy Campus, Sri Lanka. She is also the Global Harmonization Initiative (GHI) Ambassador to Sri Lanka.",institutionString:"Australian College of Business & Technology",institution:null}]},{type:"book",id:"6820",title:"Keratin",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/6820.jpg",slug:"keratin",publishedDate:"December 19th 2018",editedByType:"Edited by",bookSignature:"Miroslav Blumenberg",hash:"6def75cd4b6b5324a02b6dc0359896d0",volumeInSeries:2,fullTitle:"Keratin",editors:[{id:"31610",title:"Dr.",name:"Miroslav",middleName:null,surname:"Blumenberg",slug:"miroslav-blumenberg",fullName:"Miroslav Blumenberg",profilePictureURL:"https://mts.intechopen.com/storage/users/31610/images/system/31610.jpg",biography:"Miroslav Blumenberg, Ph.D., was born in Subotica and received his BSc in Belgrade, Yugoslavia. He completed his Ph.D. at MIT in Organic Chemistry; he followed up his Ph.D. with two postdoctoral study periods at Stanford University. Since 1983, he has been a faculty member of the RO Perelman Department of Dermatology, NYU School of Medicine, where he is codirector of a training grant in cutaneous biology. Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. He has published more than 100 peer-reviewed research articles and graduated numerous Ph.D. and postdoctoral students.",institutionString:null,institution:{name:"New York University Langone Medical Center",institutionURL:null,country:{name:"United States of America"}}}]},{type:"book",id:"7978",title:"Vitamin A",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7978.jpg",slug:"vitamin-a",publishedDate:"May 15th 2019",editedByType:"Edited by",bookSignature:"Leila Queiroz Zepka, Veridiana Vera de Rosso and Eduardo Jacob-Lopes",hash:"dad04a658ab9e3d851d23705980a688b",volumeInSeries:3,fullTitle:"Vitamin A",editors:[{id:"261969",title:"Dr.",name:"Leila",middleName:null,surname:"Queiroz Zepka",slug:"leila-queiroz-zepka",fullName:"Leila Queiroz Zepka",profilePictureURL:"https://mts.intechopen.com/storage/users/261969/images/system/261969.png",biography:"Prof. Dr. Leila Queiroz Zepka is currently an associate professor in the Department of Food Technology and Science, Federal University of Santa Maria, Brazil. She has more than fifteen years of teaching and research experience. She has published more than 550 scientific publications/communications, including 15 books, 50 book chapters, 100 original research papers, 380 research communications in national and international conferences, and 12 patents. She is a member of the editorial board of five journals and acts as a reviewer for several national and international journals. Her research interests include microalgal biotechnology with an emphasis on microalgae-based products.",institutionString:"Universidade Federal de Santa Maria",institution:{name:"Universidade Federal de Santa Maria",institutionURL:null,country:{name:"Brazil"}}}]},{type:"book",id:"7953",title:"Bioluminescence",subtitle:"Analytical Applications and Basic Biology",coverURL:"https://cdn.intechopen.com/books/images_new/7953.jpg",slug:"bioluminescence-analytical-applications-and-basic-biology",publishedDate:"September 25th 2019",editedByType:"Edited by",bookSignature:"Hirobumi Suzuki",hash:"3a8efa00b71abea11bf01973dc589979",volumeInSeries:4,fullTitle:"Bioluminescence - Analytical Applications and Basic Biology",editors:[{id:"185746",title:"Dr.",name:"Hirobumi",middleName:null,surname:"Suzuki",slug:"hirobumi-suzuki",fullName:"Hirobumi Suzuki",profilePictureURL:"https://mts.intechopen.com/storage/users/185746/images/system/185746.png",biography:"Dr. Hirobumi Suzuki received his Ph.D. in 1997 from Tokyo Metropolitan University, Japan, where he studied firefly phylogeny and the evolution of mating systems. He is especially interested in the genetic differentiation pattern and speciation process that correlate to the flashing pattern and mating behavior of some fireflies in Japan. He then worked for Olympus Corporation, a Japanese manufacturer of optics and imaging products, where he was involved in the development of luminescence technology and produced a bioluminescence microscope that is currently being used for gene expression analysis in chronobiology, neurobiology, and developmental biology. Dr. Suzuki currently serves as a visiting researcher at Kogakuin University, Japan, and also a vice president of the Japan Firefly Society.",institutionString:"Kogakuin University",institution:null}]}]},openForSubmissionBooks:{},onlineFirstChapters:{},subseriesFiltersForOFChapters:[],publishedBooks:{},subseriesFiltersForPublishedBooks:[],publicationYearFilters:[],authors:{paginationCount:617,paginationItems:[{id:"158492",title:"Prof.",name:"Yusuf",middleName:null,surname:"Tutar",slug:"yusuf-tutar",fullName:"Yusuf Tutar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/158492/images/system/158492.jpeg",biography:"Prof. Dr. Yusuf Tutar conducts his research at the Hamidiye Faculty of Pharmacy, Department of Basic Pharmaceutical Sciences, Division of Biochemistry, University of Health Sciences, Turkey. He is also a faculty member in the Molecular Oncology Program. He obtained his MSc and Ph.D. at Oregon State University and Texas Tech University, respectively. He pursued his postdoctoral studies at Rutgers University Medical School and the National Institutes of Health (NIH/NIDDK), USA. His research focuses on biochemistry, biophysics, genetics, molecular biology, and molecular medicine with specialization in the fields of drug design, protein structure-function, protein folding, prions, microRNA, pseudogenes, molecular cancer, epigenetics, metabolites, proteomics, genomics, protein expression, and characterization by spectroscopic and calorimetric methods.",institutionString:"University of Health Sciences",institution:null},{id:"180528",title:"Dr.",name:"Hiroyuki",middleName:null,surname:"Kagechika",slug:"hiroyuki-kagechika",fullName:"Hiroyuki Kagechika",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/180528/images/system/180528.jpg",biography:"Hiroyuki Kagechika received his bachelor’s degree and Ph.D. in Pharmaceutical Sciences from the University of Tokyo, Japan, where he served as an associate professor until 2004. He is currently a professor at the Institute of Biomaterials and Bioengineering (IBB), Tokyo Medical and Dental University (TMDU). From 2010 to 2012, he was the dean of the Graduate School of Biomedical Science. Since 2012, he has served as the vice dean of the Graduate School of Medical and Dental Sciences. He has been the director of the IBB since 2020. Dr. Kagechika’s major research interests are the medicinal chemistry of retinoids, vitamins D/K, and nuclear receptors. He has developed various compounds including a drug for acute promyelocytic leukemia.",institutionString:"Tokyo Medical and Dental University",institution:{name:"Tokyo Medical and Dental University",country:{name:"Japan"}}},{id:"40482",title:null,name:"Rizwan",middleName:null,surname:"Ahmad",slug:"rizwan-ahmad",fullName:"Rizwan Ahmad",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/40482/images/system/40482.jpeg",biography:"Dr. Rizwan Ahmad is a University Professor and Coordinator, Quality and Development, College of Medicine, Imam Abdulrahman bin Faisal University, Saudi Arabia. Previously, he was Associate Professor of Human Function, Oman Medical College, Oman, and SBS University, Dehradun. Dr. Ahmad completed his education at Aligarh Muslim University, Aligarh. He has published several articles in peer-reviewed journals, chapters, and edited books. His area of specialization is free radical biochemistry and autoimmune diseases.",institutionString:"Imam Abdulrahman Bin Faisal University",institution:{name:"Imam Abdulrahman Bin Faisal University",country:{name:"Saudi Arabia"}}},{id:"41865",title:"Prof.",name:"Farid A.",middleName:null,surname:"Badria",slug:"farid-a.-badria",fullName:"Farid A. Badria",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/41865/images/system/41865.jpg",biography:"Farid A. Badria, Ph.D., is the recipient of several awards, including The World Academy of Sciences (TWAS) Prize for Public Understanding of Science; the World Intellectual Property Organization (WIPO) Gold Medal for best invention; Outstanding Arab Scholar, Kuwait; and the Khwarizmi International Award, Iran. He has 250 publications, 12 books, 20 patents, and several marketed pharmaceutical products to his credit. He continues to lead research projects on developing new therapies for liver, skin disorders, and cancer. Dr. Badria was listed among the world’s top 2% of scientists in medicinal and biomolecular chemistry in 2019 and 2020. He is a member of the Arab Development Fund, Kuwait; International Cell Research Organization–United Nations Educational, Scientific and Cultural Organization (ICRO–UNESCO), Chile; and UNESCO Biotechnology France",institutionString:"Mansoura University",institution:{name:"Mansoura University",country:{name:"Egypt"}}},{id:"329385",title:"Dr.",name:"Rajesh K.",middleName:"Kumar",surname:"Singh",slug:"rajesh-k.-singh",fullName:"Rajesh K. Singh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329385/images/system/329385.png",biography:"Dr. Singh received a BPharm (2003) and MPharm (2005) from Panjab University, Chandigarh, India, and a Ph.D. (2013) from Punjab Technical University (PTU), Jalandhar, India. He has more than sixteen years of teaching experience and has supervised numerous postgraduate and Ph.D. students. He has to his credit more than seventy papers in SCI- and SCOPUS-indexed journals, fifty-five conference proceedings, four books, six Best Paper Awards, and five projects from different government agencies. He is currently an editorial board member of eight international journals and a reviewer for more than fifty scientific journals. He received Top Reviewer and Excellent Peer Reviewer Awards from Publons in 2016 and 2017, respectively. He is also on the panel of The International Reviewer for reviewing research proposals for grants from the Royal Society. He also serves as a Publons Academy mentor and Bentham brand ambassador.",institutionString:"Punjab Technical University",institution:{name:"Punjab Technical University",country:{name:"India"}}},{id:"142388",title:"Dr.",name:"Thiago",middleName:"Gomes",surname:"Gomes Heck",slug:"thiago-gomes-heck",fullName:"Thiago Gomes Heck",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/142388/images/7259_n.jpg",biography:null,institutionString:null,institution:{name:"Universidade Regional do Noroeste do Estado do Rio Grande do Sul",country:{name:"Brazil"}}},{id:"336273",title:"Assistant Prof.",name:"Janja",middleName:null,surname:"Zupan",slug:"janja-zupan",fullName:"Janja Zupan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/336273/images/14853_n.jpeg",biography:"Janja Zupan graduated in 2005 at the Department of Clinical Biochemistry (superviser prof. dr. Janja Marc) in the field of genetics of osteoporosis. Since November 2009 she is working as a Teaching Assistant at the Faculty of Pharmacy, Department of Clinical Biochemistry. In 2011 she completed part of her research and PhD work at Institute of Genetics and Molecular Medicine, University of Edinburgh. She finished her PhD entitled The influence of the proinflammatory cytokines on the RANK/RANKL/OPG in bone tissue of osteoporotic and osteoarthritic patients in 2012. From 2014-2016 she worked at the Institute of Biomedical Sciences, University of Aberdeen as a postdoctoral research fellow on UK Arthritis research project where she gained knowledge in mesenchymal stem cells and regenerative medicine. She returned back to University of Ljubljana, Faculty of Pharmacy in 2016. She is currently leading project entitled Mesenchymal stem cells-the keepers of tissue endogenous regenerative capacity facing up to aging of the musculoskeletal system funded by Slovenian Research Agency.",institutionString:null,institution:{name:"University of Ljubljana",country:{name:"Slovenia"}}},{id:"357453",title:"Dr.",name:"Radheshyam",middleName:null,surname:"Maurya",slug:"radheshyam-maurya",fullName:"Radheshyam Maurya",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/357453/images/16535_n.jpg",biography:null,institutionString:null,institution:{name:"University of Hyderabad",country:{name:"India"}}},{id:"311457",title:"Dr.",name:"Júlia",middleName:null,surname:"Scherer Santos",slug:"julia-scherer-santos",fullName:"Júlia Scherer Santos",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/311457/images/system/311457.jpg",biography:"Dr. Júlia Scherer Santos works in the areas of cosmetology, nanotechnology, pharmaceutical technology, beauty, and aesthetics. Dr. Santos also has experience as a professor of graduate courses. Graduated in Pharmacy, specialization in Cosmetology and Cosmeceuticals applied to aesthetics, specialization in Aesthetic and Cosmetic Health, and a doctorate in Pharmaceutical Nanotechnology. Teaching experience in Pharmacy and Aesthetics and Cosmetics courses. She works mainly on the following subjects: nanotechnology, cosmetology, pharmaceutical technology, aesthetics.",institutionString:"Universidade Federal de Juiz de Fora",institution:{name:"Universidade Federal de Juiz de Fora",country:{name:"Brazil"}}},{id:"219081",title:"Dr.",name:"Abdulsamed",middleName:null,surname:"Kükürt",slug:"abdulsamed-kukurt",fullName:"Abdulsamed Kükürt",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRNVJQA4/Profile_Picture_2022-03-07T13:23:04.png",biography:"Dr. Kükürt graduated from Uludağ University in Turkey. He started his academic career as a Research Assistant in the Department of Biochemistry at Kafkas University. In 2019, he completed his Ph.D. program in the Department of Biochemistry at the Institute of Health Sciences. He is currently working at the Department of Biochemistry, Kafkas University. He has 27 published research articles in academic journals, 11 book chapters, and 37 papers. He took part in 10 academic projects. He served as a reviewer for many articles. He still serves as a member of the review board in many academic journals. His research interests include biochemistry, oxidative stress, reactive species, antioxidants, lipid peroxidation, inflammation, reproductive hormones, phenolic compounds, female infertility.",institutionString:"Kafkas University",institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"178366",title:"Associate Prof.",name:"Volkan",middleName:null,surname:"Gelen",slug:"volkan-gelen",fullName:"Volkan Gelen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178366/images/system/178366.jpg",biography:"Volkan Gelen is a Physiology specialist who received his veterinary degree from Kafkas University in 2011. Between 2011-2015, he worked as an assistant at Atatürk University, Faculty of Veterinary Medicine, Department of Physiology. In 2016, he joined Kafkas University, Faculty of Veterinary Medicine, Department of Physiology as an assistant professor. Dr. Gelen has been engaged in various academic activities at Kafkas University since 2016. There he completed 5 projects and has 3 ongoing projects. He has 60 articles published in scientific journals and 20 poster presentations in scientific congresses. His research interests include physiology, endocrine system, cancer, diabetes, cardiovascular system diseases, and isolated organ bath system studies.",institutionString:"Kafkas University",institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"418963",title:"Dr.",name:"Augustine Ododo",middleName:"Augustine",surname:"Osagie",slug:"augustine-ododo-osagie",fullName:"Augustine Ododo Osagie",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/418963/images/16900_n.jpg",biography:"Born into the family of Osagie, a prince of the Benin Kingdom. I am currently an academic in the Department of Medical Biochemistry, University of Benin. Part of the duties are to teach undergraduate students and conduct academic research.",institutionString:null,institution:{name:"University of Benin",country:{name:"Nigeria"}}},{id:"192992",title:"Prof.",name:"Shagufta",middleName:null,surname:"Perveen",slug:"shagufta-perveen",fullName:"Shagufta Perveen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/192992/images/system/192992.png",biography:"Prof. Shagufta Perveen is a Distinguish Professor in the Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia. Dr. Perveen has acted as the principal investigator of major research projects funded by the research unit of King Saud University. She has more than ninety original research papers in peer-reviewed journals of international repute to her credit. She is a fellow member of the Royal Society of Chemistry UK and the American Chemical Society of the United States.",institutionString:"King Saud University",institution:{name:"King Saud University",country:{name:"Saudi Arabia"}}},{id:"49848",title:"Dr.",name:"Wen-Long",middleName:null,surname:"Hu",slug:"wen-long-hu",fullName:"Wen-Long Hu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49848/images/system/49848.jpg",biography:"Wen-Long Hu is Chief of the Division of Acupuncture, Department of Chinese Medicine at Kaohsiung Chang Gung Memorial Hospital, as well as an adjunct associate professor at Fooyin University and Kaohsiung Medical University. Wen-Long is President of Taiwan Traditional Chinese Medicine Medical Association. He has 28 years of experience in clinical practice in laser acupuncture therapy and 34 years in acupuncture. He is an invited speaker for lectures and workshops in laser acupuncture at many symposiums held by medical associations. He owns the patent for herbal preparation and producing, and for the supercritical fluid-treated needle. Dr. Hu has published three books, 12 book chapters, and more than 30 papers in reputed journals, besides serving as an editorial board member of repute.",institutionString:"Kaohsiung Chang Gung Memorial Hospital",institution:{name:"Kaohsiung Chang Gung Memorial Hospital",country:{name:"Taiwan"}}},{id:"298472",title:"Prof.",name:"Andrey V.",middleName:null,surname:"Grechko",slug:"andrey-v.-grechko",fullName:"Andrey V. Grechko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/298472/images/system/298472.png",biography:"Andrey Vyacheslavovich Grechko, Ph.D., Professor, is a Corresponding Member of the Russian Academy of Sciences. He graduated from the Semashko Moscow Medical Institute (Semashko National Research Institute of Public Health) with a degree in Medicine (1998), the Clinical Department of Dermatovenerology (2000), and received a second higher education in Psychology (2009). Professor A.V. Grechko held the position of Сhief Physician of the Central Clinical Hospital in Moscow. He worked as a professor at the faculty and was engaged in scientific research at the Medical University. Starting in 2013, he has been the initiator of the creation of the Federal Scientific and Clinical Center for Intensive Care and Rehabilitology, Moscow, Russian Federation, where he also serves as Director since 2015. He has many years of experience in research and teaching in various fields of medicine, is an author/co-author of more than 200 scientific publications, 13 patents, 15 medical books/chapters, including Chapter in Book «Metabolomics», IntechOpen, 2020 «Metabolomic Discovery of Microbiota Dysfunction as the Cause of Pathology».",institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"199461",title:"Prof.",name:"Natalia V.",middleName:null,surname:"Beloborodova",slug:"natalia-v.-beloborodova",fullName:"Natalia V. Beloborodova",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/199461/images/system/199461.jpg",biography:'Natalia Vladimirovna Beloborodova was educated at the Pirogov Russian National Research Medical University, with a degree in pediatrics in 1980, a Ph.D. in 1987, and a specialization in Clinical Microbiology from First Moscow State Medical University in 2004. She has been a Professor since 1996. Currently, she is the Head of the Laboratory of Metabolism, a division of the Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, Moscow, Russian Federation. N.V. Beloborodova has many years of clinical experience in the field of intensive care and surgery. She studies infectious complications and sepsis. She initiated a series of interdisciplinary clinical and experimental studies based on the concept of integrating human metabolism and its microbiota. Her scientific achievements are widely known: she is the recipient of the Marie E. Coates Award \\"Best lecturer-scientist\\" Gustafsson Fund, Karolinska Institutes, Stockholm, Sweden, and the International Sepsis Forum Award, Pasteur Institute, Paris, France (2014), etc. Professor N.V. Beloborodova wrote 210 papers, five books, 10 chapters and has edited four books.',institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"354260",title:"Ph.D.",name:"Tércio Elyan",middleName:"Azevedo",surname:"Azevedo Martins",slug:"tercio-elyan-azevedo-martins",fullName:"Tércio Elyan Azevedo Martins",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/354260/images/16241_n.jpg",biography:"Graduated in Pharmacy from the Federal University of Ceará with the modality in Industrial Pharmacy, Specialist in Production and Control of Medicines from the University of São Paulo (USP), Master in Pharmaceuticals and Medicines from the University of São Paulo (USP) and Doctor of Science in the program of Pharmaceuticals and Medicines by the University of São Paulo. Professor at Universidade Paulista (UNIP) in the areas of chemistry, cosmetology and trichology. Assistant Coordinator of the Higher Course in Aesthetic and Cosmetic Technology at Universidade Paulista Campus Chácara Santo Antônio. Experience in the Pharmacy area, with emphasis on Pharmacotechnics, Pharmaceutical Technology, Research and Development of Cosmetics, acting mainly on topics such as cosmetology, antioxidant activity, aesthetics, photoprotection, cyclodextrin and thermal analysis.",institutionString:null,institution:{name:"University of Sao Paulo",country:{name:"Brazil"}}},{id:"334285",title:"Ph.D. Student",name:"Sameer",middleName:"Kumar",surname:"Jagirdar",slug:"sameer-jagirdar",fullName:"Sameer Jagirdar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334285/images/14691_n.jpg",biography:"I\\'m a graduate student at the center for biosystems science and engineering at the Indian Institute of Science, Bangalore, India. I am interested in studying host-pathogen interactions at the biomaterial interface.",institutionString:null,institution:{name:"Indian Institute of Science Bangalore",country:{name:"India"}}},{id:"329795",title:"Dr.",name:"Mohd Aftab",middleName:"Aftab",surname:"Siddiqui",slug:"mohd-aftab-siddiqui",fullName:"Mohd Aftab Siddiqui",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329795/images/15648_n.jpg",biography:"Dr. Mohd Aftab Siddiqui is currently working as Assistant Professor in the Faculty of Pharmacy, Integral University, Lucknow for the last 6 years. He has completed his Doctor in Philosophy (Pharmacology) in 2020 from Integral University, Lucknow. He completed his Bachelor in Pharmacy in 2013 and Master in Pharmacy (Pharmacology) in 2015 from Integral University, Lucknow. He is the gold medalist in Bachelor and Master degree. He qualified GPAT -2013, GPAT -2014, and GPAT 2015. His area of research is Pharmacological screening of herbal drugs/ natural products in liver and cardiac diseases. He has guided many M. Pharm. research projects. He has many national and international publications.",institutionString:"Integral University",institution:null},{id:"255360",title:"Dr.",name:"Usama",middleName:null,surname:"Ahmad",slug:"usama-ahmad",fullName:"Usama Ahmad",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255360/images/system/255360.png",biography:"Dr. Usama Ahmad holds a specialization in Pharmaceutics from Amity University, Lucknow, India. He received his Ph.D. degree from Integral University. Currently, he’s working as an Assistant Professor of Pharmaceutics in the Faculty of Pharmacy, Integral University. From 2013 to 2014 he worked on a research project funded by SERB-DST, Government of India. He has a rich publication record with more than 32 original articles published in reputed journals, 3 edited books, 5 book chapters, and a number of scientific articles published in ‘Ingredients South Asia Magazine’ and ‘QualPharma Magazine’. He is a member of the American Association for Cancer Research, International Association for the Study of Lung Cancer, and the British Society for Nanomedicine. Dr. Ahmad’s research focus is on the development of nanoformulations to facilitate the delivery of drugs that aim to provide practical solutions to current healthcare problems.",institutionString:"Integral University",institution:{name:"Integral University",country:{name:"India"}}},{id:"30568",title:"Prof.",name:"Madhu",middleName:null,surname:"Khullar",slug:"madhu-khullar",fullName:"Madhu Khullar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/30568/images/system/30568.jpg",biography:"Dr. Madhu Khullar is a Professor of Experimental Medicine and Biotechnology at the Post Graduate Institute of Medical Education and Research, Chandigarh, India. She completed her Post Doctorate in hypertension research at the Henry Ford Hospital, Detroit, USA in 1985. She is an editor and reviewer of several international journals, and a fellow and member of several cardiovascular research societies. Dr. Khullar has a keen research interest in genetics of hypertension, and is currently studying pharmacogenetics of hypertension.",institutionString:"Post Graduate Institute of Medical Education and Research",institution:{name:"Post Graduate Institute of Medical Education and Research",country:{name:"India"}}},{id:"223233",title:"Prof.",name:"Xianquan",middleName:null,surname:"Zhan",slug:"xianquan-zhan",fullName:"Xianquan Zhan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/223233/images/system/223233.png",biography:"Xianquan Zhan received his MD and Ph.D. in Preventive Medicine at West China University of Medical Sciences. He received his post-doctoral training in oncology and cancer proteomics at the Central South University, China, and the University of Tennessee Health Science Center (UTHSC), USA. He worked at UTHSC and the Cleveland Clinic in 2001–2012 and achieved the rank of associate professor at UTHSC. Currently, he is a full professor at Central South University and Shandong First Medical University, and an advisor to MS/PhD students and postdoctoral fellows. He is also a fellow of the Royal Society of Medicine and European Association for Predictive Preventive Personalized Medicine (EPMA), a national representative of EPMA, and a member of the American Society of Clinical Oncology (ASCO) and the American Association for the Advancement of Sciences (AAAS). He is also the editor in chief of International Journal of Chronic Diseases & Therapy, an associate editor of EPMA Journal, Frontiers in Endocrinology, and BMC Medical Genomics, and a guest editor of Mass Spectrometry Reviews, Frontiers in Endocrinology, EPMA Journal, and Oxidative Medicine and Cellular Longevity. He has published more than 148 articles, 28 book chapters, 6 books, and 2 US patents in the field of clinical proteomics and biomarkers.",institutionString:"Shandong First Medical University",institution:{name:"Affiliated Hospital of Shandong Academy of Medical Sciences",country:{name:"China"}}},{id:"297507",title:"Dr.",name:"Charles",middleName:"Elias",surname:"Assmann",slug:"charles-assmann",fullName:"Charles Assmann",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/297507/images/system/297507.jpg",biography:"Charles Elias Assmann is a biologist from Federal University of Santa Maria (UFSM, Brazil), who spent some time abroad at the Ludwig-Maximilians-Universität München (LMU, Germany). He has Masters Degree in Biochemistry (UFSM), and is currently a PhD student at Biochemistry at the Department of Biochemistry and Molecular Biology of the UFSM. His areas of expertise include: Biochemistry, Molecular Biology, Enzymology, Genetics and Toxicology. He is currently working on the following subjects: Aluminium toxicity, Neuroinflammation, Oxidative stress and Purinergic system. Since 2011 he has presented more than 80 abstracts in scientific proceedings of national and international meetings. Since 2014, he has published more than 20 peer reviewed papers (including 4 reviews, 3 in Portuguese) and 2 book chapters. He has also been a reviewer of international journals and ad hoc reviewer of scientific committees from Brazilian Universities.",institutionString:"Universidade Federal de Santa Maria",institution:{name:"Universidade Federal de Santa Maria",country:{name:"Brazil"}}},{id:"217850",title:"Dr.",name:"Margarete Dulce",middleName:null,surname:"Bagatini",slug:"margarete-dulce-bagatini",fullName:"Margarete Dulce Bagatini",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/217850/images/system/217850.jpeg",biography:"Dr. Margarete Dulce Bagatini is an associate professor at the Federal University of Fronteira Sul/Brazil. She has a degree in Pharmacy and a PhD in Biological Sciences: Toxicological Biochemistry. She is a member of the UFFS Research Advisory Committee\nand a member of the Biovitta Research Institute. She is currently:\nthe leader of the research group: Biological and Clinical Studies\nin Human Pathologies, professor of postgraduate program in\nBiochemistry at UFSC and postgraduate program in Science and Food Technology at\nUFFS. She has experience in the area of pharmacy and clinical analysis, acting mainly\non the following topics: oxidative stress, the purinergic system and human pathologies, being a reviewer of several international journals and books.",institutionString:"Universidade Federal da Fronteira Sul",institution:{name:"Universidade Federal da Fronteira Sul",country:{name:"Brazil"}}},{id:"226275",title:"Ph.D.",name:"Metin",middleName:null,surname:"Budak",slug:"metin-budak",fullName:"Metin Budak",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/226275/images/system/226275.jfif",biography:"Metin Budak, MSc, PhD is an Assistant Professor at Trakya University, Faculty of Medicine. He has been Head of the Molecular Research Lab at Prof. Mirko Tos Ear and Hearing Research Center since 2018. His specializations are biophysics, epigenetics, genetics, and methylation mechanisms. He has published around 25 peer-reviewed papers, 2 book chapters, and 28 abstracts. He is a member of the Clinical Research Ethics Committee and Quantification and Consideration Committee of Medicine Faculty. His research area is the role of methylation during gene transcription, chromatin packages DNA within the cell and DNA repair, replication, recombination, and gene transcription. His research focuses on how the cell overcomes chromatin structure and methylation to allow access to the underlying DNA and enable normal cellular function.",institutionString:"Trakya University",institution:{name:"Trakya University",country:{name:"Turkey"}}},{id:"243049",title:"Dr.",name:"Anca",middleName:null,surname:"Pantea Stoian",slug:"anca-pantea-stoian",fullName:"Anca Pantea Stoian",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/243049/images/system/243049.jpg",biography:"Anca Pantea Stoian is a specialist in diabetes, nutrition, and metabolic diseases as well as health food hygiene. She also has competency in general ultrasonography.\n\nShe is an associate professor in the Diabetes, Nutrition and Metabolic Diseases Department, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania. She has been chief of the Hygiene Department, Faculty of Dentistry, at the same university since 2019. Her interests include micro and macrovascular complications in diabetes and new therapies. Her research activities focus on nutritional intervention in chronic pathology, as well as cardio-renal-metabolic risk assessment, and diabetes in cancer. She is currently engaged in developing new therapies and technological tools for screening, prevention, and patient education in diabetes. \n\nShe is a member of the European Association for the Study of Diabetes, Cardiometabolic Academy, CEDA, Romanian Society of Diabetes, Nutrition and Metabolic Diseases, Romanian Diabetes Federation, and Association for Renal Metabolic and Nutrition studies. She has authored or co-authored 160 papers in national and international peer-reviewed journals.",institutionString:null,institution:{name:"Carol Davila University of Medicine and Pharmacy",country:{name:"Romania"}}},{id:"279792",title:"Dr.",name:"João",middleName:null,surname:"Cotas",slug:"joao-cotas",fullName:"João Cotas",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/279792/images/system/279792.jpg",biography:"Graduate and master in Biology from the University of Coimbra.\n\nI am a research fellow at the Macroalgae Laboratory Unit, in the MARE-UC – Marine and Environmental Sciences Centre of the University of Coimbra. My principal function is the collection, extraction and purification of macroalgae compounds, chemical and bioactive characterization of the compounds and algae extracts and development of new methodologies in marine biotechnology area. \nI am associated in two projects: one consists on discovery of natural compounds for oncobiology. The other project is the about the natural compounds/products for agricultural area.\n\nPublications:\nCotas, J.; Figueirinha, A.; Pereira, L.; Batista, T. 2018. An analysis of the effects of salinity on Fucus ceranoides (Ochrophyta, Phaeophyceae), in the Mondego River (Portugal). Journal of Oceanology and Limnology. in press. DOI: 10.1007/s00343-019-8111-3",institutionString:"Faculty of Sciences and Technology of University of Coimbra",institution:null},{id:"279788",title:"Dr.",name:"Leonel",middleName:null,surname:"Pereira",slug:"leonel-pereira",fullName:"Leonel Pereira",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/279788/images/system/279788.jpg",biography:"Leonel Pereira has an undergraduate degree in Biology, a Ph.D. in Biology (specialty in Cell Biology), and a Habilitation degree in Biosciences (specialization in Biotechnology) from the Faculty of Science and Technology, University of Coimbra, Portugal, where he is currently a professor. In addition to teaching at this university, he is an integrated researcher at the Marine and Environmental Sciences Center (MARE), Portugal. His interests include marine biodiversity (algae), marine biotechnology (algae bioactive compounds), and marine ecology (environmental assessment). Since 2008, he has been the author and editor of the electronic publication MACOI – Portuguese Seaweeds Website (www.seaweeds.uc.pt). He is also a member of the editorial boards of several scientific journals. Dr. Pereira has edited or authored more than 20 books, 100 journal articles, and 45 book chapters. He has given more than 100 lectures and oral communications at various national and international scientific events. He is the coordinator of several national and international research projects. In 1998, he received the Francisco de Holanda Award (Honorable Mention) and, more recently, the Mar Rei D. Carlos award (18th edition). He is also a winner of the 2016 CHOICE Award for an outstanding academic title for his book Edible Seaweeds of the World. In 2020, Dr. Pereira received an Honorable Mention for the Impact of International Publications from the Web of Science",institutionString:"University of Coimbra",institution:{name:"University of Coimbra",country:{name:"Portugal"}}},{id:"61946",title:"Dr.",name:"Carol",middleName:null,surname:"Bernstein",slug:"carol-bernstein",fullName:"Carol Bernstein",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/61946/images/system/61946.jpg",biography:"Carol Bernstein received her PhD in Genetics from the University of California (Davis). She was a faculty member at the University of Arizona College of Medicine for 43 years, retiring in 2011. Her research interests focus on DNA damage and its underlying role in sex, aging and in the early steps of initiation and progression to cancer. In her research, she had used organisms including bacteriophage T4, Neurospora crassa, Schizosaccharomyces pombe and mice, as well as human cells and tissues. She authored or co-authored more than 140 scientific publications, including articles in major peer reviewed journals, book chapters, invited reviews and one book.",institutionString:"University of Arizona",institution:{name:"University of Arizona",country:{name:"United States of America"}}},{id:"182258",title:"Dr.",name:"Ademar",middleName:"Pereira",surname:"Serra",slug:"ademar-serra",fullName:"Ademar Serra",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/182258/images/system/182258.jpeg",biography:"Dr. Serra studied Agronomy on Universidade Federal de Mato Grosso do Sul (UFMS) (2005). He received master degree in Agronomy, Crop Science (Soil fertility and plant nutrition) (2007) by Universidade Federal da Grande Dourados (UFGD), and PhD in agronomy (Soil fertility and plant nutrition) (2011) from Universidade Federal da Grande Dourados / Escola Superior de Agricultura Luiz de Queiroz (UFGD/ESALQ-USP). Dr. Serra is currently working at Brazilian Agricultural Research Corporation (EMBRAPA). His research focus is on mineral nutrition of plants, crop science and soil science. Dr. Serra\\'s current projects are soil organic matter, soil phosphorus fractions, compositional nutrient diagnosis (CND) and isometric log ratio (ilr) transformation in compositional data analysis.",institutionString:"Brazilian Agricultural Research Corporation",institution:{name:"Brazilian Agricultural Research Corporation",country:{name:"Brazil"}}}]}},subseries:{item:{id:"7",type:"subseries",title:"Bioinformatics and Medical Informatics",keywords:"Biomedical Data, Drug Discovery, Clinical Diagnostics, Decoding Human Genome, AI in Personalized Medicine, Disease-prevention Strategies, Big Data Analysis in Medicine",scope:"Bioinformatics aims to help understand the functioning of the mechanisms of living organisms through the construction and use of quantitative tools. The applications of this research cover many related fields, such as biotechnology and medicine, where, for example, Bioinformatics contributes to faster drug design, DNA analysis in forensics, and DNA sequence analysis in the field of personalized medicine. Personalized medicine is a type of medical care in which treatment is customized individually for each patient. Personalized medicine enables more effective therapy, reduces the costs of therapy and clinical trials, and also minimizes the risk of side effects. Nevertheless, advances in personalized medicine would not have been possible without bioinformatics, which can analyze the human genome and other vast amounts of biomedical data, especially in genetics. The rapid growth of information technology enabled the development of new tools to decode human genomes, large-scale studies of genetic variations and medical informatics. The considerable development of technology, including the computing power of computers, is also conducive to the development of bioinformatics, including personalized medicine. In an era of rapidly growing data volumes and ever lower costs of generating, storing and computing data, personalized medicine holds great promises. Modern computational methods used as bioinformatics tools can integrate multi-scale, multi-modal and longitudinal patient data to create even more effective and safer therapy and disease prevention methods. Main aspects of the topic are: Applying bioinformatics in drug discovery and development; Bioinformatics in clinical diagnostics (genetic variants that act as markers for a condition or a disease); Blockchain and Artificial Intelligence/Machine Learning in personalized medicine; Customize disease-prevention strategies in personalized medicine; Big data analysis in personalized medicine; Translating stratification algorithms into clinical practice of personalized medicine.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/7.jpg",hasOnlineFirst:!0,hasPublishedBooks:!0,annualVolume:11403,editor:{id:"351533",title:"Dr.",name:"Slawomir",middleName:null,surname:"Wilczynski",slug:"slawomir-wilczynski",fullName:"Slawomir Wilczynski",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000035U1loQAC/Profile_Picture_1630074514792",biography:"Professor Sławomir Wilczyński, Head of the Chair of Department of Basic Biomedical Sciences, Faculty of Pharmaceutical Sciences, Medical University of Silesia in Katowice, Poland. His research interests are focused on modern imaging methods used in medicine and pharmacy, including in particular hyperspectral imaging, dynamic thermovision analysis, high-resolution ultrasound, as well as other techniques such as EPR, NMR and hemispheric directional reflectance. Author of over 100 scientific works, patents and industrial designs. Expert of the Polish National Center for Research and Development, Member of the Investment Committee in the Bridge Alfa NCBiR program, expert of the Polish Ministry of Funds and Regional Policy, Polish Medical Research Agency. Editor-in-chief of the journal in the field of aesthetic medicine and dermatology - Aesthetica.",institutionString:null,institution:{name:"Medical University of Silesia",institutionURL:null,country:{name:"Poland"}}},editorTwo:null,editorThree:null,series:{id:"7",title:"Biomedical Engineering",doi:"10.5772/intechopen.71985",issn:"2631-5343"},editorialBoard:[{id:"5886",title:"Dr.",name:"Alexandros",middleName:"T.",surname:"Tzallas",slug:"alexandros-tzallas",fullName:"Alexandros Tzallas",profilePictureURL:"https://mts.intechopen.com/storage/users/5886/images/system/5886.png",institutionString:"University of Ioannina, Greece & Imperial College London",institution:{name:"University of Ioannina",institutionURL:null,country:{name:"Greece"}}},{id:"257388",title:"Distinguished Prof.",name:"Lulu",middleName:null,surname:"Wang",slug:"lulu-wang",fullName:"Lulu Wang",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRX6kQAG/Profile_Picture_1630329584194",institutionString:null,institution:{name:"Shenzhen Technology University",institutionURL:null,country:{name:"China"}}},{id:"225387",title:"Prof.",name:"Reda R.",middleName:"R.",surname:"Gharieb",slug:"reda-r.-gharieb",fullName:"Reda R. 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