\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\\n"}]',published:!0,mainMedia:{caption:"Highly Cited",originalUrl:"/media/original/117"}},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 191 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 261 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\n'}],latestNews:[{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"},{slug:"intechopen-identified-as-one-of-the-most-significant-contributor-to-oa-book-growth-in-doab-20210809",title:"IntechOpen Identified as One of the Most Significant Contributors to OA Book Growth in DOAB"}]},book:{item:{type:"book",id:"8844",leadTitle:null,fullTitle:"Mechanics of Functionally Graded Materials and Structures",title:"Mechanics of Functionally Graded Materials and Structures",subtitle:null,reviewType:"peer-reviewed",abstract:"The Functionally Graded Materials (FGM) concept originated in Japan in 1984 during the spaceplane project, in the form of a proposed thermal barrier material capable of withstanding a surface temperature of 2000 K and a temperature gradient of 1000 K across a cross section <10 mm. The materials can be designed for specific function and applications. FGMs offer great promise in applications where the operating conditions are extreme. For example, wear-resistant linings for handling large, heavy, abrasive ore particles; rocket heat shields; heat exchanger tubes; thermoelectric generators; heat-engine components; plasma facings for fusion reactors; and electrically insulating metal/ceramic joints. They are also ideal for minimizing thermomechanical mismatch in metal-ceramic bonding. This book is a result of contributions of experts from the international scientific community working in different aspects of functionally graded materials and structures and reports on the latest research and development findings on this topic through original and innovative research studies. Through its six chapters, the reader will have access to works related to processing, characteristics, modeling, and applications of functionally graded materials and structures.The book contains up-to-date publications from leading experts and the edition is intended to provide valuable recent information to the professionals involved in functionally graded materials and structure analysis and applications. The text is addressed not only to researchers, but also to professional engineers, students, and other experts in a variety of disciplines, both academic and industrial, seeking to gain a better understanding of what has been done in the field recently, and what open problems are in this area.",isbn:"978-1-78984-555-6",printIsbn:"978-1-78984-554-9",pdfIsbn:"978-1-83968-404-3",doi:"10.5772/intechopen.81347",price:119,priceEur:129,priceUsd:155,slug:"mechanics-of-functionally-graded-materials-and-structures",numberOfPages:126,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"dcaee033a035bfe8daa8ffa06b37b25f",bookSignature:"Farzad Ebrahimi",publishedDate:"January 8th 2020",coverURL:"https://cdn.intechopen.com/books/images_new/8844.jpg",numberOfDownloads:4535,numberOfWosCitations:0,numberOfCrossrefCitations:1,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:3,numberOfDimensionsCitationsByBook:1,hasAltmetrics:0,numberOfTotalCitations:4,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"October 30th 2018",dateEndSecondStepPublish:"December 18th 2018",dateEndThirdStepPublish:"February 16th 2019",dateEndFourthStepPublish:"May 7th 2019",dateEndFifthStepPublish:"July 6th 2019",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6,7",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"20062",title:"Dr.",name:"Farzad",middleName:null,surname:"Ebrahimi",slug:"farzad-ebrahimi",fullName:"Farzad Ebrahimi",profilePictureURL:"https://mts.intechopen.com/storage/users/20062/images/system/20062.jpg",biography:"Dr. Farzad Ebrahimi is an Associte Professor since 2010 in Mechanical Engineering at Imam Khomeini International University, Qazvin, Iran. He has several years of teaching and industrial experience. Since 2002, he has been working at the \\\\\\Smart Materials and Structures Lab\\\\\\ Research Center of the Faculty of Mechanical Engineering at the University of Tehran, where he is a researcher of smart functionally graded materials and structures. He is involved in several international journals as editor and reviewer. He serves on the editorial board for \\\\\\Advances in mechanical engineering\\\\\\. He is the author of the books “Smart functionally graded plates” and “Progress in analysis of functionally graded structures”, Nova Science Publishers, NY. He has authored several referred international journals and conferences. His research interests focus on areas of smart materials and structures, Mechanics of Nanostructures; functionally graded materials and structures, finite element analysis; Mechanics of composite materials and structures and modeling and mechanical analysis of smart and multifunctional nanostructures and he has published several researches in these fields. His research in these areas has been presented at international conferences and has appeared in academic journals such as Composite structures; Applied physics A; Journal of Intelligent materials and Structures; Smart Materials and Structures; European Journal of Mechanics; Archive of Applied Mechanics and journal of vibration and control.",institutionString:"Imam Khomeini International University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"7",institution:null}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"817",title:"Material Engineering",slug:"material-engineering"}],chapters:[{id:"66810",title:"Free Vibration of Axially Functionally Graded Beam",doi:"10.5772/intechopen.85835",slug:"free-vibration-of-axially-functionally-graded-beam",totalDownloads:1117,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Axially functionally graded (AFG) beam is a special kind of nonhomogeneous functionally gradient material structure, whose material properties vary continuously along the axial direction of the beam by a given distribution form. There are several numerical methods that have been used to analyze the vibration characteristics of AFG beams, but it is difficult to obtain precise solutions for AFG beams because of the variable coefficients of the governing equation. In this topic, the free vibration of AFG beam using analytical method based on the perturbation theory and Meijer G-Function are studied, respectively. First, a detailed review of the existing literatures is summarized. Then, based on the governing equation of the AFG Euler-Bernoulli beam, the detailed analytic equations are derived on basis of the perturbation theory and Meijer G-function, where the nature frequencies are demonstrated. Subsequently, the numerical results are calculated and compared, meanwhile, the analytical results are also confirmed by finite element method and the published references. The results show that the proposed two analytical methods are simple and efficient and can be used to conveniently analyze free vibration of AFG beam.",signatures:"Dongxing Cao, Bin Wang, Wenhua Hu and Yanhui Gao",downloadPdfUrl:"/chapter/pdf-download/66810",previewPdfUrl:"/chapter/pdf-preview/66810",authors:[{id:"283678",title:"Prof.",name:"Dongxing",surname:"Cao",slug:"dongxing-cao",fullName:"Dongxing Cao"},{id:"295692",title:"Mr.",name:"Bin",surname:"Wang",slug:"bin-wang",fullName:"Bin Wang"},{id:"295693",title:"Dr.",name:"Wenhua",surname:"Hu",slug:"wenhua-hu",fullName:"Wenhua Hu"},{id:"295694",title:"Mr.",name:"Yanhui",surname:"Gao",slug:"yanhui-gao",fullName:"Yanhui Gao"}],corrections:null},{id:"68846",title:"Boundary Element Model for Nonlinear Fractional-Order Heat Transfer in Magneto-Thermoelastic FGA Structures Involving Three Temperatures",doi:"10.5772/intechopen.88255",slug:"boundary-element-model-for-nonlinear-fractional-order-heat-transfer-in-magneto-thermoelastic-fga-str",totalDownloads:759,totalCrossrefCites:0,totalDimensionsCites:2,hasAltmetrics:0,abstract:"The principal objective of this chapter is to introduce a new fractional-order theory for functionally graded anisotropic (FGA) structures. This theory called nonlinear uncoupled magneto-thermoelasticity theory involving three temperatures. Because of strong nonlinearity, it is very difficult to solve the problems related to this theory analytically. Therefore, it is necessary to develop new numerical methods for solving such problems. So, we propose a new boundary element model for the solution of general and complex problems associated with this theory. The numerical results are presented graphically in order to display the effect of the graded parameter on the temperatures and displacements. The numerical results also confirm the validity and accuracy of our proposed model.",signatures:"Mohamed Abdelsabour Fahmy",downloadPdfUrl:"/chapter/pdf-download/68846",previewPdfUrl:"/chapter/pdf-preview/68846",authors:[{id:"283892",title:"Associate Prof.",name:"Mohamed",surname:"Fahmy",slug:"mohamed-fahmy",fullName:"Mohamed Fahmy"}],corrections:null},{id:"66230",title:"DC Conductivity of Activated Carbon Filled Epoxy Gradient Composites",doi:"10.5772/intechopen.85233",slug:"dc-conductivity-of-activated-carbon-filled-epoxy-gradient-composites",totalDownloads:690,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"This chapter reports the DC conductivity behavior of activated carbon powder filled epoxy gradient composites. Gradient composites are the composite materials in which the there is gradually variation in some direction to achieve gradient in properties. Graded materials are generally defined as the materials, which exhibit variable functional performance with location and show continuous variations in morphology and composition. Functionally graded metal matrix composites have been of great practical importance. Graded metal matrix composite have gradual compositional variations from ceramic at one surface to metal at the other, leading to special advantages of smooth transition in thermal stresses across the thickness and minimized stress concentration at the interface of two dissimilar materials. Therefore graded metal matrix composites are finding applications in aggressive environments with steep temperature gradients such as turbine components and rocket nozzles. Since the properties of material in FGMs are variable across the entire material, and depends on the spatial position of the material. Functionally graded materials are designed with varying properties such as changing their chemical properties, changing mechanical, magnetic, thermal, and electrical properties. Now a days there are FGMs designed as stepwise-graded materials, while others are fabricated to have continuous-graded materials depending on their areas of application.",signatures:"Archana Nigrawal",downloadPdfUrl:"/chapter/pdf-download/66230",previewPdfUrl:"/chapter/pdf-preview/66230",authors:[{id:"257011",title:"Dr.",name:"Archana",surname:"Nigrawal",slug:"archana-nigrawal",fullName:"Archana Nigrawal"}],corrections:null},{id:"66961",title:"The Stochastic Finite Element in the Natural Frequency of Functionally Graded Material Beams",doi:"10.5772/intechopen.86013",slug:"the-stochastic-finite-element-in-the-natural-frequency-of-functionally-graded-material-beams",totalDownloads:693,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"In this study, the stochastic finite element solution is given to obtain the variability in the natural frequency of functionally graded material (FGM) beam. The elastic modulus is assumed to vary in the thickness direction and the width of the beam to vary as well in the longitudinal direction following the exponential law. The random material properties of elastic modulus and mass density of the FGM beam are assumed to be one-dimensional homogeneous stochastic processes. The stochastic finite element analysis of FGM beam is performed in conjunction with Monte Carlo simulation (MCS) employing the spectral representation method for 16, the description of random processes of the random material properties under consideration. The response variability of the natural frequency due to random elastic modulus is evaluated for various states of randomness. Furthermore, the investigation on the effect of the correlation between random elastic modulus and random mass density on the response variability is addressed in detail as well.",signatures:"Nguyen Van Thuan and Noh Hyuk Chun",downloadPdfUrl:"/chapter/pdf-download/66961",previewPdfUrl:"/chapter/pdf-preview/66961",authors:[{id:"287934",title:"Dr.",name:"Nguyen",surname:"Van Thuan",slug:"nguyen-van-thuan",fullName:"Nguyen Van Thuan"}],corrections:null},{id:"67159",title:"Development of Functionally Gradient Cu-Sn-Ni Alloy Using GTA Heat Source",doi:"10.5772/intechopen.86315",slug:"development-of-functionally-gradient-cu-sn-ni-alloy-using-gta-heat-source",totalDownloads:643,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The impact of nickel content on surface hardness, microstructure and wear properties of surface alloyed Cu-10Sn bronze composite was examined in this chapter. Gas Tungsten Arc (GTA) was utilized as the heat source for the surface alloying/modification process. The surface modification process was carried out on bronze samples coated with various Nickel coating thicknesses. Vickers hardness tester was used to measure the surface hardness as well as the hardness along the depth of the modified layer and wear rate was measured using a pin-on-disc tribometer. The Ni concentration profiling was carried out using EDAX. Surface modification process resulted in the formation of a layered functionally graded bronze alloy. The average grain size was found to reduce upon surface modification process. Ni addition was observed to increase the hardness and reduce wear rate for the modified samples.",signatures:"Cherian Paul and Ramasamy Sellamuthu",downloadPdfUrl:"/chapter/pdf-download/67159",previewPdfUrl:"/chapter/pdf-preview/67159",authors:[{id:"295062",title:"Dr.",name:"Cherian",surname:"Paul",slug:"cherian-paul",fullName:"Cherian Paul"},{id:"298259",title:"Dr.",name:"Ramasamy",surname:"Sellamuthu",slug:"ramasamy-sellamuthu",fullName:"Ramasamy Sellamuthu"}],corrections:null},{id:"69315",title:"Axisymmetric Indentation Response of Functionally Graded Material Coating",doi:"10.5772/intechopen.89312",slug:"axisymmetric-indentation-response-of-functionally-graded-material-coating",totalDownloads:637,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"In this chapter, the indentation response of the functionally graded material (FGM) coating is considered due to the contact between the coating and axisymmetric indenter. The mechanical properties of FGM coating is assumed to vary along the thickness direction. Three kinds of models are applied to simulate the variation of elastic parameter in the FGM coating based on the cylindrical coordinate system. The axisymmetric frictionless and partial slip contact problems are reduced to a set of Cauchy singular integral equations that can be numerically calculated by using the Hankel integral transform technique and the transfer matrix method. The effect of gradient of coating on the distribution of contact stress is presented. The present investigation will provide the guidance for the indentation experiment of coating.",signatures:"Tie-Jun Liu",downloadPdfUrl:"/chapter/pdf-download/69315",previewPdfUrl:"/chapter/pdf-preview/69315",authors:[{id:"305673",title:"Prof.",name:"Tiejun",surname:"Liu",slug:"tiejun-liu",fullName:"Tiejun Liu"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"111",title:"Advances in Vibration Analysis Research",subtitle:null,isOpenForSubmission:!1,hash:"37f0b30e647599448abb4a02ca595dde",slug:"advances-in-vibration-analysis-research",bookSignature:"Farzad Ebrahimi",coverURL:"https://cdn.intechopen.com/books/images_new/111.jpg",editedByType:"Edited by",editors:[{id:"20062",title:"Dr.",name:"Farzad",surname:"Ebrahimi",slug:"farzad-ebrahimi",fullName:"Farzad Ebrahimi"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5097",title:"Advances in Functionally Graded Materials and Structures",subtitle:null,isOpenForSubmission:!1,hash:"3132c367d705b55e9a912527efef76ab",slug:"advances-in-functionally-graded-materials-and-structures",bookSignature:"Farzad Ebrahimi",coverURL:"https://cdn.intechopen.com/books/images_new/5097.jpg",editedByType:"Edited by",editors:[{id:"20062",title:"Dr.",name:"Farzad",surname:"Ebrahimi",slug:"farzad-ebrahimi",fullName:"Farzad Ebrahimi"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6244",title:"Surface Waves",subtitle:"New Trends and Developments",isOpenForSubmission:!1,hash:"48a2c4d0d993b62e4fe46a77a7a6cc4c",slug:"surface-waves-new-trends-and-developments",bookSignature:"Farzad Ebrahimi",coverURL:"https://cdn.intechopen.com/books/images_new/6244.jpg",editedByType:"Edited by",editors:[{id:"20062",title:"Dr.",name:"Farzad",surname:"Ebrahimi",slug:"farzad-ebrahimi",fullName:"Farzad Ebrahimi"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"4753",title:"Graphene",subtitle:"New Trends and Developments",isOpenForSubmission:!1,hash:"7a2a89285055016ae39942309f30c4b5",slug:"graphene-new-trends-and-developments",bookSignature:"Farzad Ebrahimi",coverURL:"https://cdn.intechopen.com/books/images_new/4753.jpg",editedByType:"Edited by",editors:[{id:"20062",title:"Dr.",name:"Farzad",surname:"Ebrahimi",slug:"farzad-ebrahimi",fullName:"Farzad Ebrahimi"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6020",title:"Shape Memory Alloys",subtitle:"Fundamentals and Applications",isOpenForSubmission:!1,hash:"89ba319783170fefc256fcfa0613a6c0",slug:"shape-memory-alloys-fundamentals-and-applications",bookSignature:"Farzad Ebrahim",coverURL:"https://cdn.intechopen.com/books/images_new/6020.jpg",editedByType:"Edited by",editors:[{id:"20062",title:"Dr.",name:"Farzad",surname:"Ebrahimi",slug:"farzad-ebrahimi",fullName:"Farzad Ebrahimi"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3272",title:"Piezoelectric Materials and Devices",subtitle:"Practice and Applications",isOpenForSubmission:!1,hash:"a41c5bb092cc30980df760d6bec44c20",slug:"piezoelectric-materials-and-devices-practice-and-applications",bookSignature:"Farzad Ebrahimi",coverURL:"https://cdn.intechopen.com/books/images_new/3272.jpg",editedByType:"Edited by",editors:[{id:"20062",title:"Dr.",name:"Farzad",surname:"Ebrahimi",slug:"farzad-ebrahimi",fullName:"Farzad Ebrahimi"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5271",title:"Advances in Tribology",subtitle:null,isOpenForSubmission:!1,hash:"cef4274b28d575de81e692b8d88b750d",slug:"advances-in-tribology",bookSignature:"Pranav H. 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Some of these issues, like privacy or intellectual property, have existed for a long time, but the extent, depth and speed of dissemination allowed by new digital technologies have created an entirely new array of ethical problems. Digital Ethics or Cyber Ethics has earned a unique position in the realm of Applied Ethics. Twenty or so years ago, ethicist philosophers formulated the legendary runaway trolley dilemma, with no idea that it would become a critical issue in the design and operation of self-driving cars. On the other hand, Robotics, Artificial Intelligence, Bioinformatics, Nanotechnology and the Internet of Things, to mention just a few of the emerging and converging new technologies, have challenged us with ethical issues never imagined before. Discussing these new and transformed ethical issues is critical to understanding how new digital technologies will shape our lives in the near and distant future. This book aims to collect the contributions of international experts in the fields of Engineering, Computer Science and Philosophy to address these issues and to formulate solutions to the challenges they create.
",isbn:null,printIsbn:"979-953-307-X-X",pdfIsbn:null,doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,isSalesforceBook:!1,hash:"9119dac235241d72c012b2b3391b3390",bookSignature:"Dr. Orlando Baiocchi",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/8567.jpg",keywords:"Online Communities, Social Networks, Big Data, Data Mining, Cloud Computing, Roboethics, Autonomous Machines, Robot Soldiers, Emerging/Converging Technologies, Nanotechnology, Virtual Reality, Bioinformatics, Internet of Things, Cybercrimes, Privacy and Security, Denial of Service, Cyber Terrorism, Ambient Intelligence, Moral Agents, Machine Learning, Nanobots",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"March 21st 2019",dateEndSecondStepPublish:"April 11th 2019",dateEndThirdStepPublish:"November 30th 2019",dateEndFourthStepPublish:"August 29th 2019",dateEndFifthStepPublish:"February 29th 2020",remainingDaysToSecondStep:"3 years",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:null,coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"228587",title:"Dr.",name:"Orlando",middleName:null,surname:"Baiocchi",slug:"orlando-baiocchi",fullName:"Orlando Baiocchi",profilePictureURL:"https://mts.intechopen.com/storage/users/228587/images/system/228587.jpg",biography:"Orlando R Baiocchi is a University of Washington Tacoma Endowed Professor in Engineering Systems. He has BS and MS degrees in Electrical and Civil Engineering from Brazilian universities and a Ph.D. in Electrical Engineering from the University College London, UK. He has extensive experience in academic administration, international cooperation, teaching, and research both in Brazil and in the United States. His areas of expertise and interest include Electromagnetics, Linear and Nonlinear Wave Propagation, Wireless Sensor Networks, Energy Harvesting, Engineering Education, Technology and Society, and Cyber Ethics. 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The development and the severity of liver fibrosis in those children are strongly related to the extent of the liver iron overload and to the presence of chronic hepatitis C. Chronic hepatitis C (CHC) in most infected patients lead to the development of liver fibrosis, cirrhosis, portal hypertension and hepatocellular carcinoma. Therefore, all persons with positive anti-HCV antibody tests must undergo additional testing for the presence of the HCV itself using polymerase chain reaction (PCR). Combined pegylated interferon-α and ribavirin with its limitations and serious complications remained the standard therapy for pediatric HCV infections until early 2017. Fortunately, the recent development of the direct-acting antiviral agents (DAAs) and the FDA approval of ledipasvir/sofosbuvir in the adult dose, to treat HCV in children and adolescents aged 12 years and older or weighing at least 35 kilograms has revolutionized the treatment of HCV infection.
The prevalence of HCV is increasing and estimates of the future burden of CHC predict at least a threefold rise in chronic liver disease and cirrhosis by the year 2020 [1].
About 3% of the worldwide population is infected by HCV with a significant racial difference. Males are more commonly affected than females due to frequent exposure to intravenous drug and alcohol abuse. Females are frequently infected from blood product transfusions [2]. The most affected regions are Eastern Mediterranean and European Regions [3]. Egypt has possibly the highest HCV prevalence in the world where 10–20% of the general population is infected [3]. The prevalence of HCV in North Egypt and South Egypt is 15.8 and 6.7%, respectively [4].
The prevalence of HCV infection is relatively low in children. Asymptomatic HCV is detectable in 2.02% of Egyptian children [5]. However, seroprevalence rates of 10–20% have been reported among children who received blood products for conditions such as thalassemia or hemophilia or those with a variety of other potential exposures such as malignancy, hemodialysis, extracorporeal membrane oxygen, or surgery for different reasons [6, 7]. A study in Mid-Delta, Egypt, reports 40% of patients with thalassemia are infected with HCV [8].
Hepatitis C virus is small, single-stranded, enveloped RNA virus of the flaviviridae family [9]. The only natural host is man. Currently, there are six HCV genotypes and many subtypes (1a, 1b, 1c, etc.). All HCV genotypes have a common ancestor virus. However, HCV genotypes 1, 2 and 4 are more prevalent in Central and Western Africa, genotype 5 in South Africa and genotypes 3 and 6 in China, South-East Asia and the Indian subcontinent [10]. Genotype 4 is widespread in East Africa and Egypt [11]. Approximately 90% of Egyptian HCV isolates belong to a single subtype, 4a, which responds less successfully to interferon therapy than other subtypes [12].
The main mode of transmission in children has changed over time. Before 1990, when HCV had not been identified, transfusion of blood and blood products and organ transplantation were the usual mode of transmission. One of the major routes of transmission is the reuse or inadequate sterilization of medical equipment, especially syringes and needles in healthcare settings. Currently, perinatal transmission accounts for most of cases [13].
Vertical transmission is almost always confined to women with detectable HCV RNA. The rate of vertical transmission is approximately 5%. Mothers with higher titers of HCV RNA and those who are HIV positive are more liable to pass the infection to their babies with transmission rates varying from 2 to 12%, according to maternal infectivity. Hepatitis C antibody is passively transmitted, and so all infants will have HCV antibody for up to 13–18 months. Measurement of HCV RNA is necessary to detect active infection, but it is unreliable before 3 months of age. Breastfeeding is safe in mothers with low titers of HCV RNA [14]. In children with beta thalassemia, the blood transfusion is not the only way of transmission but community and environmental factors may play a role [8].
Multicenter cross-sectional studies have reported that the development and the severity of liver fibrosis are strongly related to the extent of the liver iron overload and to the presence of chronic HCV infection [15]. HCV infection is the main risk factor for liver fibrosis in transfusion-dependent thalassemia. Excess liver iron is now clearly recognized as a cofactor for the development of advanced fibrosis in patients with HCV infection [16]. Despite its clinical relevance, thalassemia-associated liver damage has been insufficiently characterized [17].
Most of HCV-RNA negative patients with low iron load did not develop liver fibrosis, while HCV-RNA positive patients infected with genotype 1 or 4 and iron overload more frequently developed advanced fibrosis. Adequate chelation therapy usually prevents the development of liver fibrosis in patients free of HCV infection and reduces the risk of developing severe fibrosis in thalassemics with chronic hepatitis C (CHC) [15].
Hepatitis C virus infection is responsible for 80–90% of post transfusion cases of hepatitis in patients who have received blood transfusions (more than 75% of HCV infection become chronic and up to 20–30% progress to cirrhosis) [18]. The main causes of liver fibrosis in transfusion-dependent thalassemia major are HCV infection and hepatic iron overload [16].
Chronic hepatitis in most infected patients lead to the development of liver fibrosis, cirrhosis and hepatocellular carcinoma. Patients with HCV have mildly to moderately increased hepatic iron concentration and occasionally have severe hepatic iron overload [13]. The increased iron stores may be due to release from damaged hepatocytes, to the virus itself or to genetic determinants so that the iron can influence the progression of chronic hepatitis C [19].
In patients with CHC, the degree of liver fibrosis and hepatic iron concentration were correlated. However, this correlation cannot be translated as a causal relation. It is not clear whether this correlation merely reflects the presence of more active disease or iron exacerbates chronic HCV-induced damage through activation of hepatic stellate cells (HSC) and regeneration of hepatocytes [20].
Iron overload induces oxidative stress leading to cell membrane damage, DNA instability and mutagenesis [21]. Due to these effects, iron can be considered a proinflammatory, profibrogenic factor and a potential carcinogen [22].
Increased hepatic iron potentiates progression toward liver fibrosis and contributes to poor response to interferon therapy [18]. There is evidence that excess iron is known to promote oxidative stress and cause direct liver damage and accelerate progression to both micronodular cirrhosis and hepatocellular carcinoma [23]. Based on the above-mentioned observations, iron overload has been suggested as a negative prognostic factor of chronic hepatitis C with influence on the increased aminotransferase activity, exacerbation of inflammation, progression of liver fibrosis and decrease in antiviral therapy effectiveness [24]. Iron accumulation in the liver induces oxidative stress which accelerates lipid peroxidation, resulting in destruction of organelle membrane and cell death via hepatocyte necrosis or/and apoptosis [25]. Also, oxidative stress products induce a focal inflammatory reaction which in turn stimulates hepatic macrophages and release of profibrogenic cytokines [26]. These mechanisms trigger the activation of hepatic stellate cells (HSC) which are major sources of collagen and other extracellular matrix elements that gradually accumulate in perisinusoidal spaces of liver parenchyma [27]. Longer hepatocyte exposure to excess iron is associated with greater risk of progressive fibrosis and development of liver cirrhosis with irreversible nodular reconstruction of the organ, replacement of the functional liver parenchyma with the connective tissue and loss of function [28]. Due to these effects, there is evidence that moderate to severe liver iron concentration and chronic HCV infection in thalassemia patients have a potentiating effect on hepatic fibrogenesis [29].
Acute HCV infection becomes chronic in 70% of patients, which represents a high rate of chronicity for a viral infection. Most patients with CHC and compensated hepatic synthetic functions are usually asymptomatic. They may have nonspecific complaints like fatigue or malaise. However, patients with decompensated cirrhosis post HCV infection have the same symptoms observed in other patients with decompensated liver diseases.
Manifestations in patients with decompensated liver disease occur merely due to synthetic dysfunction and portal hypertension. These include mental status changes (hepatic encephalopathy), ankle edema and abdominal distention (ascites), and hematemesis or melena (variceal bleeding). Sometimes, extrahepatic manifestations of HCV are the first symptoms observed; most commonly, it involves the joints, muscle and skin [30].
As most patients of hepatitis C experience no or non-specific symptoms during acute phase, they usually do not seek medical advice and diagnosis is rarely made at this phase of the disease. The clinical diagnosis of hepatitis C in chronic phase is also challenging as the patient may spend decades with compensated liver functions lacking any specific symptoms until advanced liver disease develops [31].
Chronic hepatitis C may be suspected clinically on the basis of the medical history. A history of unsafe injections as IV drug abuse or inhaled substance usage, such as cocaine, piercings or tattoos, sharing toothbrushes or personal sharp objects (e.g. nail scissors or cutters) with HCV patient raise the suspicion of HCV infection. Unexplained easy fatigability, with abnormal liver enzymes or liver function tests found during routine blood testing may be the clue. Also, hepatitis C may be diagnosed as a result of targeted screening; such as screening of blood donors or HCV contact tracing [32].
Diagnosis of HCV can never be made on clinical bases only. Serological blood test is the first step in diagnosis. The test is used to detect antibodies to HCV. Anti-HCV antibodies can be detected in 80% of patients within 15 weeks after exposure, in >90% within 5 months, and in >97% by 6 months after exposure and may persist for life even in treated patients. This makes the test more valuable to diagnose infection but not to test cure of HCV chronic infection. HCV antibody tests have a strong positive predictive value for exposure to HCV but may miss patients in early phase who have not yet developed antibodies, or those who have an insufficient level of antibodies to detect [31, 32].
Immunocompromised individuals infected with HCV may never develop antibodies to the virus. So, using HCV antibody test is of no value in screening immuncompromised patients for HCV, and they should be screened using a test to detect the virus itself if HCV infection is suspected [33].
Anti-HCV antibodies indicate exposure to the virus but cannot determine the presence of ongoing infection. So, all persons with positive serology must undergo additional testing to confirm the presence of current infection. Molecular nucleic acid testing methods, such as polymerase chain reaction (PCR) are used to test the presence of virus RNA in the blood [34]. HCV RNA PCR is a quantitative test that has the capacity to detect not only the presence but also the amount of virus copies present in the blood which is also known as “viral load”. HCV viral load neither indicate disease severity nor prognosis. It was a predictor of response to interferon-based therapy but not important now with the current therapy [33].
Genotype testing was generally recommended before therapy as it was used to determine the required length and potential response to interferon-based therapy. This concept was changed with the introduction of direct-acting antiviral drugs [35].
The treatment of HCV infection in children was difficult as few options were available. The standard therapy for children aged 3 years and older was combined pegylated interferon (PEG-IFN) α-2a or 2b and ribavirin, and the duration of therapy was dependent on HCV genotype. This treatment regimen was developed first in adults [36, 37]. Combined pegylated interferon-α and ribavirin with its limitations and serious complications remained the standard therapy for pediatric HCV infections till 2017 [38].
In recent years, many direct-acting antiviral agents (DAAs) are under development for treatment of CHC. DAAs reduce the amount of HCV in the body by blocking viral replication inhibiting directly one of the several steps of the HCV lifecycle preventing the virus from multiplying, and in most cases, they cure HCV. DAAs are classified into several categories based on their molecular target [39, 40]. The recent development of DAAs has shown promising results in clinical trials for use in children and adults and has dramatically increased the rates of sustained virological response (SVR) while improving side effect profiles as compared to interferon-based treatments [41]. Prior to 2017, new DAAs available for adults have still not been approved for treatment in children [37, 38, 41, 42].
Recently (on April 7, 2017), the US Food and Drug Administration (FDA) approved the first DAAs for children that included sofosbuvir (Sovaldi) and sofosbuvir/ledipasvir (Harvoni) to treat HCV in children and adolescents aged 12 years and older or weighing at least 35 kg. These DAAs (Harvoni and Sovaldi) were previously approved to treat HCV in adults. These approvals will help change the landscape for HCV treatment by addressing an unmet need in children and adolescents [43]. The adult fixed-dose of ledipasvir/sofosbuvir, 90/400 mg, resulted in similar plasma exposure of ledipasvir, sofosbuvir and GS-331007 (the inactive metabolite of sofosbuvir) in adolescents as in adults, thus the adult dose was used for this age group [44]. Similarly, giving half the adult fixed-dose of ledipasvir/ sofosbuvir, 45/200 mg, to children ages 6–11 years resulted in comparable plasma exposure of ledipasvir, sofobuvir and GS-331007 as in adults, without any severe adverse events or laboratory abnormalities [45].
The impact of brain aging on cognition is far from uniform, ranging from perfect fitness to cognitive impairment. The prevalence of dementia is estimated to increase from 57.4 million in 2019 to 152.8 million in 2050 [1], thus representing a major public health problem. Still, evidence shows that more than one-third of all cases of dementia could be prevented or modified by changes in lifestyle, correction of risk factors, and specific therapeutic interventions [2, 3, 4, 5]. In fact, despite the absence of pharmacological treatment for degenerative diseases, such as Alzheimer’s disease (AD), it is known that vascular risk factors increase the likelihood of cognitive decline. Simple measures, the control of hypertension, for instance, may revert cognitive impairment and reduce conversion to dementia [6]. Likewise, healthy lifestyle patterns, physical exercise, and intellectual and social enrichment may improve performance and change the biomarker trajectories of individuals classified as cognitively impaired [7, 8, 9].
Promoting the presence of protective factors throughout life may help to cope with the negative consequences of pathology through resilience or resistance mechanisms. The term “resistance” refers to the notion of avoiding pathology (i.e., being free from significant AD pathology) in the sense that it is inferred from an observed absence or lower level of dementia-associated brain injury, relative to an expected greater frequency or severity based on age, genetic factors, or other individual characteristics. On the other hand, “resilience” is mostly used in the sense of coping with pathology (i.e., remaining cognitively intact despite significant AD pathology) and is inferred from the observation of a higher than expected cognitive functioning related to the level of brain injury [10, 11]. While the first is linked to an absence or delay of brain changes (“brain maintenance”), the latter is closely associated with the concept of the reserve, which can be measured or inferred either as brain structural and/or physiological premorbid capacity [11, 12].
The construct of reserve firstly emerged to describe patients with extensive destruction of nervous tissue following brain damage but not the expected level of functional changes [13]. It was then proposed that larger brains, with greater weight and a larger number of neurons, could have protective effects on the cognitive decline due to a higher “brain reserve” capacity [14]. Years later, Stern [15] defined the concept of Cognitive Reserve (CR) as the brain’s ability to optimize and maximize performance through the differential recruitment of brain networks or the use of alternative cognitive strategies to cope with brain dysfunction. Stern’s proposal claims that the mechanisms underlying CR are active processes by which the brain tries to compensate for the neural loss. These processes can be influenced by the interaction between innate factors (e.g., in utero or genetically determined) and, mainly, lifelong experience (e.g., intelligence, education, occupation, physical exercise, leisure activities, or social involvement). In contrast, the passive models propose that response to neural damage is related to brain size or the number of synapses (brain reserve), which can affect the threshold for clinical expression [16]. Brain reserve and CR are not mutually exclusive in the sense that brain reserve does not protect against the accumulation of pathology, but it does protect against its negative effects [17]. Instead, they influence each other—life experiences and the involvement in stimulating cognitive activities can modify brain anatomy (i.e., neurogenesis, angiogenesis, and resistance to apoptosis) and positively regulate compounds that promote neural plasticity [18].
The concept of CR has progressively evolved in such a way that it is now central in the literature on normal and pathological aging, notwithstanding the theoretical pitfalls and methodological controversies generated by years of studies and reserve-associated concepts. The most striking challenges are the absence of an operational definition of CR and the lack of clarification of its neural bases, the relationship between the brain and CR, and which factors affect brain reserve [19]. Making an effort to overcome these difficulties, a consensus report tried to clarify CR terminology [17] by claiming “resilience” as an umbrella concept that describes the process of coping with age- and disease-related changes, which includes multiple reserve related-concepts, such as brain reserve, brain maintenance, and CR.
Normal aging is characterized by several brain changes at the morphometric and functional level, and associated neuropsychological changes, that are particularly relevant in the frontal lobes on which Executive Functions (EF) heavily depend upon [20]. Among other areas of cognition, EF play a critical role in everyday life, allowing individuals to plan ahead, focus attention, and switch between tasks, hence maintaining effective levels of independent functioning. Variable EF trajectories include development into early adulthood and decline into older age, associated with structural and functional changes in the prefrontal cortex [21]. Despite this age-related decline, EF also assumes an important role in maintaining global cognitive efficiency in the late period of life, thanks to a higher CR [22].
There is considerable interest in understanding the processes underlying cognitive decline (and whether they result from specific or general impairments that reflect different patterns and different pathological processes) but also in how the brain actively copes with these deleterious effects on EF so functional independence can be maintained. Next in this chapter, we will review evidence that focuses on certain socio-behavioral CR proxies (e.g., education, occupational complexity, leisure activities, and social involvement), how they may help to cope with age-related changes and brain pathology, and how they relate with EF. Further, differences between “active” versus “passive” models of reserve and the underlying CR mechanism (“neural reserve” vs. “neural compensation”) are described.
One of the major limitations of the CR construct is that it can hardly be measured directly. Three methods are usually used to quantify and measure it—(a) socio-behavioral indicators, (b) residual approach, and (c) functional neuroimaging studies [17]. Hence, studies should include not only measures of the status of the brain (reflecting brain alteration or pathology), but also clinical or cognitive performance (consequences of brain damage), and socio-behavioral indicators (e.g., an index of life-long experience/premorbid capacity) when assessing the role of CR. The goal is to be able to predict an individual’s cognitive performance through the interaction between the proposed CR factors and the state of the brain/pathology.
Several studies have shown that CR proxies may decrease the rate of conversion to dementia in subjects with identical degrees of the pathological burden of AD [23, 24], and even have a protective role against the cognitive impairment associated with brain white-matter changes (WMC) or higher ventricular volume [25, 26] delaying the onset of clinical deficits [27]. Understanding the role of these proxies on the prediction of cognitive trajectories serves a two-fold objective, either it is disease prevention or disease diagnosis.
Different CR proxies have been identified [28], but recent systematic reviews indicate that education, occupational attainment, leisure activities, and social involvement are the most common indicators [29, 30, 31].
The number of years of formal education is the most consistently used across studies. A protective effect of education for age-associated cognitive decline appears to result in higher levels of CR [30, 32]. This is supported by strong positive associations between the number of years of formal education and crystallized measures (e.g., vocabulary) and EF, explaining, in the latter case, even more variance than age itself [33, 34, 35], compared with fluid abilities, such as processing speed, memory, or visuospatial abilities [34, 36, 37]. Robust scientific evidence also supports that lower-educated individuals are more likely to suffer from dementia in a wide range of settings [38]. For example, Contador et al. [39] found that living in a rural area (early and mid-life stages) increased the likelihood of dementia, with the risk being particularly high in people with low education. However, the effect of education on age-related cognitive changes remains controversial [40]. Kremen et al. [41] sought to demonstrate that the impact of CR factors is primarily downstream of intellectual capacity. These researchers concluded that brain development is substantial during childhood and adolescence and that further education from the age of 20 years would contribute much less to brain development. Moreover, it should be considered that the quality of the educational experience is not the same for all individuals, which may influence its potential impact as a CR proxy.
The protective effect of education not only mediates the transition between normal and pathological aging but also between stages of cognitive impairment. Based on the hypothesis that less automatized cognitive domains (or those that did not achieve proper consolidation throughout life) may deteriorate sooner than more consolidated ones, a recent retrospective study aimed to investigate whether education modifies the profile of cognitive/executive performance (i.e., sustained and divided attention, inhibitory control, working memory, verbal, motor and graphomotor fluency, planning, abstract reasoning, and episodic memory) in Mild Cognitive Impairment (MCI). It was found that despite a similar pattern of cognitive decline in both higher and lower education groups, patients with higher education revealed a trend toward a higher proportion of abnormal performances (≤ −1.5 standard deviation on age- and education-adjusted normative scores) and a steeper decline in measures of sustained attention and episodic memory [42]. These findings suggest that patients with higher levels of education have a higher CR because they show a more pronounced decline in executive control that does not reflect differences in clinical disease staging [35, 43, 44]. On the opposite extreme of educational level, elderly illiterate subjects may be more vulnerable to cognitive decline and dementia, due to the lack of the protective effect of education [45, 46, 47, 48, 49].
It is worth noting that, although education is usually measured by the number of years of formal education, there may be other indicators that better capture its true impact. In a recent prospective longitudinal cohort study on aging and cognition, which recruited and followed 275 healthy community subjects seen in primary care settings, with 50 years or older, over a 5-year period, investigators found that being male, older, and with a lower age- and education-adjusted z-scores on divided attention/mental flexibility measures were significant independent predictors of cognitive impairment 5 years later. Moreover, vocabulary emerged as a stronger predictor of cognitive stability or decline than education, independently of their correlation [50]. This highlights the relevance of this measure by reflecting more accurately the degree of cognitive stimulation and intellectual enrichment that may account for subtle differences between subjects at the same educational level, particularly relevant in overall low-literacy populations.
Occupational and leisure activities may also have markedly significant protective effects on cognitive decline and dementia, especially for individuals whose jobs involve social interaction [51]. In fact, it is known that engagement in mentally stimulating activities throughout life may promote neural connectivity [52]. With respect to occupational activity, cognitively demanding work conditions are associated with a decreased risk of cognitive decline in older adults [53]. Middle-aged people at risk for AD (decreased hippocampal volume and increased brain atrophy) with greater occupational complexity (e.g., involving complex social interactions) maintained a similar level of cognitive performance as those with less pathology [51, 54]. However, since higher levels of education are usually associated with jobs that are more cognitively demanding, whether or not the protective effect of education is independent of the levels of work complexity in middle age remains controversial [55, 56]. Moreover, a synergistic effect of low education and occupation on the risk of developing AD was described by Stern et al. [57], particularly when it is combined with cognitively demanding work activity in adulthood [55, 57]. For instance, some studies indicate that level of literacy is a more accurate measure of CR than years of education [58], especially in those individuals from disadvantaged groups or with null/low educational attainment [39, 59]. Regarding involvement in leisure activities, it has also been associated with a reduced risk of AD [60, 61] and protective effects against cognitive decline [62, 63].
There seems to be evidence that lifestyle and the environment effectively regulate cognitive aging and that this regulation may be particularly relevant in the hippocampal-mediated memory functions in mammals. Although the causal nature of this relationship has not yet been established [64], studies in animal models seem to indicate that it may exist, but more clinical studies are needed to specifically understand how social involvement and integration can be used to prevent cognitive decline. Additionally, the mechanisms underlying this relationship seem to indicate a relevant role for growth factors, neuroinflammation, and neurogenesis processes. In this context, physical activity, for instance, has been identified as inducing neurogenesis due to its benefits on structural and functional plasticity in hippocampus-dependent learning and memory tasks. Accordingly, maintaining an active social life at older ages can improve CR and benefit cognitive function. This is especially relevant since some aspects, such as education or occupational complexity, developed at a young age and middle age cannot be modified. Social activity can contribute to an increased reserve even in a more advanced stage of life, with gains in cognitive performance. In fact, living alone was significantly associated with an increase in cognitive complaints and a significant predictor of future cognitive decline in specific linguistic/executive measures, such as verbal fluency over a 5-year follow-up [33, 65, 66]. Social interactions can be viewed as natural forms of cognitive stimulation and may play a relevant part in the stimulation of language skills, whereas living alone would represent a relative cognitive deprivation situation, with reduced cognitive stimulation and lower CR [67, 68]. Interventions that reduce social isolation at a more advanced stage can benefit cognitive function both directly and indirectly by building reserve, especially in individuals with low CR in middle age. This aspect has important implications for interventions suggesting that combating social isolation can contribute to a healthier cognition [69].
Traditionally, late-mature regions, such as the frontal lobes, are considered especially vulnerable to normal age changes, inspiring theories of cognitive aging, such as the “last in, first-out” or “retrogenesis” hypothesis. This hypothesis considers an anteroposterior gradient of age vulnerability, which explains the decline in EF often observed in healthy older adults [70].
Executive functions, such as processing speed, working memory, inhibitory control, top–down suppression, or shifting ability, are shaped by education and by other CR proxies. A decline in executive performance has been shown to be associated with low performance in activities of daily living and to predict conversion from MCI to dementia [71, 72]. Moreover, EF are known to be sensitive to damage in other parts of the brain, such as subcortical white matter changes [34], thalamic nuclei, the limbic system, and basal ganglia [73] apart from prefrontal lobe damage.
The perspective that age-related cognitive decline emerges when a person is no longer able to compensate for the reduced functioning of the primary brain structures and circuits, is largely supported in the literature. Relevant conceptual models have emerged over the last 20 years, aiming to describe and understand brain reorganization in response to age-related changes and brain injury. Older adults may use alternative networks to aim for the same level of functioning as younger individuals, which can represent a mechanism of neural compensation [74, 75]. The “Scaffolding Theory of Aging and Cognition” (STAC) model proposed by Park and Reuter-Lorenz [76] claims the recruitment of additional circuits as a way to strengthen the declining structures whose functioning has become inefficient. These strategies lose efficiency in the aged brain and are eventually no longer accessible when there is cerebral pathology, as in the case of AD. The “normalcy-pathology homology” phenomenon suggests that there are regions more vulnerable to age-related changes and that this age vulnerability renders them more susceptible to additional pathological AD-related changes. This is particularly clear in frontotemporal regions where the elderly, even with a low risk of AD, present prominent cortical reductions [70].
The Cognitive Reserve framework suggests that individual differences in cognitive performance are based on more efficient recruitment of brain networks (neural reserve) or the enhanced ability to recruit alternate (compensation) brain networks [15, 77]. Regarding neural reserve, it is postulated that inter-individual variability related to the efficiency, capacity, or flexibility of the brain networks will influence how the healthy brain can deal with the demands imposed by the emergence of brain injuries or pathologies. The neural reserve allows healthy young individuals with greater CR to solve tasks more efficiently and more capably and, in turn, may better confront the disruptions imposed by brain pathology due to the increased flexibility of brain networks. Neural compensation concerns task-related activation, a mechanism that only appears when new resources are needed to maintain or improve performance due to changes in the brain structure. Hence, neural compensation is a mechanism usually referring to people who have brain pathology [15, 77]. The degree of compensation can also vary in individuals in terms of expression and effectiveness. In fact, neural compensation refers to inter-individual variability to compensate for the disruption of standard processing networks. In this situation, brain structures or networks that are not normally used by individuals with intact brains become activated. Both neural reserve and neural compensation support CR, with compensation being the most common mechanism in more advanced stages of the aging spectrum [78].
As previously stated, individuals with higher CR can maintain a more efficient and capable network or compensate advantageously in the face of a comparable amount of brain pathology [79]. Accordingly, Scarmeas et al. [80], using a set of memory tasks, identified brain regions where systematic relationships between CR and brain activation differed as a function of aging. Thus, when facing certain tasks, young and older people activate similar brain regions but as the difficulty of the memory task increased the magnitude of activation was often higher in older individuals, suggesting more efforts to achieve a comparable level of performance, which can be related to network efficiency. In addition, the older adults recruited additional regions of the brain not used by young people while performing certain memory tasks, which can represent a form of active neural compensation [80]. A similar pattern of compensation was also found when comparing old adults schooled later in life with old adults schooled at the proper age, in a memory recognition task using Magnetoencephalography (MEG), and the first ones displayed additional activations to keep the level of performance [81].
In the last few decades, scientific studies have tried to capture the “neural implementation” of CR through functional neuroimaging [78]. This approach seeks to identify resting state or task-related functional activation brain networks that may underlie CR. Potentially, the expression of these networks may be associated with the influence of CR proxies, moderating the effect of brain changes on cognition. If these networks were identified through functional neuroimaging research methods (not properly used in clinical practice), their degree of manifestation would be a more direct measure of CR than other types of proxies [17]. Tucker and Stern [37] suggested that there may be at least one “generic CR network” that can be activated during the performance of many tasks, explaining how CR protects against brain pathology, which seems to be a promising line of future investigation [17].
A recent systematic review indicates that a resting-state network, implicating medial temporal regions and cingulate cortex (anterior or posterior), is associated with neural reserve, whereas frontal regions and the dorsal attentional network (DAN), activated during the cognitive engagement, are related to neural compensation [78]. Task-related studies have found a positive correlation between CR proxies (mostly premorbid IQ and education) and higher frontal activity in healthy older adults compared to young adults [82, 83, 84, 85]. Moreover, a positive association between CR (i.e., education-occupation attainment, premorbid IQ , and leisure activities) and frontal activity in MCI and AD patients compared to healthy older adults has been found [86, 87].
The mechanisms on which the function and resilience of large-scale brain networks are based are still poorly understood. Early lifespan environmental influences can contribute to understanding phenomena such as reserve, as, at least partially, to determine the variance of the underlying structural network. This may have implications for global and regional network controllability. A dynamic network theory can be crucial for advancing the understanding of the resilience of the human brain, reinforcing the need for a spatiotemporal analysis in complex systems [88]. In fact, the human capacity to perform a variety of tasks seems to be associated with cognitive control networks, specifically the frontoparietal control network (FPN) in the left posterior parietal cortex. The adaptability of this network, whose global connectivity pattern seems to change more than other networks, and the connectivity patterns that can be used to identify task performance, point to the importance of this network in cognitive control and task performance. It seems to be possible through “flexible hubs,” that is, regions that quickly update their connectivity pattern according to task demands [89].
This greater variability in FPN connectivity, both between networks and between tasks, supports the notion that this network implements core flexible hubs, allowing cognitive control across various and distinct tasks [89]. This is especially relevant for this chapter’s purpose as the existence of this control network appears to be crucial for reserve. Specifically, one of its hubs, the left frontal cortex (LFC, covering BA 6/44) [90, 91], is a likely candidate for the neural implementation of CR. The resting-state connectivity of that LFC hub region had previously been associated with protective factors such as high IQ and high cognitive performance. Concretely, it had already been demonstrated that the lateral prefrontal cortex (LPFC) is a hub region with an especially high global connectivity but, more than that, it has been shown that this global connectivity could predict the fluid intelligence of individuals, appearing to be a global hub connector [92]. This level of the organization thus appears to be especially relevant for understanding the brain and CR that involve distributed circuits and complex psychological constructs.
Global connectivity of the LFC hub (close to the Broca area), in resting-state fMRI, is associated with more years of education (CR proxy) and with milder effects of FDG-PET hypometabolism on memory performance in prodromal AD [91]. This can be important for instance in the selection of participants for intervention trials since MCI patients with higher CR seem to have a higher likelihood to benefit from a cognitive intervention [93].
Increased frontoparietal activation may reflect a compensatory mechanism, helping to protect memory task performance in early-stage AD. Additionally, increased global connectivity of LFC can support frontoparietal increased activation and that is associated with CR, moderating the association between AD neuropathology and cognitive decline, and helping to maintain better memory performance [90]. In a task-related fMRI study, the authors tried to understand if LFC hub connectivity during an episodic memory task was associated with a reserve in aging and MCI. More years of education were associated with increased LFC connectivity during memory processing, and increased LFC connectivity was associated with a higher reserve in the memory domain. This result pattern was found in controls and MCI groups, which was interpreted as suggestive that connectivity of a key hub of the frontoparietal control network contributes to reserve in both normal and pathological aging. This conclusion reinforces that LFC is a good candidate for the neural basis of reserve and that a higher LFC connectivity may be a long-lasting trait that is influenced by environmental stimuli, namely education [91]. In fact, CR, being the result of multiple and distinct stimulations, involves connectivity between different tasks and domains. Consistently with this, the LFC (BA 6/44) ranks among the top 5% of brain regions in terms of number of connections in the brain, being high and globally connected to the rest of the brain and is a key connector hub between different functional networks [91]. Taken together the results seem to point out that the cognitive control network, particularly LFC, works as a hub of the frontoparietal control network, which is associated with greater reserve. Later work showed that education is associated with better performance on memory tasks thanks to greater efficiency of functional networks, clearly demonstrating the effects of education on DMN/DAN small-worldness, mediated via LFC connectivity, and reinforcing its role as a neural basis of the reserve [94].
Moreover, evidence also shows that education facilitates the brain’s ability to form segregated functional groups of networks, with stronger signals in parietal and occipital regions [95]. This fact reinforces the perspective that more years of schooling trigger a more specialized use of neural processing. However, CR (residual variance in memory and general executive functioning) was also associated with higher global network efficiency (i.e., functional integration). In this sense, this study corroborates that CR is associated both with increased functional connectivity and better organization of the network topology.
The protective role of higher global functional connectivity in the FPN and higher local connectivity between the salience network (anterior cingulate cortex) and medial frontal cortex can significantly mitigate the impact of white matter lesions on EF [96], emphasizing the role of the cognitive control network as a neural substrate for CR. As pointed out by the authors, both the salience and the FPN are important cognitive control networks, that are crucial for appropriate brain functioning, with the FPN flexibly regulating the activity of other networks and the salience network integrating inputs from different sources. Their results reinforce the notion that cognitive control networks may play a role in brain resilience mechanisms with increased connectivity being linked to better cognition.
Overall, these findings suggest that greater activity of frontal regions, namely via LFC connectivity, is a potential component of functional networks underlying neural compensation. Conversely, MTL regions, which are known to be critical for the conversion from MCI to AD, may reflect the capacity of the neural reserve [97, 98].
The understanding of the mechanisms involved with successful aging is far from straightforward and the growing number of publications in this field shows the interest of the scientific community to understand the importance of complex related concepts in its promotion. In this chapter, we focused on several socio-behavioral CR proxies identified as protective factors against cognitive decline and dementia and how they impact EF by means of neural compensation mechanisms related to the increased functional activity of the frontal lobe.
The relationship between CR proxies and the maintenance of cognitive efficiency in the context of age-related changes/brain pathology is dynamic. Not only do the skills, social involvement, and occupational attainment developed throughout life have a mediating role in improving neural connections (i.e., in terms of activation, flexibility, and efficiency), but also this enhancement of brain connectivity patterns expresses itself in better cognitive performance. Despite its vulnerability to the effects of senescence, the frontal lobes play a key role in CR allowing for the preservation of the overall cognitive function by means of enrichment of EF (e.g., planning, sequencing, inhibitory control, abstract reasoning) via a higher CR. Indeed, people with high CR show an advantage in the use of these more developed EF, thus increasing frontal lobe activity. The use of alternative task-relevant circuits compensates for effectiveness (e.g., MTL, especially relevant for memory and selectively affected in AD) thus mitigating the clinical expression of dementia. In this compensation mechanism, DAN and FPN networks are particularly relevant, with a sub-region in the LFC being identified as a potential candidate for a neural marker of CR.
Several caveats still, however, need to be fully addressed. First and foremost, it is unclear how CR proxies may specifically influence different aetiologies of dementia and modulate different cognitive trajectories. Second, EF cannot have a double role as an age−/pathology-dependent measure and as a factor that changes the relationship. As a consequence, all EF may not be appropriate measures for CR, since it is not stable throughout life and is vulnerable to age-related changes. Thus, according to the gain/loss hypothesis, one should carefully select aspects of EF that are robust and resistant to aging, in order to include them as components of CR. Stern et al. [99] considered that this approach should be better explored in the future, despite currently presenting some limitations that are difficult to overcome. From the outset, the fact that the brain measures used to predict cognition only partially capture brain pathology or physiology and different lifestyles cannot be explained by known brain predictors can lead to a high risk of including many aspects that are not reserved. Third, the differential impact of CR depending on the demographic characteristics of the population or discrepancies in measuring CR measures or outcomes (i.e., cognitive or functional) needs to be addressed as well. In fact, precise operational definitions of CR and other related theoretical constructs are needed. Advances in multimodal imaging, preferably longitudinal studies, will allow a better understanding of the neural mechanisms underlying CR. Future work should focus on the design of studies that will help to clarify the relationship between CR proxies and brain reserve, as well as improve their measurement. These studies will make it possible to improve and integrate the existing conceptual models of the moderation of CR in cognitive performance. Further, it is expected that the contribution of these investigations could lead to objective guidelines and strategies for the development of differentiated, validated, and accessible intervention programs aimed to provide more functionality and better quality of life in older adults [17].
If the existence of a compensatory capacity in individuals with a high CR seems to be clear, it is consensual that it is still not entirely clear what reserve consists of in neural terms. Potential candidates have been proposed but the discovery of this neural basis is particularly relevant as, in addition to traditional cognitive and psychosocial stimulation techniques, it could also open doors to more direct brain stimulation allowing the use of a whole arsenal of new non-invasive brain stimulation technologies which is predicted to have increasing importance in intervention.
This work is financially supported by the National Funds through FCT—Fundação para a Ciência e a Tecnologia, I.P., under the project UIDB/04279/2020. The authors thank the Centre for Interdisciplinary Research in Health and Católica Research Centre for Psychological, Family & Social Wellbeing, Universidade Católica Portuguesa for their support.
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Aalborg University has Two Satellite Campuses, one in Copenhagen (Aalborg University Copenhagen) and the other in Esbjerg (Aalborg University Esbjerg).\n· He is a member of prestigious IEEE (Institute of Electrical and Electronics Engineers), and IAENG (International Association of Engineers) organizations. \n· He is the chief Editor of the Journal of Software Engineering.\n· He is the member of the Editorial Board of International Journal of Computer Science and Software Technology (IJCSST) and International Journal of Computer Engineering and Information Technology. \n· He is also the Editor of Communication in Computer and Information Science CCIS-20 by Springer.\n· Reviewer For Many Conferences\nHe is the lead person in making collaboration agreements between Aalborg University and many universities of Pakistan, for which the MOU’s (Memorandum of Understanding) have been signed.\nProfessor Akbar is working in Academia since 1990, he started his career as a Lab demonstrator/TA at the University of Sussex. After finishing his P. hD degree in 1992, he served in the Industry as a Scientific Officer and continued his academic career as a visiting scholar for a number of educational institutions. In 1996 he joined National University of Science & Technology Pakistan (NUST) as an Associate Professor; NUST is one of the top few universities in Pakistan. In 1999 he joined an International Company Lineo Inc, Canada as Manager Compiler Group, where he headed the group for developing Compiler Tool Chain and Porting of Operating Systems for the BLACKfin processor. The processor development was a joint venture by Intel and Analog Devices. In 2002 Lineo Inc., was taken over by another company, so he joined Aalborg University Denmark as an Assistant Professor.\nProfessor Akbar has truly a multi-disciplined career and he continued his legacy and making progress in many areas of his interests both in teaching and research. 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Besides its wide and promiscuous tropism, AAV infection does not result in considerable toxicity or pathogenicity and is capable of achieving adequate and long-term levels of gene transfer, especially following generation of the AAV recombinant variant: rAAV. Due to these properties, rAAV has gained special attention as a viral vector for gene therapy in the last decade. Currently, there are 130 clinical trials taking place worldwide for several diseases testing the safety and efficacy profiles of rAAV. During preclinical and clinical studies, several challenges have arisen in terms of reaching the full therapeutic potential of rAAV, such as efficient delivery of the virus in a targeted and specific manner to a desired tissue. Importantly, the development of immune responses towards the viral capsids poses an obstacle to rAAV applicability in the clinical setting. 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Saxena is a vice dean and professor at King George's Medical University, Lucknow, India. His research interests involve understanding the molecular mechanisms of host defense during human viral infections and developing new predictive, preventive, and therapeutic strategies for them using Japanese encephalitis virus (JEV), HIV, and emerging viruses as a model via stem cell and cell culture technologies. His research work has been published in various high-impact factor journals (Science, PNAS, Nature Medicine) with a high number of citations. He has received many awards and honors in India and abroad including various Young Scientist Awards, BBSRC India Partnering Award, and Dr. JC Bose National Award of Department of Biotechnology, Min. of Science and Technology, Govt. of India. 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He is a vice-president of the Latin American Society for Travel Medicine (SLAMVI) and a Member of the Council of the International Society for Infectious Diseases (ISID). Since 2014, he has been recognized as a Senior Researcher, at the Ministry of Science of Colombia. He is a professor at the Faculty of Medicine of the Fundacion Universitaria Autonoma de las Americas, in Pereira, Risaralda, Colombia. He is an External Professor, Master in Research on Tropical Medicine and International Health, Universitat de Barcelona, Spain. He is also a professor at the Master in Clinical Epidemiology and Biostatistics, Universidad Científica del Sur, Lima, Peru. In 2021 he has been awarded the “Raul Isturiz Award” Medal of the API. Also, in 2021, he was awarded with the “Jose Felix Patiño” Asclepius Staff Medal of the Colombian Medical College, due to his scientific contributions to COVID-19 during the pandemic. 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That is exactly what he does, diving into Machine Learning algorithms and technologies to help TECNALIA to decide whether something is great in theory or will actually impact on the product or processes of its projects. So, he is expert at framing experiments, developing hypotheses, and proving whether they’re true or not, in order to investigate fundamental problems with a longer time horizon. He is also able to design and develop PoCs and system prototypes in simulation. He has participated in several national and internacional R&D projects.\n\nAs another relevant part of his everyday research work, he usually publishes his findings in reputed scientific refereed journals and international conferences, occasionally acting as reviewer and Programme Commitee member. Concretely, since 2018 he has published 9 JCR (8 Q1) journal papers, 9 conference papers (e.g. ECML PKDD 2021), and he has co-edited a book. He is also active in popular science writing data science stories for reputed blogs (KDNuggets, TowardsDataScience, Naukas). Besides, he has recently embarked on mentoring programmes as mentor, and has also worked as data science trainer.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"339677",title:"Dr.",name:"Mrinmoy",middleName:null,surname:"Roy",slug:"mrinmoy-roy",fullName:"Mrinmoy Roy",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/339677/images/16768_n.jpg",biography:"An accomplished Sales & Marketing professional with 12 years of cross-functional experience in well-known organisations such as CIPLA, LUPIN, GLENMARK, ASTRAZENECA across different segment of Sales & Marketing, International Business, Institutional Business, Product Management, Strategic Marketing of HIV, Oncology, Derma, Respiratory, Anti-Diabetic, Nutraceutical & Stomatological Product Portfolio and Generic as well as Chronic Critical Care Portfolio. A First Class MBA in International Business & Strategic Marketing, B.Pharm, D.Pharm, Google Certified Digital Marketing Professional. Qualified PhD Candidate in Operations and Management with special focus on Artificial Intelligence and Machine Learning adoption, analysis and use in Healthcare, Hospital & Pharma Domain. Seasoned with diverse therapy area of Pharmaceutical Sales & Marketing ranging from generating revenue through generating prescriptions, launching new products, and making them big brands with continuous strategy execution at the Physician and Patients level. Moved from Sales to Marketing and Business Development for 3.5 years in South East Asian Market operating from Manila, Philippines. Came back to India and handled and developed Brands such as Gluconorm, Lupisulin, Supracal, Absolut Woman, Hemozink, Fabiflu (For COVID 19), and many more. In my previous assignment I used to develop and execute strategies on Sales & Marketing, Commercialization & Business Development for Institution and Corporate Hospital Business portfolio of Oncology Therapy Area for AstraZeneca Pharma India Ltd. Being a Research Scholar and Student of ‘Operations Research & Management: Artificial Intelligence’ I published several pioneer research papers and book chapters on the same in Internationally reputed journals and Books indexed in Scopus, Springer and Ei Compendex, Google Scholar etc. Currently, I am launching PGDM Pharmaceutical Management Program in IIHMR Bangalore and spearheading the course curriculum and structure of the same. I am interested in Collaboration for Healthcare Innovation, Pharma AI Innovation, Future trend in Marketing and Management with incubation on Healthcare, Healthcare IT startups, AI-ML Modelling and Healthcare Algorithm based training module development. I am also an affiliated member of the Institute of Management Consultant of India, looking forward to Healthcare, Healthcare IT and Innovation, Pharma and Hospital Management Consulting works.",institutionString:null,institution:{name:"Lovely Professional University",country:{name:"India"}}},{id:"1063",title:"Prof.",name:"Constantin",middleName:null,surname:"Volosencu",slug:"constantin-volosencu",fullName:"Constantin Volosencu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/1063/images/system/1063.png",biography:"Prof. Dr. Constantin Voloşencu graduated as an engineer from\nPolitehnica University of Timișoara, Romania, where he also\nobtained a doctorate degree. He is currently a full professor in\nthe Department of Automation and Applied Informatics at the\nsame university. Dr. Voloşencu is the author of ten books, seven\nbook chapters, and more than 160 papers published in journals\nand conference proceedings. He has also edited twelve books and\nhas twenty-seven patents to his name. He is a manager of research grants, editor in\nchief and member of international journal editorial boards, a former plenary speaker, a member of scientific committees, and chair at international conferences. His\nresearch is in the fields of control systems, control of electric drives, fuzzy control\nsystems, neural network applications, fault detection and diagnosis, sensor network\napplications, monitoring of distributed parameter systems, and power ultrasound\napplications. He has developed automation equipment for machine tools, spooling\nmachines, high-power ultrasound processes, and more.",institutionString:"Polytechnic University of Timişoara",institution:{name:"Polytechnic University of Timişoara",country:{name:"Romania"}}},{id:"221364",title:"Dr.",name:"Eneko",middleName:null,surname:"Osaba",slug:"eneko-osaba",fullName:"Eneko Osaba",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/221364/images/system/221364.jpg",biography:"Dr. Eneko Osaba works at TECNALIA as a senior researcher. He obtained his Ph.D. in Artificial Intelligence in 2015. He has participated in more than twenty-five local and European research projects, and in the publication of more than 130 papers. He has performed several stays at universities in the United Kingdom, Italy, and Malta. Dr. Osaba has served as a program committee member in more than forty international conferences and participated in organizing activities in more than ten international conferences. He is a member of the editorial board of the International Journal of Artificial Intelligence, Data in Brief, and Journal of Advanced Transportation. He is also a guest editor for the Journal of Computational Science, Neurocomputing, Swarm, and Evolutionary Computation and IEEE ITS Magazine.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"275829",title:"Dr.",name:"Esther",middleName:null,surname:"Villar-Rodriguez",slug:"esther-villar-rodriguez",fullName:"Esther Villar-Rodriguez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/275829/images/system/275829.jpg",biography:"Dr. Esther Villar obtained a Ph.D. in Information and Communication Technologies from the University of Alcalá, Spain, in 2015. She obtained a degree in Computer Science from the University of Deusto, Spain, in 2010, and an MSc in Computer Languages and Systems from the National University of Distance Education, Spain, in 2012. Her areas of interest and knowledge include natural language processing (NLP), detection of impersonation in social networks, semantic web, and machine learning. Dr. Esther Villar made several contributions at conferences and publishing in various journals in those fields. Currently, she is working within the OPTIMA (Optimization Modeling & Analytics) business of TECNALIA’s ICT Division as a data scientist in projects related to the prediction and optimization of management and industrial processes (resource planning, energy efficiency, etc).",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"49813",title:"Dr.",name:"Javier",middleName:null,surname:"Del Ser",slug:"javier-del-ser",fullName:"Javier Del Ser",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49813/images/system/49813.png",biography:"Prof. Dr. Javier Del Ser received his first PhD in Telecommunication Engineering (Cum Laude) from the University of Navarra, Spain, in 2006, and a second PhD in Computational Intelligence (Summa Cum Laude) from the University of Alcala, Spain, in 2013. He is currently a principal researcher in data analytics and optimisation at TECNALIA (Spain), a visiting fellow at the Basque Center for Applied Mathematics (BCAM) and a part-time lecturer at the University of the Basque Country (UPV/EHU). His research interests gravitate on the use of descriptive, prescriptive and predictive algorithms for data mining and optimization in a diverse range of application fields such as Energy, Transport, Telecommunications, Health and Industry, among others. In these fields he has published more than 240 articles, co-supervised 8 Ph.D. theses, edited 6 books, coauthored 7 patents and participated/led more than 40 research projects. He is a Senior Member of the IEEE, and a recipient of the Biscay Talent prize for his academic career.",institutionString:"Tecnalia Research & Innovation",institution:null},{id:"278948",title:"Dr.",name:"Carlos Pedro",middleName:null,surname:"Gonçalves",slug:"carlos-pedro-goncalves",fullName:"Carlos Pedro Gonçalves",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRcmyQAC/Profile_Picture_1564224512145",biography:'Carlos Pedro Gonçalves (PhD) is an Associate Professor at Lusophone University of Humanities and Technologies and a researcher on Complexity Sciences, Quantum Technologies, Artificial Intelligence, Strategic Studies, Studies in Intelligence and Security, FinTech and Financial Risk Modeling. He is also a progammer with programming experience in:\n\nA) Quantum Computing using Qiskit Python module and IBM Quantum Experience Platform, with software developed on the simulation of Quantum Artificial Neural Networks and Quantum Cybersecurity;\n\nB) Artificial Intelligence and Machine learning programming in Python;\n\nC) Artificial Intelligence, Multiagent Systems Modeling and System Dynamics Modeling in Netlogo, with models developed in the areas of Chaos Theory, Econophysics, Artificial Intelligence, Classical and Quantum Complex Systems Science, with the Econophysics models having been cited worldwide and incorporated in PhD programs by different Universities.\n\nReceived an Arctic Code Vault Contributor status by GitHub, due to having developed open source software preserved in the \\"Arctic Code Vault\\" for future generations (https://archiveprogram.github.com/arctic-vault/), with the Strategy Analyzer A.I. module for decision making support (based on his PhD thesis, used in his Classes on Decision Making and in Strategic Intelligence Consulting Activities) and QNeural Python Quantum Neural Network simulator also preserved in the \\"Arctic Code Vault\\", for access to these software modules see: https://github.com/cpgoncalves. He is also a peer reviewer with outsanding review status from Elsevier journals, including Physica A, Neurocomputing and Engineering Applications of Artificial Intelligence. Science CV available at: https://www.cienciavitae.pt//pt/8E1C-A8B3-78C5 and ORCID: https://orcid.org/0000-0002-0298-3974',institutionString:"University of Lisbon",institution:{name:"Universidade Lusófona",country:{name:"Portugal"}}},{id:"241400",title:"Prof.",name:"Mohammed",middleName:null,surname:"Bsiss",slug:"mohammed-bsiss",fullName:"Mohammed Bsiss",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/241400/images/8062_n.jpg",biography:null,institutionString:null,institution:null},{id:"276128",title:"Dr.",name:"Hira",middleName:null,surname:"Fatima",slug:"hira-fatima",fullName:"Hira Fatima",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/276128/images/14420_n.jpg",biography:"Dr. Hira Fatima\nAssistant Professor\nDepartment of Mathematics\nInstitute of Applied Science\nMangalayatan University, Aligarh\nMobile: no : 8532041179\nhirafatima2014@gmal.com\n\nDr. Hira Fatima has received his Ph.D. degree in pure Mathematics from Aligarh Muslim University, Aligarh India. Currently working as an Assistant Professor in the Department of Mathematics, Institute of Applied Science, Mangalayatan University, Aligarh. She taught so many courses of Mathematics of UG and PG level. Her research Area of Expertise is Functional Analysis & Sequence Spaces. She has been working on Ideal Convergence of double sequence. She has published 17 research papers in National and International Journals including Cogent Mathematics, Filomat, Journal of Intelligent and Fuzzy Systems, Advances in Difference Equations, Journal of Mathematical Analysis, Journal of Mathematical & Computer Science etc. She has also reviewed few research papers for the and international journals. She is a member of Indian Mathematical Society.",institutionString:null,institution:null},{id:"302698",title:"Dr.",name:"Yao",middleName:null,surname:"Shan",slug:"yao-shan",fullName:"Yao Shan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Dalian University of Technology",country:{name:"China"}}},{id:"125911",title:"Prof.",name:"Jia-Ching",middleName:null,surname:"Wang",slug:"jia-ching-wang",fullName:"Jia-Ching Wang",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"National Central University",country:{name:"Taiwan"}}},{id:"357085",title:"Mr.",name:"P. Mohan",middleName:null,surname:"Anand",slug:"p.-mohan-anand",fullName:"P. Mohan Anand",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Indian Institute of Technology Kanpur",country:{name:"India"}}},{id:"356696",title:"Ph.D. Student",name:"P.V.",middleName:null,surname:"Sai Charan",slug:"p.v.-sai-charan",fullName:"P.V. Sai Charan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Indian Institute of Technology Kanpur",country:{name:"India"}}},{id:"357086",title:"Prof.",name:"Sandeep K.",middleName:null,surname:"Shukla",slug:"sandeep-k.-shukla",fullName:"Sandeep K. Shukla",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Indian Institute of Technology Kanpur",country:{name:"India"}}},{id:"356823",title:"MSc.",name:"Seonghee",middleName:null,surname:"Min",slug:"seonghee-min",fullName:"Seonghee Min",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Daegu University",country:{name:"Korea, South"}}},{id:"353307",title:"Prof.",name:"Yoosoo",middleName:null,surname:"Oh",slug:"yoosoo-oh",fullName:"Yoosoo Oh",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:"Yoosoo Oh received his Bachelor's degree in the Department of Electronics and Engineering from Kyungpook National University in 2002. He obtained his Master’s degree in the Department of Information and Communications from Gwangju Institute of Science and Technology (GIST) in 2003. In 2010, he received his Ph.D. degree in the School of Information and Mechatronics from GIST. In the meantime, he was an executed team leader at Culture Technology Institute, GIST, 2010-2012. In 2011, he worked at Lancaster University, the UK as a visiting scholar. In September 2012, he joined Daegu University, where he is currently an associate professor in the School of ICT Conver, Daegu University. Also, he served as the Board of Directors of KSIIS since 2019, and HCI Korea since 2016. From 2017~2019, he worked as a center director of the Mixed Reality Convergence Research Center at Daegu University. From 2015-2017, He worked as a director in the Enterprise Supporting Office of LINC Project Group, Daegu University. His research interests include Activity Fusion & Reasoning, Machine Learning, Context-aware Middleware, Human-Computer Interaction, etc.",institutionString:null,institution:{name:"Daegu Gyeongbuk Institute of Science and Technology",country:{name:"Korea, South"}}},{id:"262719",title:"Dr.",name:"Esma",middleName:null,surname:"Ergüner Özkoç",slug:"esma-erguner-ozkoc",fullName:"Esma Ergüner Özkoç",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Başkent University",country:{name:"Turkey"}}},{id:"419199",title:"Dr.",name:"Qun",middleName:null,surname:"Yang",slug:"qun-yang",fullName:"Qun Yang",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Auckland",country:{name:"New Zealand"}}},{id:"351158",title:"Prof.",name:"David W.",middleName:null,surname:"Anderson",slug:"david-w.-anderson",fullName:"David W. Anderson",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Calgary",country:{name:"Canada"}}},{id:"351159",title:"BSc.",name:"Kalum J.",middleName:null,surname:"Ost",slug:"kalum-j.-ost",fullName:"Kalum J. Ost",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Calgary",country:{name:"Canada"}}},{id:"325029",title:"Dr.",name:"Prem Chand",middleName:null,surname:"Jain",slug:"prem-chand-jain",fullName:"Prem Chand Jain",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Shiv Nadar University",country:{name:"India"}}},{id:"357275",title:"Dr.",name:"Thomas",middleName:null,surname:"Mih",slug:"thomas-mih",fullName:"Thomas Mih",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Buea",country:{name:"Cameroon"}}},{id:"305305",title:"Dr.",name:"Arturo Yosimar",middleName:null,surname:"Jaen-Cuellar",slug:"arturo-yosimar-jaen-cuellar",fullName:"Arturo Yosimar Jaen-Cuellar",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Autonomous University of Queretaro",country:{name:"Mexico"}}},{id:"305315",title:"Dr.",name:"David Alejandro",middleName:null,surname:"Elvira-Ortiz",slug:"david-alejandro-elvira-ortiz",fullName:"David Alejandro Elvira-Ortiz",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Autonomous University of Queretaro",country:{name:"Mexico"}}},{id:"344374",title:"Dr.",name:"Manuel",middleName:null,surname:"Toledano-Ayala",slug:"manuel-toledano-ayala",fullName:"Manuel Toledano-Ayala",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Autonomous University of Queretaro",country:{name:"Mexico"}}}]}},subseries:{item:{id:"27",type:"subseries",title:"Multi-Agent Systems",keywords:"Collaborative Intelligence, Learning, Distributed Control System, Swarm Robotics, Decision Science, Software Engineering",scope:"Multi-agent systems are recognised as a state of the art field in Artificial Intelligence studies, which is popular due to the usefulness in facilitation capabilities to handle real-world problem-solving in a distributed fashion. The area covers many techniques that offer solutions to emerging problems in robotics and enterprise-level software systems. Collaborative intelligence is highly and effectively achieved with multi-agent systems. Areas of application include swarms of robots, flocks of UAVs, collaborative software management. Given the level of technological enhancements, the popularity of machine learning in use has opened a new chapter in multi-agent studies alongside the practical challenges and long-lasting collaboration issues in the field. It has increased the urgency and the need for further studies in this field. We welcome chapters presenting research on the many applications of multi-agent studies including, but not limited to, the following key areas: machine learning for multi-agent systems; modeling swarms robots and flocks of UAVs with multi-agent systems; decision science and multi-agent systems; software engineering for and with multi-agent systems; tools and technologies of multi-agent systems.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/27.jpg",hasOnlineFirst:!1,hasPublishedBooks:!1,annualVolume:11423,editor:{id:"148497",title:"Dr.",name:"Mehmet",middleName:"Emin",surname:"Aydin",slug:"mehmet-aydin",fullName:"Mehmet Aydin",profilePictureURL:"https://mts.intechopen.com/storage/users/148497/images/system/148497.jpg",biography:"Dr. Mehmet Emin Aydin is a Senior Lecturer with the Department of Computer Science and Creative Technology, the University of the West of England, Bristol, UK. His research interests include swarm intelligence, parallel and distributed metaheuristics, machine learning, intelligent agents and multi-agent systems, resource planning, scheduling and optimization, combinatorial optimization. Dr. Aydin is currently a Fellow of Higher Education Academy, UK, a member of EPSRC College, a senior member of IEEE and a senior member of ACM. In addition to being a member of advisory committees of many international conferences, he is an Editorial Board Member of various peer-reviewed international journals. He has served as guest editor for a number of special issues of peer-reviewed international journals.",institutionString:null,institution:{name:"University of the West of England",institutionURL:null,country:{name:"United Kingdom"}}},editorTwo:null,editorThree:null,series:{id:"14",title:"Artificial Intelligence",doi:"10.5772/intechopen.79920",issn:"2633-1403"},editorialBoard:[{id:"275140",title:"Dr.",name:"Dinh Hoa",middleName:null,surname:"Nguyen",slug:"dinh-hoa-nguyen",fullName:"Dinh Hoa Nguyen",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRbnKQAS/Profile_Picture_1622204093453",institutionString:null,institution:{name:"Kyushu University",institutionURL:null,country:{name:"Japan"}}},{id:"20259",title:"Dr.",name:"Hongbin",middleName:null,surname:"Ma",slug:"hongbin-ma",fullName:"Hongbin Ma",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRhDJQA0/Profile_Picture_2022-05-02T08:25:21.jpg",institutionString:null,institution:{name:"Beijing Institute of Technology",institutionURL:null,country:{name:"China"}}},{id:"28640",title:"Prof.",name:"Yasushi",middleName:null,surname:"Kambayashi",slug:"yasushi-kambayashi",fullName:"Yasushi Kambayashi",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYOQxQAO/Profile_Picture_1625660525470",institutionString:null,institution:{name:"Nippon Institute of Technology",institutionURL:null,country:{name:"Japan"}}}]},onlineFirstChapters:{paginationCount:7,paginationItems:[{id:"79909",title:"Cryopreservation Methods and Frontiers in the Art of Freezing Life in Animal Models",doi:"10.5772/intechopen.101750",signatures:"Feda S. 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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.",annualVolume:11403,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/7.jpg",editor:{id:"351533",title:"Dr.",name:"Slawomir",middleName:null,surname:"Wilczynski",fullName:"Slawomir Wilczynski",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000035U1loQAC/Profile_Picture_1630074514792",institutionString:null,institution:{name:"Medical University of Silesia",institutionURL:null,country:{name:"Poland"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"5886",title:"Dr.",name:"Alexandros",middleName:"T.",surname:"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",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",middleName:"R.",surname:"Gharieb",fullName:"Reda Gharieb",profilePictureURL:"https://mts.intechopen.com/storage/users/225387/images/system/225387.jpg",institutionString:"Assiut University",institution:{name:"Assiut University",institutionURL:null,country:{name:"Egypt"}}}]},{id:"8",title:"Bioinspired Technology and Biomechanics",keywords:"Bioinspired Systems, Biomechanics, Assistive Technology, Rehabilitation",scope:'Bioinspired technologies take advantage of understanding the actual biological system to provide solutions to problems in several areas. Recently, bioinspired systems have been successfully employing biomechanics to develop and improve assistive technology and rehabilitation devices. The research topic "Bioinspired Technology and Biomechanics" welcomes studies reporting recent advances in bioinspired technologies that contribute to individuals\' health, inclusion, and rehabilitation. Possible contributions can address (but are not limited to) the following research topics: Bioinspired design and control of exoskeletons, orthoses, and prostheses; Experimental evaluation of the effect of assistive devices (e.g., influence on gait, balance, and neuromuscular system); Bioinspired technologies for rehabilitation, including clinical studies reporting evaluations; Application of neuromuscular and biomechanical models to the development of bioinspired technology.',annualVolume:11404,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/8.jpg",editor:{id:"144937",title:"Prof.",name:"Adriano",middleName:"De Oliveira",surname:"Andrade",fullName:"Adriano Andrade",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRC8QQAW/Profile_Picture_1625219101815",institutionString:null,institution:{name:"Federal University of Uberlândia",institutionURL:null,country:{name:"Brazil"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"49517",title:"Prof.",name:"Hitoshi",middleName:null,surname:"Tsunashima",fullName:"Hitoshi Tsunashima",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYTP4QAO/Profile_Picture_1625819726528",institutionString:null,institution:{name:"Nihon University",institutionURL:null,country:{name:"Japan"}}},{id:"425354",title:"Dr.",name:"Marcus",middleName:"Fraga",surname:"Vieira",fullName:"Marcus Vieira",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003BJSgIQAX/Profile_Picture_1627904687309",institutionString:null,institution:{name:"Universidade Federal de Goiás",institutionURL:null,country:{name:"Brazil"}}},{id:"196746",title:"Dr.",name:"Ramana",middleName:null,surname:"Vinjamuri",fullName:"Ramana Vinjamuri",profilePictureURL:"https://mts.intechopen.com/storage/users/196746/images/system/196746.jpeg",institutionString:"University of Maryland, Baltimore County",institution:{name:"University of Maryland, Baltimore County",institutionURL:null,country:{name:"United States of America"}}}]},{id:"9",title:"Biotechnology - Biosensors, Biomaterials and Tissue Engineering",keywords:"Biotechnology, Biosensors, Biomaterials, Tissue Engineering",scope:"The Biotechnology - Biosensors, Biomaterials and Tissue Engineering topic within the Biomedical Engineering Series aims to rapidly publish contributions on all aspects of biotechnology, biosensors, biomaterial and tissue engineering. We encourage the submission of manuscripts that provide novel and mechanistic insights that report significant advances in the fields. Topics can include but are not limited to: Biotechnology such as biotechnological products and process engineering; Biotechnologically relevant enzymes and proteins; Bioenergy and biofuels; Applied genetics and molecular biotechnology; Genomics, transcriptomics, proteomics; Applied microbial and cell physiology; Environmental biotechnology; Methods and protocols. Moreover, topics in biosensor technology, like sensors that incorporate enzymes, antibodies, nucleic acids, whole cells, tissues and organelles, and other biological or biologically inspired components will be considered, and topics exploring transducers, including those based on electrochemical and optical piezoelectric, thermal, magnetic, and micromechanical elements. Chapters exploring biomaterial approaches such as polymer synthesis and characterization, drug and gene vector design, biocompatibility, immunology and toxicology, and self-assembly at the nanoscale, are welcome. Finally, the tissue engineering subcategory will support topics such as the fundamentals of stem cells and progenitor cells and their proliferation, differentiation, bioreactors for three-dimensional culture and studies of phenotypic changes, stem and progenitor cells, both short and long term, ex vivo and in vivo implantation both in preclinical models and also in clinical trials.",annualVolume:11405,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/9.jpg",editor:{id:"126286",title:"Dr.",name:"Luis",middleName:"Jesús",surname:"Villarreal-Gómez",fullName:"Luis Villarreal-Gómez",profilePictureURL:"https://mts.intechopen.com/storage/users/126286/images/system/126286.jpg",institutionString:null,institution:{name:"Autonomous University of Baja California",institutionURL:null,country:{name:"Mexico"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"35539",title:"Dr.",name:"Cecilia",middleName:null,surname:"Cristea",fullName:"Cecilia Cristea",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYQ65QAG/Profile_Picture_1621007741527",institutionString:null,institution:{name:"Iuliu Hațieganu University of Medicine and Pharmacy",institutionURL:null,country:{name:"Romania"}}},{id:"40735",title:"Dr.",name:"Gil",middleName:"Alberto Batista",surname:"Gonçalves",fullName:"Gil Gonçalves",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYRLGQA4/Profile_Picture_1628492612759",institutionString:null,institution:{name:"University of Aveiro",institutionURL:null,country:{name:"Portugal"}}},{id:"211725",title:"Associate Prof.",name:"Johann F.",middleName:null,surname:"Osma",fullName:"Johann F. 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