\\n\\n
IntechOpen Book Series will also publish a program of research-driven Thematic Edited Volumes that focus on specific areas and allow for a more in-depth overview of a particular subject.
\\n\\nIntechOpen Book Series will be launching regularly to offer our authors and editors exciting opportunities to publish their research Open Access. We will begin by relaunching some of our existing Book Series in this innovative book format, and will expand in 2022 into rapidly growing research fields that are driving and advancing society.
\\n\\nLaunching 2021
\\n\\nArtificial Intelligence, ISSN 2633-1403
\\n\\nVeterinary Medicine and Science, ISSN 2632-0517
\\n\\nBiochemistry, ISSN 2632-0983
\\n\\nBiomedical Engineering, ISSN 2631-5343
\\n\\nInfectious Diseases, ISSN 2631-6188
\\n\\nPhysiology (Coming Soon)
\\n\\nDentistry (Coming Soon)
\\n\\nWe invite you to explore our IntechOpen Book Series, find the right publishing program for you and reach your desired audience in record time.
\\n\\nNote: Edited in October 2021
\\n"}]',published:!0,mainMedia:{caption:"",originalUrl:"/media/original/132"}},components:[{type:"htmlEditorComponent",content:'With the desire to make book publishing more relevant for the digital age and offer innovative Open Access publishing options, we are thrilled to announce the launch of our new publishing format: IntechOpen Book Series.
\n\nDesigned to cover fast-moving research fields in rapidly expanding areas, our Book Series feature a Topic structure allowing us to present the most relevant sub-disciplines. Book Series are headed by Series Editors, and a team of Topic Editors supported by international Editorial Board members. Topics are always open for submissions, with an Annual Volume published each calendar year.
\n\nAfter a robust peer-review process, accepted works are published quickly, thanks to Online First, ensuring research is made available to the scientific community without delay.
\n\nOur innovative Book Series format brings you:
\n\nIntechOpen Book Series will also publish a program of research-driven Thematic Edited Volumes that focus on specific areas and allow for a more in-depth overview of a particular subject.
\n\nIntechOpen Book Series will be launching regularly to offer our authors and editors exciting opportunities to publish their research Open Access. We will begin by relaunching some of our existing Book Series in this innovative book format, and will expand in 2022 into rapidly growing research fields that are driving and advancing society.
\n\nLaunching 2021
\n\nArtificial Intelligence, ISSN 2633-1403
\n\nVeterinary Medicine and Science, ISSN 2632-0517
\n\nBiochemistry, ISSN 2632-0983
\n\nBiomedical Engineering, ISSN 2631-5343
\n\nInfectious Diseases, ISSN 2631-6188
\n\nPhysiology (Coming Soon)
\n\nDentistry (Coming Soon)
\n\nWe invite you to explore our IntechOpen Book Series, find the right publishing program for you and reach your desired audience in record time.
\n\nNote: Edited in October 2021
\n'}],latestNews:[{slug:"intechopen-supports-asapbio-s-new-initiative-publish-your-reviews-20220729",title:"IntechOpen Supports ASAPbio’s New Initiative Publish Your Reviews"},{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{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"}]},book:{item:{type:"book",id:"10807",leadTitle:null,fullTitle:"Teacher Education - New Perspectives",title:"Teacher Education",subtitle:"New Perspectives",reviewType:"peer-reviewed",abstract:"Teacher education is an increasingly complex and challenging area of research and practice ultimately vital for generations. This book imparts insight and directions for both research and practice in teacher education. Chapters cover a variety of topics, such as collaborative teaching experiences, creativity education in curricula, innovations in science and technology in education, new techniques for learning and teaching subjects such as entrepreneurship, history, mathematics, science, technology, heritage, and early childhood education, and using online social platforms in education.",isbn:"978-1-83969-289-5",printIsbn:"978-1-83969-288-8",pdfIsbn:"978-1-83969-290-1",doi:"10.5772/intechopen.94952",price:119,priceEur:129,priceUsd:155,slug:"teacher-education-new-perspectives",numberOfPages:172,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"3baeedd4e6dfcdbccca461891bd66a8d",bookSignature:"Ulas Kayapinar",publishedDate:"September 22nd 2021",coverURL:"https://cdn.intechopen.com/books/images_new/10807.jpg",numberOfDownloads:3387,numberOfWosCitations:0,numberOfCrossrefCitations:1,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:2,numberOfDimensionsCitationsByBook:0,hasAltmetrics:0,numberOfTotalCitations:3,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"October 22nd 2020",dateEndSecondStepPublish:"November 12th 2020",dateEndThirdStepPublish:"January 11th 2021",dateEndFourthStepPublish:"April 1st 2021",dateEndFifthStepPublish:"May 31st 2021",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"232425",title:"Dr.",name:"Ulas",middleName:null,surname:"Kayapinar",slug:"ulas-kayapinar",fullName:"Ulas Kayapinar",profilePictureURL:"https://mts.intechopen.com/storage/users/232425/images/system/232425.png",biography:"Ulas Kayapinar holds an MA and Ph.D. in Applied Linguistics. He is currently working at the American University of the Middle East, Kuwait, where he received the Faculty Award for Outstanding Teaching and Learning. His research interests lie in language teaching and testing. He has authored two books, one chapter, and numerous articles in internationally indexed journals.",institutionString:"American University of the Middle East",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"American University of the Middle East",institutionURL:null,country:{name:"Kuwait"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"265",title:"Education",slug:"social-sciences-education"}],chapters:[{id:"75218",title:"Let’s Team Up! Measuring Student Teachers’ Perceptions of Team Teaching Experiences",doi:"10.5772/intechopen.96069",slug:"let-s-team-up-measuring-student-teachers-perceptions-of-team-teaching-experiences",totalDownloads:305,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Since collaboration within schools gains importance and is considered significant for teachers’ professional development in order to meet the new 21st-century educational demands, teacher education institutes show a growing interest in field experiences inspired by collaborative learning, such as team teaching. Team teaching is a teaching model in which (student) teachers work collaboratively in the preparation, teaching and evaluation of a course. In order to assess team teaching practices in teacher education by monitoring perceptions of collaborative team teaching experiences, an instrument is needed that offers insights to guide the learning process and support well-founded decision making. Therefore, an easy-to-use quantitative questionnaire to explore student teachers’ team teaching perceptions was developed and validated in four stages: an extensive literature review (1) resulting in a preliminary questionnaire containing advantages and disadvantages of team teaching (2). Next, a pilot study was conducted with 14 student teachers (3), followed by a further validation and reliability study based on exploratory factor analysis, peer debriefing, confirmatory factor analysis and internal consistency analysis with 181 participating student teachers (4). The final questionnaire comprises 29 Likert-items in four scales – collaboration, co-creation, coaching and complexity – and appears to be both valid and reliable.",signatures:"Loan De Backer, Mathea Simons, Wouter Schelfhout and Ellen Vandervieren",downloadPdfUrl:"/chapter/pdf-download/75218",previewPdfUrl:"/chapter/pdf-preview/75218",authors:[{id:"335096",title:"Associate Prof.",name:"Mathea",surname:"Simons",slug:"mathea-simons",fullName:"Mathea Simons"},{id:"335099",title:"Dr.",name:"Wouter",surname:"Schelfhout",slug:"wouter-schelfhout",fullName:"Wouter Schelfhout"},{id:"335100",title:"Prof.",name:"Ellen",surname:"Vandervieren",slug:"ellen-vandervieren",fullName:"Ellen Vandervieren"},{id:"345074",title:"Ph.D. Student",name:"Loan",surname:"De Backer",slug:"loan-de-backer",fullName:"Loan De Backer"}],corrections:null},{id:"76737",title:"Development of Creative Thinking Skills in the Teaching-Learning Process",doi:"10.5772/intechopen.97780",slug:"development-of-creative-thinking-skills-in-the-teaching-learning-process",totalDownloads:556,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Creativity is one of the most appreciated learning skills current the XXI century. The development of creativity has been considered essential in order to achieve an effective and a high-level learning. As different approaches to its study, creativity has been defined as a result, as a process, as a construct derived from the influence of the context and of the experience and as a personality feature of human nature. The aim of this contribution is to explain the study of creativity from the mentioned approaches to achieve a comprehension of such construct. In addition, the focus has been centred on highlight the development of creativity from an educational approach, starting from the description, implication of the use and application of creative strategies in the teaching and learning processes. Finally, a brief description is made of the most important or relevant strategies found in the literature, with emphasis on the incorporation of these strategies in the problem-solving process.",signatures:"Natalia Larraz-Rábanos",downloadPdfUrl:"/chapter/pdf-download/76737",previewPdfUrl:"/chapter/pdf-preview/76737",authors:[{id:"334947",title:"Ph.D.",name:"Natalia",surname:"Larraz-Rábanos",slug:"natalia-larraz-rabanos",fullName:"Natalia Larraz-Rábanos"}],corrections:null},{id:"74953",title:"The Nature of Science and Technology in Teacher Education",doi:"10.5772/intechopen.95829",slug:"the-nature-of-science-and-technology-in-teacher-education",totalDownloads:599,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,abstract:"This chapter is about the Nature of Science (NOS) and the Nature of Technology (NOT) in education. Science includes the systematic study of the structure and actions of the physical and natural world through observation and experiment, and technology is the application of scientific knowledge for practical purposes. NOS and NOT have been used to refer to the epistemology of science, science as a way of knowing, or the values and beliefs inherent to the development of scientific knowledge. These characterizations, nevertheless, remain general, and philosophers of science, historians of science, and the same goes for NOT. Subsequently, an individual’s understanding that observations are constrained by our perceptual apparatus and are characteristically theory-laden is part of that individuals understanding of the NOS and NOT. In general, NOS and NOT refers to principles and ideas which provide a description of science and technology as a way of knowing, as well as characteristics of scientific knowledge. Many of these intrinsic ideas are lost in the everyday aspects of a science classroom, resulting in students learning misaligned ideas about how science is conducted. Understanding how technology relates with science and society is critical for individuals to make informed personal and societal decisions. Nevertheless, in most STEM education contexts, learning about technology typically only means learning how to be an efficient user or, perhaps, an informed competent designer of. A meaningful technology education stresses that science education efforts also teach students about NOT. Essential questions like what technology is, how it is related to, yet distinct from, science, how it shapes and is shaped by society, and perhaps most importantly, how technologies impact the way individuals think and act.",signatures:"Bodil Svendsen",downloadPdfUrl:"/chapter/pdf-download/74953",previewPdfUrl:"/chapter/pdf-preview/74953",authors:[{id:"335363",title:"Associate Prof.",name:"Bodil",surname:"Svendsen",slug:"bodil-svendsen",fullName:"Bodil Svendsen"}],corrections:null},{id:"75118",title:"Learning and Teaching Mathematics with Online Social Networks: The Case of Facebook",doi:"10.5772/intechopen.95998",slug:"learning-and-teaching-mathematics-with-online-social-networks-the-case-of-facebook",totalDownloads:344,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"We present here a study in which a digital-based communication platform is used for collaborative work in the learning and teaching processes. In this case, we focused on Facebook as the online social network to help motivate high-school students to become well prepared for their Bagrut (matriculation) exam in mathematics. To this end, the Center for Educational Technology (CET) established a “virtual review session” on Facebook before the exam in which 614 students and 16 teachers participated. We aimed to answer two questions: what learning and teaching opportunities can Facebook offer to prepare students for the mathematics matriculation exam? and how do students and teachers perceive learning processes via social networks? Our analysis was qualitative. The findings indicate that Facebook, for one, can offer excellent learning and teaching opportunities as a result of the interactions that evolve between the students themselves and between the students and teachers. For the students, this digital social platform helps promote peer evaluation, exposes them to a wide range of questions and solutions, and fosters the development of mathematical thinking and creativity. For the teachers, it helps expand their technological and pedagogical-mathematical knowledge.",signatures:"Yaniv Biton and Ruti Segal",downloadPdfUrl:"/chapter/pdf-download/75118",previewPdfUrl:"/chapter/pdf-preview/75118",authors:[{id:"334761",title:"Dr.",name:"Ruti",surname:"Segal",slug:"ruti-segal",fullName:"Ruti Segal"},{id:"341943",title:"Dr.",name:"Yaniv",surname:"Biton",slug:"yaniv-biton",fullName:"Yaniv Biton"}],corrections:null},{id:"75144",title:"Building Historical Narratives about Controversial Issues on Twitter: An Analysis of Digital Literacy Levels in Secondary School Students",doi:"10.5772/intechopen.95972",slug:"building-historical-narratives-about-controversial-issues-on-twitter-an-analysis-of-digital-literacy",totalDownloads:297,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"This research analyses the literacy levels of a group of Spanish secondary school history students (n = 42) in digital environments (Twitter), with the aim of providing educational clues about the ways in which social discourses are constructed on controversial issues, in particular those generated by the Spanish Civil War. From a qualitative research approach, the most recurrent digital narrative data has been emptied and analyzed, based on three a priori categories of social analysis: gender, historical empathy and social conscience. The results report the predominance of cognitive/inferential literacy skills and, consequently, the need to incorporate new scenarios for teaching-learning history from the theoretical principles of critical pedagogy and education for active, critical and committed citizenship with social participation.",signatures:"Delfín Ortega-Sánchez and César Barba Alonso",downloadPdfUrl:"/chapter/pdf-download/75144",previewPdfUrl:"/chapter/pdf-preview/75144",authors:[{id:"302925",title:"Dr.",name:"Delfín",surname:"Ortega-Sánchez",slug:"delfin-ortega-sanchez",fullName:"Delfín Ortega-Sánchez"},{id:"334489",title:"MSc.",name:"César",surname:"Barba Alonso",slug:"cesar-barba-alonso",fullName:"César Barba Alonso"}],corrections:null},{id:"75693",title:"Research Trends in the Measurement of Entrepreneurial Education: A Bibliographic Coupling Analysis",doi:"10.5772/intechopen.96821",slug:"research-trends-in-the-measurement-of-entrepreneurial-education-a-bibliographic-coupling-analysis",totalDownloads:301,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The literature recognizes the importance of entrepreneurship for the development of students’ job skills and for the socio-economic development of the countries, however, there are mixed results regarding the impact of entrepreneurial education and few validated measures for its evaluation. According to the above, we conducted a bibliometric study related to trends in the measurement of entrepreneurial education. We performed a bibliographic coupling analysis to identify the most relevant publications in this field of study. We identified eleven research trends: (1) Entrepreneurial self-efficacy. (2) Entrepreneurial intention. (3) Entrepreneurship education in higher education institutions. (4) Entrepreneurial skills. (5) Individual and national level determinants of entrepreneurial activity. (6) Drivers of entrepreneurial intention. (7) Assessment instruments of entrepreneurial education impact. (8) University entrepreneurship education program. (9) Social impact of entrepreneurship education. (10) Pedagogies used in entrepreneurship education. (11) Effectiveness of entrepreneurial education. We suggest future lines of research based on the results of our study.",signatures:"Vanessa Pertuz and Luis Francisco Miranda",downloadPdfUrl:"/chapter/pdf-download/75693",previewPdfUrl:"/chapter/pdf-preview/75693",authors:[{id:"334552",title:"Ph.D.",name:"Vanessa",surname:"Pertuz",slug:"vanessa-pertuz",fullName:"Vanessa Pertuz"},{id:"334553",title:"Dr.",name:"Luis Francisco",surname:"Miranda",slug:"luis-francisco-miranda",fullName:"Luis Francisco Miranda"}],corrections:null},{id:"76033",title:"Male Educator Recruitment in Early Childhood Centres: Implications for Teacher Education",doi:"10.5772/intechopen.97085",slug:"male-educator-recruitment-in-early-childhood-centres-implications-for-teacher-education",totalDownloads:399,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The absent male educators in the Early Childhood Development (ECD) programmes have created a gap in the momentum of success gained through fathers’ involvement in the early life of children. Worldwide, the gender imbalance trends in early childhood education and lower primary classes have been immemorial female skewed with men becoming extinct in the arena. Hitherto, copious studies testify of men’s involvement as fathers in young children’s early life as crucial for their social, emotional, and cognitive development. This chapter focuses on the importance of having male educators in the foundation phase of children’s care and learning, barriers to male involvement as educators in early care and learning centres, and how learning institutions can recruit and train male educators specific for the ECD. Male educators in the ECD have been confronted by stigmatisation, ridiculed, hit glass ceilings, and are viewed with hostility and suspicion. A preliminary exploration of literature from renowned published work that focuses extensively on various countries across continents will be covered in this review. This chapter envisaged strategies that could be employed in the recruitment, retention, and active participation of male educators in the ECD settings that will inform policy and teacher education.",signatures:"Joyce Mathwasa and Lwazi Sibanda",downloadPdfUrl:"/chapter/pdf-download/76033",previewPdfUrl:"/chapter/pdf-preview/76033",authors:[{id:"310698",title:"Dr.",name:"Joyce",surname:"Mathwasa",slug:"joyce-mathwasa",fullName:"Joyce Mathwasa"}],corrections:null},{id:"75567",title:"Living Heritage Educational Experiences in a Pandemic Scenario. The Case Study of the Ethnomedicine Museum A. Scarpa",doi:"10.5772/intechopen.96399",slug:"living-heritage-educational-experiences-in-a-pandemic-scenario-the-case-study-of-the-ethnomedicine-m",totalDownloads:273,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Heritage is inherently communicative; it is designed to transmit and represent. As stated by UNESCO, living heritage is fundamental because it provides communities and individuals with a sense of identity and continuity. It can help promote social cohesion, respect for cultural diversity and human creativity, as well as help communities build resilient, peaceful and inclusive societies. Ensuring that cultural heritage fulfils the function for which it was conceived and generated, even in the case of closures forced by health emergencies, means enhancing it, giving it the possibility to continue transmitting culture. In the current COVID-19 global pandemic scenario, we are helped by the many educational strategies available today thanks to science and technology that enable people of all ages to learn continuously, anytime, anywhere and in a variety of situations combining formal, non-formal and informal learning. The current scenario has forced a redesign of the way citizens, and especially students, access their formal education. This contribution aims to highlight the importance of using the self-determined approach for training and proposes a blended learning model (formal in virtual classrooms and informal in a museum) for intercultural education of health professionals. A model which can be reproduced in continuing education and which represents an innovative way of experiencing heritage in any situation.",signatures:"Anna Siri",downloadPdfUrl:"/chapter/pdf-download/75567",previewPdfUrl:"/chapter/pdf-preview/75567",authors:[{id:"334840",title:"Prof.",name:"Anna",surname:"Siri",slug:"anna-siri",fullName:"Anna Siri"}],corrections:null},{id:"75119",title:"Disrupting Certainties: History Education for Informed Lived Citizenships",doi:"10.5772/intechopen.95821",slug:"disrupting-certainties-history-education-for-informed-lived-citizenships",totalDownloads:314,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"How might teacher education engage pre-service teachers with unfamiliar voices and historical representation in an age of diversity, and view history as a critical project for young citizens? This context is situated in an Aotearoa New Zealand university’s initial teacher education (ITE) secondary programme. As a history educator, I negotiate multiple sites’ cultural practices and legacies of doing and being. I juggle professional, curriculum and assessment discursive practices and teachers’ certainties about their history programmes. This involves history theorising, scholarship and expectations. Tensions exist in relation to ‘sacred’ history contexts and knowledge claims embedded in curriculum and assessment standards that act to lessen possibilities of critical approaches. Critical pedagogy informs my stance that young citizens need to be confident and informed about their identity/ies and lived pasts to question what counts as knowledge and in whose interests this knowledge serves. Problematised history pedagogy (PHP) research aimed to disrupt pre-service teachers’ normative discourses. Emergent findings have subsequently shaped my history programme’s pedagogic approaches and evidence-informed assessment. Recent scholarly and public interest in histories that ‘play out’ in Aotearoa New Zealand’s present, serve to refocus history in ITE and schooling spaces to disrupt pedagogic certainties and exclusive notions of citizenship.",signatures:"Philippa A. Hunter",downloadPdfUrl:"/chapter/pdf-download/75119",previewPdfUrl:"/chapter/pdf-preview/75119",authors:[{id:"335578",title:"Dr.",name:"Philipa",surname:"Hunter",slug:"philipa-hunter",fullName:"Philipa Hunter"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"6674",title:"Contemporary Pedagogies in Teacher Education and Development",subtitle:null,isOpenForSubmission:!1,hash:"33d1ab42e6304ea91a1ee326da9b4101",slug:"contemporary-pedagogies-in-teacher-education-and-development",bookSignature:"Yehudith Weinberger and Zipora Libman",coverURL:"https://cdn.intechopen.com/books/images_new/6674.jpg",editedByType:"Edited by",editors:[{id:"201297",title:"Dr.",name:"Yehudith",surname:"Weinberger",slug:"yehudith-weinberger",fullName:"Yehudith 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It is an idiopathic cerebral vasculopathy characterised by progressive stenosis of the terminal internal carotid artery and its branches, usually on both sides, and the development of a compensatory network of abnormal collateral vessels [2]. Unilateral involvement does not rule out this disease [3]. It affects mainly the middle (MCA) and anterior cerebral (ACA) arteries, less commonly the posterior cerebral or the middle meningeal arteries, and in a few cases the arteries that supply other organs [4], like the lungs or kidneys [5]. Some MMD patients suffer from pulmonary artery hypertension, which usually starts in adolescence or young adulthood and progresses slowly [5].
The collateral vessels that develop as the disease progresses [6] have a thin and weak non-elastic wall with aneurysm formation prone to haemorrhages [7, 8, 9]. These aneurysms’ prevalence varies in the different series between 1.9 [10], 2.8% [11], 3.9 [12], 8.3 [6] and 14% [13]. They are usually located in deep areas [11], small in size and with very fragile walls, making their treatment, endovascular or surgical, extremely challenging [11, 12, 14]. They can also be found at the circle of Willis [9, 11, 15, 16], where they usually have a fusiform shape [11, 17] and can lead to a subarachnoid haemorrhage [11]. The prognosis in the case of this type of haemorrhage is poor [11]. Their recommended treatment is brain revascularization (BR) [12, 18, 19] as many regress spontaneously after their haemodynamic stress is reduced [11, 20, 21, 22, 23, 24].
MMD can be associated with other diseases like Down syndrome (trisomy 21) [25], sickle cell disease [26], neurofibromatosis type 1 [27], thalassemia [28], Graves’ disease [29] and after head- and neck-radiotherapy [30]. In this case, it is known as moyamoya syndrome [3].
MMD patients have impaired cerebral haemodynamics with a low cerebral blood flow (CBF) or a poor brain vasodilatory capacity, making them prone to cerebrovascular events [31], particularly at the frontal lobe [32]. The CBF and the cerebral vascular reserve (CVR) capacity are used to evaluate the need for surgical treatment [33, 34, 35, 36].
Although it is a rare disease, it is the leading cause of ischemic stroke in the paediatric population in Korea and Japan [37, 38, 39].
Digital subtraction angiography (DSA) is the gold standard for diagnosis, but Magnetic Resonance Angiography (MRA) is also helpful [40, 41]. More specific methods but not currently used because of the costs and equipment involved are xenon-enhanced CT, DSC, MRI, H2[ [15]O]-PET and [42] I aromatic amines SPECT [43, 44, 45, 46, 47, 48]. These diagnostic techniques are used for preoperative evaluation to decide the best surgical approach. Their drawbacks are that they require contrast agents’ intravenous injection and entail radiation exposure that can be harmful to patients, particularly in the paediatric age group. Preoperative transcranial colour-duplex sonography is a non-invasive method used to evaluate the degree of vascular impairment in MMD and monitor the results after surgical BR [49, 50, 51].
The patients’ mean age at diagnosis peaks at ten and 30–50 years [9, 12, 52] with a ratio of women-to-men 1.00:1.03 [12].
MMD two basic clinical manifestation types are ischemic (30.4%) and haemorrhagic (70.9%) stroke [12]. The ischemic type is more common in children and the haemorrhagic in adults [13, 53]. Other clinical symptoms are headache [54], epilepsy [55], chorea movements [56] and cognitive decline [53, 57]. In comparison, haemorrhages are more frequent in the adult MMD population [58] and ischemic events in the paediatric age group [59, 60, 61, 62]. Patients starting with ischemic symptoms like transitory ischemic attack (TIA) are more prone to develop an ischemic than a haemorrhagic stroke [63, 64]. In the paediatric population, multiple ischemic strokes, significantly if both hemispheres are affected, can lead to severe cognitive impairment and developmental delay [65, 66, 67]. Brain infarcts present in the ACA and MCA territories and less commonly in the posterior cerebral artery (PCA) covered area and vertebrobasilar system [68]. Posterior circulation involvement leads to more severe symptomatology and worse outcomes [69]. Haemorrhagic strokes are often followed by rebleeding and infarction in short to medium follow-up [70].
Unless surgical BR is undertaken, the stroke rate is 18% for the first year and 3.2–5% for the following years [71, 72, 73]. Once patients suffer an ischemic or haemorrhagic stroke, the risk of a new cerebrovascular insult in the following five years is 65% [74, 75].
In MMD, the PCA provides the collateral flow to the anterior circulation [32, 76, 77, 78, 79] with choroidal anastomosis and hypertrophic collateral vessel formation [76, 80]. This increased blood flow through the PCA creates haemodynamic stress on the vertebrobasilar system and facilitates aneurysm formation [76, 81]. The choroidal collateral vessels are potential sources of haemorrhages and rebleeding [82]. A common complication is a brain haemorrhage [80, 83, 84], usually intraventricular [80, 85], particularly in the rear brain areas [80]. Moreover, MMD patients with haemorrhages in the posterior part of the brain have a higher risk of rebleeding than those with haemorrhages located in the anterior part [85]. PCA stenosis is typical of juvenile-onset MMD [86].
Microbleeds’ are more common in MMD than in the general population [87] and usually in the periventricular areas, followed by the basal ganglia and thalamus [87, 88, 89]. The asymptomatic microbleeds are related to hypertrophy, dilatation and aneurysm formation of the posterior communicating and anterior choroidal arteries [90, 91, 92]. Those areas are where the MMD related haemorrhagic strokes typically happen, and these microbleeds are an excellent prognosticator of future haemorrhages [83, 93, 94].
Asymptomatic MMD patients have a 3.2% annual stroke risk [95], more often haemorrhagic than ischemic, showing an evolving situation that is usually is not silent nor stable [72, 96], particularly in those with a compromised CVR capacity [97]. Moreover, cognitive decline over time is the rule [98]. Thus, asymptomatic MMD patients should be monitored closely and submitted to surgical BR at the slightest sign of deterioration [99].
Although there might be a subgroup of children with a benign course [100], most have a relentless and progressive worsening [99], and unilateral disease often evolves to bilateral [99]. Predictors of unfavourable outcome are onset at a younger age, a long time before BR, brain infarcts, and PCA involvement [86]. Children under nine years of age with minor changes in the contralateral brain hemisphere are most likely to undergo disease progression [101, 102].
This disease, particularly if untreated, can induce severe disability and even death [3]. White matter involvement, particularly in adults, correlates with cognitive impairment [57].
Without a known aetiology, the only treatment is symptomatic. The medical treatment does not affect this disease’s relentless progression [103, 104], and patients under drug treatment alone have a 5-year 65% stroke risk [72, 105, 106, 107] which climbs up to a dismal 82% in case of bilateral involvement [105]. In children, it has been reported that under conservative treatment, 37% will present clinical symptoms of neurological damage, and 3% will eventually die [108]. It can be helpful, though, to alleviate some symptoms like headache or epileptic seizures [109]. Endovascular treatment has been attempted in some cases with unsatisfactory results [110, 111, 112]. The surgical treatment with BR offloads the haemodynamic stress [113] and reduces the risk of subsequent ischemic and haemorrhagic cerebrovascular events [104, 114, 115, 116, 117, 118, 119, 120, 121, 122], providing symptom improvement to 87% of patients [104].
BR techniques can be classified into two main groups: direct and indirect. The first involves artery-to-artery bypasses between an external carotid artery branch and a brain arterial vessel, usually between the superficial temporal (STA) and MCA [42, 115, 123]. Other donor vessels are the occipital [69, 124], deep temporal, and middle meningeal [125] arteries. The STA can be connected to a branch of the middle cerebral [126] or anterior cerebral [127] arteries. Meanwhile, the occipital artery is sutured to the PCA [128] but can also be used to revascularize the MCA territory [129]. The size of the donor artery should be >0.8 mm to allow the surgical manoeuvres [130]. In children under four years of age, both the STA and the possible recipient brain arteries usually have an insufficient diameter to enable a bypass [131]. Its most significant advantage is that it provides immediate brain haemodynamic improvement. This fast improvement in the brain blood flow reduces the risk of ischemic and haemorrhagic strokes faster than the indirect techniques, which require 3–4 months to achieve the same result [132]. Its main risk is a hyperperfusion-reperfusion syndrome, which can induce haemorrhages with neurological deterioration and worsening [115, 133, 134]. This risk can be minimised with strict postoperative blood pressure control and mild hypotension in symptomatic cerebral hyperperfusion [135]. Direct BR is mainly used to increase the perfusion of the MCA territory [99]. Direct BR of the anterior or PCA branches is challenging as the donor’s vessels are further away, a severe problem when those vascular territories are affected [99]. Under experienced hands, the patency rates are over 90% [136]. As the cortical arteries atrophy, it is increasingly difficult to find a suitable recipient vessel to perform a direct bypass [137]. The ideal is an M3 branch, but micro-anastomoses with these vessels are technically very difficult [138].
In the indirect BR, no arterial anastomoses are performed. Instead, a pedicle graft vascularized by the external carotid artery is placed over the brain’s surface and rely on the new collateral vessel formation between the donor tissue and the ischemic underlying brain [139]. For a successful result, three elements are needed—first, a well-vascularized donor tissue. Second, intimate contact between donor tissue and recipient brain vascularization. And third, a good selection of the hypoperfused recipient brain areas [140]. Indirect BR requires forming a fibrous scar at the donor tissue-brain interface with new collateral vessel formation between the donor and recipient vascular beds [141]. The possibilities of indirect BR techniques are broad [104]. Depending on the donor tissue used, the options are encephalo-myo-synangiosis (EMS) [142] when a muscle is used, encephalo-duro-synangiosis (EDS) [143] with dural graft, split-duro-encephalo-synangiosis (DES) [144, 145] with a split dura graft, encephalo-duro-myo-synangiosis (EDMS) [146] with dural and muscle graft, encephalo-duro-arterio-synangiosis (EDAS) [147, 148, 149, 150] with dura and external carotid artery branch, encephalo-duro-arterio-myo-synagiosis (EDAMS) [151] with dura, an external carotid artery branch and muscle, encephalo-galeo-synangiosis (EGS) [152, 153] with galea, encephalo-pericranium-synangiosis (EPS) [140, 154, 155] with pericranium, omentum transplantation [156, 157] and multiple burr-hole (MBH) [158, 159]. This last surgical technique consists of performing numerous burr holes (10 to 24) through the frontal, parietal and occipital bones, opening the dura and arachnoid and introducing a pericranium flap inside each burr-hole [160]. It can be used isolated, as part of other BR techniques or as a rescue procedure when other surgical approaches have failed or proved insufficient [160, 161, 162]. Not only is it technically effortless and straightforward, but it can be performed under local anaesthesia, which is an advantage in patients in a seriously compromised status [161]. As the dura is also an essential source of collateral vessel formation, a small craniotomy (3–3.5 cm in diameter) placing the pericranium directly over the brain surface provides better results than MBH [140]. Contrarywise, extensive craniotomies are not recommended because they disrupt the already spontaneously formed collateral vascularization increasing the risk of postoperative brain ischemic events [140]. The EPS is particularly helpful to provide collateral circulation to the anterior and PCA territories, areas not easily covered by the STA [140]. Duropexy is crucial in all indirect BR techniques [140].
Direct BR is preferred whenever possible because the haemodynamically compromised hemisphere gets an immediate increase in blood flow, reducing sooner the ischemic and haemorrhagic stroke risk [113, 163]. In contrast, with the indirect techniques, the new collateral vascularization takes 3 to 4 months to develop [53, 164, 165], but long-term, the blood–brain supply is better than with the direct BR [141]. In this period in which the collateral vessel formation is taking place, may persist brain hypoperfusion symptoms, and at times the final result may require an additional surgical BR procedure [128, 166, 167, 168].
With the direct bypass, the brain perfusion improvement is limited to the area where it is undertaken and is not helpful to perfuse extensive ischemic areas [169]. Contrarywise indirect brain vascularization can cover vast vascular territories, mainly if different techniques are employed, like the EDAS combined with MBH [5, 159]. This combination can provide new blood supply to the whole brain, including the interhemispheric frontal areas and occipital lobe [68].
MMD related aneurysms were treated with embolization or surgical clipping [11], and many improved with BR alone [11, 12].
Yaşargil performed the first superficial-temporal artery bypass procedure for an MMD patient in 1972 [170]. In Japan, the first case was completed in 1973 by Kikuchi and Karasawa [171]. In the following years, Karasawa and colleagues in Japan refined this surgical procedure and reported their results in 1978 [123].
The first indirect MMD BR was reported by Karasawa in 1977 and was called encephalo-myo-synangiosis (EMS) [142]. Several researchers confirmed that placement of the temporalis muscle directly over the brain induced collateral vessel formation [172, 173, 174]. In 1980 Matsushima et al. introduced a new indirect BR technique, the EDAS [175]. The STA with a strip of its surrounding galea was placed directly over the brain through a linear dural incision [176]. The galea was sutured to the dural edges, and the STA left over the brain without interrupting its flow, waiting for collateral vessel formation between the dura, the galea, the STA and the brain. It became widely accepted [149, 153, 177, 178, 179, 180]. The EMS was the ground stone for other indirect BR techniques introduced in the following years that used different donor tissues, including other scalp arteries [177], split dura [145], neck [181] or distant [182, 183, 184] muscles and the omentum [156]. Others reported using the pericranium introduced though multiple burr-holes [185]. These techniques revascularized the MCA territory but not those of the anterior and posterior cerebral arteries. In 1992, Inoue et al. [186] introduced the frontal EDAMS to selectively revascularize the anterior cerebral bed to overcome this drawback. Kinugasa et al. [187] two years later reported the ribbon EDAMS, in which a strip of galea and pericranium were placed over the frontal lobes, including the interhemispheric areas. Tenjin et al. [177] published in 1997 the occipital artery’s use to revascularize the PCA territory. Ever since a combination of direct and indirect BR techniques is recommended to achieve a good collateral flow in all three brain arterial territories (anterior, middle, and posterior cerebral arteries).
The hemisphere with the worse vascularization is operated first [12]. If both hemispheres are equally affected, the recommendation is to start with the dominant one and revascularize the other six months latter [178].
In unilateral involvement, if the patients’ symptoms disappear with the unilateral BR and an asymptomatic contralateral hemisphere, no further brain vascularization is advised for the time being [12] as contralateral hemisphere surgical BR in patients with unilateral involvement is controversial [99]. In an ischemic or haemorrhagic stroke, surgical BR is delayed for at least six weeks [188], and ideally, three months [12] and the BR of the contralateral cerebral hemisphere postponed at least 4–6 weeks [148]. Nevertheless, delaying surgical treatment is not advisable in late Suzuki stages [2], as BR improves brain collateral vascularization but not the stroke rate [178]. So, once the diagnosis is made, it is better to avoid unnecessary delays, particularly in children [178].
Direct BR is particularly indicated in adult and adolescent MMD patients [189, 190] but not recommended before ten years of age [191]. An STA to MCA bypass is strongly advised as it corrects the MMD related hemodynamic insufficiency [71, 121]. For a successful result, both the donor and recipient arteries must be at least 0.8 mm in outer diameter [192].
Indirect techniques are much less demanding [193] but are not as valuable for adults as for children [99, 149, 150, 152, 159, 179, 194, 195]. Its main drawback is that BR takes time, on average 3–4 months [196], during which there is a continued risk of cerebrovascular events [140]. In the paediatric age group, these indirect surgical techniques are preferred because the vessels are often of insufficient size and maturity to safely allow a direct arterial bypass [197], significantly below ten years of age [198]. One of the main advantages of indirect BR is the possibility of improving the anterior and PAC territories’ blood perfusion apart from the area covered by the MCA [146, 199]. This possibility of a wider area covered by the BR is crucial in children [99, 152, 158] as they often develop long-term symptoms secondary to hypoperfusion of the whole hemisphere [99]. The BR that use the temporalis muscle is not recommended in children [200] because it thickens with time, compressing the brain and inducing ischemia [201] and because it adheres to the brain and when it contracts can cause long-term neurological damage [202]. Additionally, it generates an unsightly cosmetic head [200].
A combination of direct and indirect BR procedures is often used to profit from the advantages of each of them [34, 114, 136, 150, 160, 203], because the reported results are better than isolated direct or indirect techniques [204, 205, 206, 207]. The treatment strategy has to be tailored to the specific needs of each patient [136, 160, 208]. Combining more than one indirect BR techniques has similar mortality and morbidity as any of them isolated [136].
During the surgical procedure, it is essential to avoid hypotension, hyperthermia, hypocarbia, hypercarbia, and epileptic seizures as they all increase the brain metabolism and thus the chance of an ischemic event [148, 149, 188, 200, 209, 210, 211] and perioperative morbidity [212]. It is vital to control the pain and cry in the postoperative period to avoid hyperventilation as this will produce hypocarbia and an increased risk of ischemia [149, 213]. It is recommended to provide intravenous fluids at 1.5 times the regular maintenance rate for 48–72 hours [3, 149]. Platelet counts and prothrombin time must be monitored and controlled with transfusions if needed [148]. The blood haemoglobin must be kept above the 12–13 g/dL range [148].
Some improvements in the surgical technique have eased the surgical manoeuvres and improved the clinical results. Among them is placing 10-0 Proline sutures to the arachnoid membrane in both sides of the brain sulcus. When some retraction is applied, the recipient artery is brought to the surface, and the STA to MCA bypass is made more easily [192].
While it seems intuitive that arachnoid removal will improve the collateral vessel formation between the donor artery or tissue and the brain [153], it is no longer recommended in indirect BR because it is associated with a significantly higher complication risk with no improvement in the final clinical outcome [148]. Among these complications are the postoperative ischemic strokes secondary to the vasospasm induced by the arachnoid dissection [148]. Preserving the arachnoid membrane reduces the operating time at an average of 30 minutes [148].
The middle meningeal artery provides a vital source of collateral circulation, so during the surgical procedure, this artery and its main branches should be preserved as much as possible [191]. Preservation of this crucial source of collateral vessel formation requires gentle dura handling and careful planning of any dural incisions.
Some have recommended medical treatment for asymptomatic MMD because it is associated with a 5.3% rate of clinical progression [97] unless they have reduced cerebral vascular reserve [97, 103, 214] or smoke [97, 215]. Most of these asymptomatic patients will undergo disease progression [103, 216]. When that happens, surgical BR is advisable [95, 103, 215].
In case of failure to initial BR, a new procedure, direct, indirect or combined, should be attempted, as good outcomes are common [166, 217].
BR decreased both the haemorrhagic [115] and the ischemic stroke [164, 218], but it is more effective in the first than in the second [219, 220, 221]. On one-year follow-up, haemorrhagic stroke was 4.6% for those who underwent BR versus 18.6% for those managed conservatively [115, 116, 164, 219]. The mortality rate due to haemorrhagic stroke is four times higher in the conservative than in the BR group [116, 164, 220]. The medical treatment had even worse results in the paediatric than in the adult MMD age group [107, 222].
Younger age at BR surgery correlates with better results and long-term prognosis [62, 164, 205]. In children, indirect BR is associated with a 0.4%/year symptomatic haemorrhage and 0.2%/year infarction rates, with cumulative incidences of 1.8% at ten, 7.3% at 20 and 7.3% at 30 years [223, 224]. There are no statistically significative differences in clinical outcome between direct, indirect and combined BR procedures [99, 205]. The average good clinical outcome is 84.8–88% [143, 205] with a 6.4% 5-year risk of ischemic or haemorrhagic stroke [143]. Children seem to improve more than adults (93% versus 82.7%) [205].
Direct BR with extra-intracranial artery bypass significantly decreases the haemorrhagic stroke rate [115, 223], particularly in the patients with haemorrhages in the posterior half of the brain [85]. Compared to indirect procedures, it reduces the stroke risk [116, 205, 219, 221], particularly the haemorrhagic type in adults [225] and adolescents [196]. These differences are not so evident in children as adults due to the technical difficulty in performing a successful arterial bypass in the first group [140]. Both in adults and the paediatric population, direct BR is technically more challenging that indirect BR, demands a longer operating time, and there is always the risk of hyperperfusion syndrome [116]. There no statistically significative difference in the number of perioperative complications between direct and indirect BR techniques [219]. The direct bypass was accompanied by an annual stroke rate of 0–6% for children and 1.4% for adults, while the indirect techniques had a 1.6% stroke rate for the same period of time [196]. Direct BR is recommended whenever it is technically feasible [197, 221].
Indirect BR is easier to perform, but 40–50% of adult MMD patients do not develop an adequate collateral arterial circulation [53, 62, 141, 226]. These results have been improved with changes in the surgical technique and perioperative care [140], but a new surgical procedure with a combined approach will be needed if there is an unsatisfactory outcome [189, 207, 224]. Meanwhile, paediatric patients submitted to indirect BR have low middle and long term haemorrhagic stroke rates [227, 228].
Perioperative complications happen in 9.4–13.6% of BR procedures [116, 149, 194, 205, 219, 221, 226] with a 0–0.5% [188] mortality rate. Indirect BR has a significantly higher postoperative stroke rate than direct techniques [116, 205] but fewer haemorrhages and no hyperperfusion syndrome [140, 229, 230]. The incidence of postoperative surgical complications is higher in Asian than other racial groups (6.51/100,00 inhabitants/year versus 5.21/100,000/persons/year) [198, 231]. They also show a different response to BR [198]. Patients with MMD associated with other diseases have a higher perioperative complication rate than regular MMD patients [188].
Preoperative infarction is related to a greater risk of postoperative complications [232, 233].
Direct or combined BR is associated with better outcomes than indirect BR, particularly in the ischemic type MMD [140, 190, 205]. Meanwhile, for haemorrhagic strokes, there are no differences between direct, indirect or combined BR, and thus the indirect techniques are recommended because they are more accessible to perform [205].
The best collateral vessel formation results are obtained using a superficial temporal to MCA bypass combined with an EDAMS and lowest with EDAS [140]. Nevertheless, EDAS combined with multiple burr-holes can provide similar outcomes with a less technically demanding procedure and fewer postoperative negative events [159, 177].
Surgical BR in MMD can prevent future cerebrovascular insults and avoid cognitive decline [116, 117, 227]. It is indicated in asymptomatic patients at the slightest sign of disease progression or patient neurological or mental impairment [103, 234, 235], particularly in the paediatric age group [62, 103]. If performed early before irreversible damage, it can improve the neurological status and prevent the cognitive decline [103], stopping or at least slowing the progression of this nasty disease [136, 206, 234]. Ideally, in children, the surgical BR should be performed not later than three months after the first symptoms appear at a young age [190], the best before six years of age [106].
MMD is an uncommon cerebrovascular disorder with a higher frequency among people with Asian ancestry. Medical treatment is not helpful to stop the MMD progression and only can control minor symptoms but not ischemic nor haemorrhagic events. BR can improve brain vascularization, providing a collateral blood supply source that contains this nasty disease’s progression. Direct BR is more effective in adults and adolescents than in the paediatric population. Children benefit most from indirect BR. Combined BR improves the results from direct and indirect BR and can also be used as a rescue procedure. Although controversial, many surgeons posit that asymptomatic MMD patients should be submitted to preventive BR before irreversible brain damage happens.
ACA | anterior cerebral artery |
BR | brain revascularization |
CBF | cerebral blood flow |
CVR | cerebral vascular reserve |
DES | split-duro-encephalo-synangiosis |
EDS | encephalo-duro-synangiosis |
EDAMS | encephalo-duro-arterio-myo-synagiosis |
EDAS | encephalo-duro-arterio-synangiosis |
EDMS | encephalo-duro-myo-synangiosis |
EGS | encephalo-galeo-synangiosis |
EMS | encephalo-myo-synangiosis |
EPS | encephalo-pericranium-synangiosis |
MBH | multiple burr-hole |
MCA | middle cerebral artery |
MMD | moyamoya disease |
PCA | posterior cerebral artery |
STA | superficial temporal artery |
TIA | transitory ischemic attack |
Kisspeptins are a family of neuropeptides with diverse functions in humans. They are cleaved from a precursor peptide encoded by the
Kisspeptin neurons are primarily located in the preoptic area and hypothalamic arcuate nucleus and function as upstream regulators of GnRH neurons [10]. In both of these anatomic locations, serum estrogen and progesterone concentrations have been shown to regulate kisspeptin-mediated GnRH secretion [11]. During the early follicular phase of the menstrual cycle, estrogen exerts negative feedback on GnRH stimulation of luteinizing hormone (LH) secretion. As the follicular phase progresses, rising estrogen levels result in pulsatile secretion of GnRH, which then stimulates the pulsatile release of follicle-stimulating hormone (FSH) and LH [10]. This pulsatile secretion pattern is likely mediated by kisspeptin through regulation of GnRH neurons. Involvement of kisspeptin in this regulatory pathway is suspected because GnRH neurons lack estrogen and progesterone receptors, and thus cannot directly respond to serum sex steroid concentrations [12, 13]. The absence of a direct biochemical connection between the gonads and hypothalamus suggests the presence of an intermediary signal. This “missing link” is thought to be kisspeptin neurons, which express estrogen receptors and secrete a ligand that can bind to GnRH [12].
During the early follicular phase when follicles are underdeveloped, kisspeptin levels are low [4, 14]. A study by Zhai et al. showed that kisspeptin levels sharply increase when the dominant follicle reaches 1.2 cm in diameter [14]. Kisspeptin levels during the periovulatory period are then high [4, 14, 15], and may have potential in predicting development of the dominant ovarian follicle [14]. A study by Dhillo et al. demonstrated that administration of exogenous kisspeptin to healthy women results in increased gonadotropin secretion; this response is most potent during the preovulatory phase [16].
A study by Meczekalski et al. demonstrated that kisspeptin and LH are co-secreted (i.e. each kisspeptin pulse is accompanied by a pituitary LH pulse in response to a hypothalamic GnRH pulse) [11]. Another study demonstrated that blockade of the kisspeptin receptor (GPR54) resulted in blockade of pulsatile LH secretion [17]. There is also topographical evidence of the connection between GnRH and kisspeptin neurons – in several species, it has been shown that GnRH neuronal axons extend from the arcuate nucleus, where kisspeptin neurons are located, to the median eminence, where GnRH is secreted [12]. Human studies have not reproducibly demonstrated this neuroanatomy for all GnRH neurons, which may suggest that kisspeptin neuronal connections in humans are more complex [11, 18].
At mid-cycle, estrogen secreted by the preovulatory follicle eventually triggers GnRH neurons to transition from pulsatile GnRH secretion to sustained secretion. The mechanism by which estrogen transforms from a negative to positive feedback signal on the hypothalamus still remains unclear. Estrogen binds to the ERα receptor on kisspeptin neurons in the arcuate nucleus, inhibiting kisspeptin secretion and subsequent GnRH secretion [15]. In the anteroventral periventricular nucleus, estrogen binds kisspeptin ERα receptors and exerts positive feedback, which ultimately initiates the LH surge associated with ovulation.
The sustained secretion of high concentrations of GnRH (GnRH surge) occurs for over 24 hours and triggers the pituitary gland to secrete high levels of LH (LH surge) [19]. The LH surge is what ultimately triggers ovulation [7]. The LH surge is also the target of at-home ovulation predictor kits [14]. This cascade of hormone surges is thought to be primarily regulated by kisspeptin; in fact, kisspeptin is the most potent activator of GnRH neurons discovered to date [5]. It is suspected that rising estrogen levels during the follicular phase stimulate kisspeptin neurons, which then activate GnRH neurons to initiate the GnRH surge [7]. In contrast, administration of a monoclonal antibody that blocks kisspeptin has been shown to prevent ovulation in rat models [20].
It is postulated that kisspeptin could be useful as a biomarker of the periovulatory/ovulatory phase [14]. This would be clinically useful because kisspeptin surges prior to LH and therefore could predict the time of ovulation before it happens (rather than as it happens). The target of most ovulation prediction kits is LH, which surges at the time of ovulation. According to Zhai et al., the probability of ovulation is increased when kisspeptin surges on the 11th day and LH surges on the 14th day [14]. In comparison, a study by Goto et al. showed that administration of a kisspeptin antagonist resulted in shrinkage of ovarian follicles and delayed ovulation [21].
Kisspeptin is not only expressed in the central nervous system – it also performs peripheral functions. Expression of kisspeptin and its receptor KISS-1 has been demonstrated in the human ovary, fallopian tube, uterus, and placenta [22]. It is thought that kisspeptin primarily functions in the hypothalamus, but also interacts between the signaling pathways of the central and peripheral reproductive systems [23]. In fact, several studies have supported the idea that kisspeptin exerts direct effects on ovarian tissue via ovarian kisspeptin receptors [24, 25, 26].
A number of studies have demonstrated that kisspeptin is expressed at the maternal-fetal interface of many species, including humans [27]. In the human uterus, kisspeptin is expressed in the endometrial epithelial and stromal cells, but not in the myometrium [28]. In the early placenta, kisspeptin is initially produced by villous cytotrophoblast cells, then villous syncytiotrophoblast cells and the placental bed [29, 30]. As pregnancy progresses, placental production of kisspeptin declines [31, 32].
Kisspeptin expression in the endometrium is absent during the proliferative and early secretory phases but becomes abundant during the late secretory phase [27, 33]. This indicates a potential role of kisspeptin in the preparation of endometrial tissue for implantation. Kisspeptin knockout mice exhibit thin, weak uteri with almost no endometrial glands, suggesting kisspeptin is an important regulator of normal endometrial development [34]. Kisspeptin may also act as a mediator that facilitates implantation of the growing embryo to the uterine wall. It has been shown that exogenous kisspeptin administration strengthens adhesion of kisspeptin-expressing trophoblast cells to collagen present in uterine tissue [34]. Immediately after implantation, kisspeptin levels are known to rise; this suggests involvement of kisspeptin during the decidualization process [35]. A study by Wu et al. demonstrated a dose-dependent relationship between kisspeptin expression and inhibition of cell invasion/migration in human decidualized endometrial cells [29]. In contrast, a kisspeptin antagonist called kisspeptin 234 stimulates the process of decidual invasion and migration [29]. Similarly, when small interfering RNAs that antagonize kisspeptin are introduced, stromal decidualization is impaired [35]. In a study by Calder et al., ablation of the KISS-1 gene and subsequent absence of kisspeptin expression resulted in infertile mice [36]. Even in mice that received rescue gonadotropins and estradiol, which restored ovulation, the mice embryos could not implant in the mice that lacked KISS-1. These embryos were, however, able to implant in wildtype mice [36].
Kisspeptin was originally identified as a suppressor of cancer metastasis; its function in the regulation of cellular proliferation and growth is also integral to the process of placentation. The early placenta expresses high levels of kisspeptin, perhaps to tame the invasive and migratory capability of trophoblasts [32]. Kisspeptin decreases the activity of collagenases, matrix metalloproteinases, and vascular endothelial growth factor, which are all signaling proteins involved in trophoblast proliferation [31, 37]. Kisspeptin also supports the adhesion of extravillous trophoblasts to the endometrium, which inhibits migration [38]. This careful balance between invasion and the prevention of invasion is essential to the placentation process as well as the appropriate remodeling of the maternal uterine wall [34]. As the placenta develops throughout pregnancy, it exhibits a pattern of kisspeptin expression that follows a circadian rhythm [39]. The term placenta demonstrates kisspeptin surges at 0400 and 1200 daily. This rhythm correlates with circadian expression of other proteins involved in placental physiology, including TNFα, melatonin, and oxytocin [39].
Maternal kisspeptin levels rise dramatically during pregnancy, then return to normal within 15 days of delivery [28]. Unlike β-hCG, kisspeptin levels rise steadily and do not plateau [40]. It is thought that the primary source of maternal kisspeptin is placental tissue [27], and that maternal kisspeptin levels reflect the volume of viable placental tissue [41]. Kisspeptin may be useful as a biomarker of pregnancy due to its association with placental invasion and apoptosis [42]. It also has potential utility as a biomarker of miscarriage.
Spontaneous abortion (SAB) is a common experience, seen in 10–20% of clinically recognized pregnancies [43]. A study by Jayasena et al. showed that maternal plasma kisspeptin is significantly lower in women with early pregnancies who later develop SAB compared to women who have a viable intrauterine pregnancy (IUP) [44]. Maternal kisspeptin levels also had higher diagnostic performance than β-hCG in detecting SAB [44]. Wu et al. demonstrated that women with recurrent SAB have decreased decidual kisspeptin expression compared to women with IUP [45]. Kavvasoglu also showed decreased maternal kisspeptin levels in women with SAB compared to healthy IUPs [46]. Sullivan et al. validated a serum kisspeptin-54 assay as well as confirmed that maternal kisspeptin levels are positively correlated with fetal gestational age and pregnancy viability [40].
There is currently no established clinical test for early miscarriage; diagnosis relies on serial β-hCG measurements and correlation with ultrasound. This requires multiple maternal encounters with the healthcare system, a prolonged timeframe, and can involve considerable distress of the patient and partner. Jayasena et al. describes the current diagnostic pathway for establishing fetal viability as having limited clinical utility due to delay and a high degree of uncertainty [44]. Thus, there is interest in establishing a more accurate and streamlined diagnostic marker of viable IUP vs. SAB.
Kisspeptin has been shown to be massively downregulated in the case of ectopic pregnancy [47]. Ectopic pregnancy occurs when a fertilized ovum implants and develops outside the uterine cavity. Similarly to SAB, ectopic pregnancy is currently diagnosed by serial β-hCG measurements in correlation with ultrasound. Definitive diagnosis may require direct visualization via laparoscopy [48]. A study by Romero-Ruiz et al. explored the roll of kisspeptin in individuals with ectopic pregnancy. They found that maternal circulating kisspeptins gradually increased during the first trimester of pregnancy in healthy controls. However, in those with ectopic pregnancy, kisspeptin levels were suppressed. The study correlated these results to levels of microRNAs (miRNA) (small noncoding RNAs that can modulate gene and protein expression). In particular, miR-324-3p is known to inhibit kisspeptin function. Romero-Ruiz et al. found that in ectopic pregnancies, miR-324-3p was significantly increased in placental tissue (though maternal circulating levels were low). This finding suggests defective export of the miRNA from its embryonic/placental source in ectopic pregnancy, which may further contribute to the local suppression of kisspeptin. The authors suggested that correlation of maternal miR-324-3p with kisspeptin and β-hCG levels could provide a better modality for timely diagnosis of ectopic pregnancy, especially considering the stability of miRNA in maternal serum [46].
Kisspeptin could also have diagnostic utility in identifying women at risk of preeclampsia. A study by Qaio showed that the placentas of term preeclamptic pregnancies express significantly lower kisspeptin levels compared to healthy pregnancies [49]. These findings were reproduced by Farina et al., which demonstrated lower KISS-1 expression in preeclamptic patients compared to healthy pregnant patients [50]. The study also suggested KISS-1 cell-free mRNA has potential to serve as a predictive biomarker of preeclampsia [50]. Matjila et al. investigated the relationship between maternal kisspeptin levels and placental kisspeptin expression in preeclamptic pregnancies – they found that preeclamptic placentas demonstrated high kisspeptin expression but low maternal kisspeptin levels [30]. It is speculated that elevated kisspeptin expression in diseased placentas may inhibit trophoblast invasion and contribute to the development of preeclampsia [30, 34]. Kisspeptin therefore has potential to offer predictive information about the risk of preeclampsia.
Because of its apparent role in reproduction and fertility, there is interest in the use of kisspeptin as a tool to aid in assisted reproductive technology. Exogenous kisspeptin has been used to trigger oocyte maturation in women undergoing in vitro fertilization (IVF) with very low rates of ovarian hyperstimulation syndrome (OHSS) [41, 51]. Oocyte maturation is the process during which an oocyte transitions from metaphase I to metaphase II; at this time, it is capable of becoming fertilized [51]. Jayasena et al. demonstrated that a single kisspeptin bolus was capable of producing an LH surge that induced oocyte maturation in women undergoing IVF [41]. This was an important study, as it was the first to label kisspeptin as an effective maturation trigger. 92% of the study participants who received kisspeptin had at least one embryo available for transfer [41]. A study by Owens et al. then demonstrated that when kisspeptin is administered as an oocyte trigger during IVF cycles, granulosa cell gene expression is altered in such a way that increases FSH and LH receptor expression [52]. This altered gene expression is postulated to augment downstream signaling, resulting in increased sex steroid synthesis [52]. In fact, kisspeptin is currently considered to be the most potent stimulator of GnRH secretion [53, 54].
OHSS is considered a serious adverse event during IVF treatment and is typically related to the use of hCG as a trigger for oocyte maturation. This syndrome is characterized by extreme vascular permeability, which can result in pleural effusions, ascites, renal impairment, and in severe cases, death [51]. This vascular permeability is a downstream effect of hCG-mediated release of vascular endothelial growth factor (VEGF) from the ovary [55]. Kisspeptin has been shown to directly inhibit ovarian VEGF production, which significantly decreases the risk of OHSS when used as a trigger for ovulation induction [56]. Moreover, kisspeptin acts to release endogenous GnRH, which triggers an LH surge dependent on the individual’s own GnRH reserves, and is unlikely to excessively or pathologically stimulate the ovaries [57].
In addition to its role in pregnancy and fertility, kisspeptin is also implicated in sexual development in humans. The target of the kisspeptin molecule is G-protein coupled receptor 54 (GPR54) [58]. A study by de Roux et al. demonstrated that humans with a defect in the
Kisspeptin is thought to be imperative in all phases of sexual development, beginning in the embryonic phase. During the second trimester of pregnancy, GnRH secretion first occurs and is required for normal testicular development [62]. Aberrant gonadal pathways can result in male infants born with microphallus or cryptorchidism [63]. Kisspeptin is suspected to be crucial in the stimulation of GnRH secretion in both infancy and puberty [62].
Kisspeptins have a multitude of regulatory neuroendocrine functions that span the sexual life cycle. Though its mechanisms are not entirely characterized, there is strong evidence supporting its involvement in puberty and development, ovulation, implantation, and pregnancy. Because of their role in these reproductive processes, kisspeptins have potential to be useful as biomarkers in a variety of contexts, such as ovulation prediction and diagnosis of viable IUP. Kisspeptins may also be useful in the advancement of assisted reproductive technology. Continued exploration of kisspeptin function will help to develop and standardize practices that harness its diagnostic and therapeutic potential.
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',metaTitle:"Terms and Conditions",metaDescription:"These terms and conditions outline the rules and regulations for the use of IntechOpen Website at https://intechopen.com and all its subdomains owned by Intech Limited located at 7th floor, 10 Lower Thames Street, London, EC3R 6AF, UK.",metaKeywords:null,canonicalURL:"/page/terms-and-conditions",contentRaw:'[{"type":"htmlEditorComponent","content":"By accessing the website at www.intechopen.com you are agreeing to be bound by these Terms of Service, all applicable laws and regulations, and agree that you are responsible for compliance with any applicable local laws. Use and/or access to this site is based on full agreement and compliance of these Terms. All materials contained on this website are protected by applicable copyright and trademark laws.
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He is a full professor of signal processing and pattern recognition and is head of the Signals and Communications Department at ULPGC, teaching from 2001 on subjects on signal processing and learning theory. His research lines are biometrics, biomedical signals and images, data mining, classification system, signal and image processing, machine learning, and environmental intelligence. He has researched in 52 international and Spanish research projects, some of them as head researcher. He is co-author of 4 books, co-editor of 27 proceedings books, guest editor for 8 JCR-ISI international journals, and up to 24 book chapters. He has over 450 papers published in international journals and conferences (81 of them indexed on JCR – ISI - Web of Science). He has published seven patents in the Spanish Patent and Trademark Office. He has been a supervisor on 8 Ph.D. theses (11 more are under supervision), and 130 master theses. 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He has (co)authored more than 150 publications in indexed journals, international conferences and book chapters, 1 book (in Greek), 3 edited books, and 5 journal special issues. His publications have more than 2100 citations with h-index 27 (GoogleScholar). His research interests include computer/machine vision, machine learning, pattern recognition, computational intelligence. \nDr. Papakostas served as a reviewer in numerous journals, as a program\ncommittee member in international conferences and he is a member of the IAENG, MIR Labs, EUCogIII, INSTICC and the Technical Chamber of Greece (TEE).",institutionString:null,institution:{name:"International Hellenic University",institutionURL:null,country:{name:"Greece"}}},editorTwo:null,editorThree:null},{id:"25",title:"Evolutionary Computation",coverUrl:"https://cdn.intechopen.com/series_topics/covers/25.jpg",isOpenForSubmission:!0,editor:{id:"136112",title:"Dr.",name:"Sebastian",middleName:null,surname:"Ventura Soto",slug:"sebastian-ventura-soto",fullName:"Sebastian Ventura Soto",profilePictureURL:"https://mts.intechopen.com/storage/users/136112/images/system/136112.png",biography:"Sebastian Ventura is a Spanish researcher, a full professor with the Department of Computer Science and Numerical Analysis, University of Córdoba. Dr Ventura also holds the positions of Affiliated Professor at Virginia Commonwealth University (Richmond, USA) and Distinguished Adjunct Professor at King Abdulaziz University (Jeddah, Saudi Arabia). Additionally, he is deputy director of the Andalusian Research Institute in Data Science and Computational Intelligence (DaSCI) and heads the Knowledge Discovery and Intelligent Systems Research Laboratory. He has published more than ten books and over 300 articles in journals and scientific conferences. Currently, his work has received over 18,000 citations according to Google Scholar, including more than 2200 citations in 2020. In the last five years, he has published more than 60 papers in international journals indexed in the JCR (around 70% of them belonging to first quartile journals) and he has edited some Springer books “Supervised Descriptive Pattern Mining” (2018), “Multiple Instance Learning - Foundations and Algorithms” (2016), and “Pattern Mining with Evolutionary Algorithms” (2016). He has also been involved in more than 20 research projects supported by the Spanish and Andalusian governments and the European Union. He currently belongs to the editorial board of PeerJ Computer Science, Information Fusion and Engineering Applications of Artificial Intelligence journals, being also associate editor of Applied Computational Intelligence and Soft Computing and IEEE Transactions on Cybernetics. Finally, he is editor-in-chief of Progress in Artificial Intelligence. 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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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