Collagen types, associated-diseases and mouse models.
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Barely three months into the new year and we are happy to announce a monumental milestone reached - 150 million downloads.
\n\nThis achievement solidifies IntechOpen’s place as a pioneer in Open Access publishing and the home to some of the most relevant scientific research available through Open Access.
\n\nWe are so proud to have worked with so many bright minds throughout the years who have helped us spread knowledge through the power of Open Access and we look forward to continuing to support some of the greatest thinkers of our day.
\n\nThank you for making IntechOpen your place of learning, sharing, and discovery, and here’s to 150 million more!
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Because it is a mental disorder and psychiatry is a branch of medicine, the question how mind and body interact in depression should be treated as a medical rather than metaphysical mind-body problem. The relation between mind and body as it pertains to this illness should be construed in teleological rather than causal terms. Mental states like beliefs and emotions serve an adaptive purpose by constraining the physiologic systems involved in the body's stress response, thus preserving homeostasis and protecting us from various disorders. Depression results when the mind fails its constraining role.",isbn:"978-953-51-3060-4",printIsbn:"978-953-51-3059-8",pdfIsbn:"978-953-51-4891-3",doi:"10.5772/63698",price:119,priceEur:129,priceUsd:155,slug:"depression",numberOfPages:110,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"55a9dc35540a109935252f1cdae88e83",bookSignature:"Dagmar Breznoščáková",publishedDate:"March 29th 2017",coverURL:"https://cdn.intechopen.com/books/images_new/5613.jpg",numberOfDownloads:10366,numberOfWosCitations:6,numberOfCrossrefCitations:8,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:13,numberOfDimensionsCitationsByBook:0,hasAltmetrics:1,numberOfTotalCitations:27,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"June 2nd 2016",dateEndSecondStepPublish:"June 23rd 2016",dateEndThirdStepPublish:"September 19th 2016",dateEndFourthStepPublish:"December 18th 2016",dateEndFifthStepPublish:"February 16th 2017",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"99961",title:"Dr.",name:"Dagmar",middleName:null,surname:"Breznoscakova",slug:"dagmar-breznoscakova",fullName:"Dagmar Breznoscakova",profilePictureURL:"https://mts.intechopen.com/storage/users/99961/images/5320_n.png",biography:"Since 2016, Dagmar Breznoščáková, MD, PhD, has been the vice-president of Slovak Psychiatric Association and CPT member of the Council of Europe with respect to Slovak Republic. Since 2012, she has been the chairwoman of the Section of Psychopharmacology Slovak Psychiatric Association, Slovak Medical Association. In 2006, she was registered in the List of Experts of the Ministry of Justice SR and has since worked as an expert witness in psychiatry. Since 2006, she has also been engaging in private outpatient psychiatric care and psychotherapy. She successfully completed a 4.5-year European training in cognitive behavioral psychotherapy and completed her postgraduate studies at the Masaryk University in Brno, Czech Republic. The topic of her postgraduate study was “Carbohydrate Metabolism and Depression.” After graduation, she started to work as a resident at the Department of Psychiatry, Faculty of Medicine, UPJŠ, and Faculty Hospital in Košice. Since 2005, she has been working as an assistant professor at the Faculty of Medicine, Faculty of Law and Philosophy UPJŠ in Košice. She also lectures and publishes in her field, focusing on affective and anxiety disorders, particularly bipolar disorder, comorbidity of mental disorders, and psychosomatic connections. She is a coauthor of several chapters in foreign as well as domestic publications and author of psychoeducational handbooks for patients and their relatives, all in all over 150 publication outputs. She holds prizes for the best original work for the journal of psychiatry practice and figures in the biographical encyclopedia of Slovak republic personalities Who Is Who. She organizes and actively participates in various psychoeducational and antistigma activities and is the chairwoman of ROZ ODOS Košice o. z., joining together patients, their relatives, professionals, as well as the general public or supporters.",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"University of Pavol Jozef Šafárik",institutionURL:null,country:{name:"Slovakia"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"1057",title:"Neuropsychiatry",slug:"neuropsychiatry"}],chapters:[{id:"54006",title:"Clock Genes in Depression",doi:"10.5772/67261",slug:"clock-genes-in-depression",totalDownloads:1539,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Data demonstrate that abnormal regulation of the circadian system can result in cardiovascular disease, metabolic syndrome, obesity, immune dysfunction, increased risk for cancer, reproductive complications, etc. It is highly individual among depressed patients and may be expressed as a phase advance or phase delay of rhythms and/or increase or decrease in the amplitude. The stress-induced anhedonic-like state characterizes by hypothermia, hypercortisolemia, and hypermelatoninemia associated with disturbances in the circadian system. Mainly Per2 and Bmal1 demonstrate altered expression in the brain and liver: expression of Per2 is sensitive to stress and changes in Bmal1 mostly associated with depressive behavior. The Per1 expression is sustainable in maintaining the circadian rhythm. A normalization of the expression patterns is likely to be essential for the recovery from the pathological state. Depression is a high prevalent disorder. The number of incidents is rising due to changes in lifestyle. The symptomatology is inconsistent and it is difficult to agree on one hypothesis. The disturbances of the 24 h circadian rhythm may be a factor in the development of major depressive disorder. The molecular biology underlying a causal relationship between circadian rhythm and mood disorders is slowly being unraveled. However, many questions still need to be answered.",signatures:"Sofie Laage Christiansen and Elena V. Bouzinova",downloadPdfUrl:"/chapter/pdf-download/54006",previewPdfUrl:"/chapter/pdf-preview/54006",authors:[{id:"193626",title:"Ph.D.",name:"Elena V.",surname:"Bouzinova",slug:"elena-v.-bouzinova",fullName:"Elena V. Bouzinova"},{id:"203327",title:"Dr.",name:"Sofie",surname:"Laage Christiansen",slug:"sofie-laage-christiansen",fullName:"Sofie Laage Christiansen"}],corrections:null},{id:"54141",title:"Brain Lateralization of Emotional Processing in Depression",doi:"10.5772/66828",slug:"brain-lateralization-of-emotional-processing-in-depression",totalDownloads:1885,totalCrossrefCites:2,totalDimensionsCites:4,hasAltmetrics:1,abstract:"There are three major hypotheses regarding the lateralization of emotion in the brain—the right-hemisphere hypothesis (RHH), the valence hypothesis, and the approach-withdrawal hypothesis. The approach-withdrawal hypothesis, which is the most widely accepted, states that emotions that elicit approach behaviors are lateralized to the left hemisphere, while emotions that elicit withdrawal behaviors are lateralized to the right hemisphere. In line with this hypothesis, it has been found that persons with depression show left frontal hypoactivity and right frontal hyperactivity. This hemispheric asymmetry appears not to influence mood but rather emotional reactions to affective stimuli. That is, a person with such an asymmetry does not show a predominant negative mood, but rather heightened negative reactions to occurrences in the environment. The asymmetry may also be a biological marker of depression, with research evidence that it is found in remitted depressives and in infants of depressed mothers. Currently, research in this area focuses on identifying the mechanism underlying the link between the asymmetry and depression.",signatures:"Danielle M. Pereira and Azizuddin Khan",downloadPdfUrl:"/chapter/pdf-download/54141",previewPdfUrl:"/chapter/pdf-preview/54141",authors:[{id:"193068",title:"Associate Prof.",name:"Azizuddin",surname:"Khan",slug:"azizuddin-khan",fullName:"Azizuddin Khan"},{id:"194237",title:"Ms.",name:"Danielle",surname:"Danielle Pereira",slug:"danielle-danielle-pereira",fullName:"Danielle Danielle Pereira"}],corrections:null},{id:"53855",title:"Anxiety and Depression in Cardiovascular Surgery",doi:"10.5772/67064",slug:"anxiety-and-depression-in-cardiovascular-surgery",totalDownloads:1441,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Although anxiety and depression are psychological risk factors for coronary artery disease (CAD), psychological aspect in patients with cardiovascular surgery has been less considered. Cognitive and psychological deficit has been still concerning in spite of notable improvement of cardiovascular surgery using cardiopulmonary bypass perfusion. The purpose of this chapter review is to discuss recent data concerning the prevalence and trend of anxiety and depression of patients with cardiovascular surgery and to introduce the nonpharmacological intervention studies. The prevalence of anxiety and depression of patients after cardiovascular surgeries has varied from 10 to 60% and has been likely higher than that of general people. From the limited studies about patients over 6 months after surgery, we guessed the followings about the trends of anxiety and depression of patients with CABG without any other additional intervention programs before/after surgery: (1) patients improved scores of anxiety and depression 3–6 months after surgery, (2) anxiety decreased considerably for about 6 months after CABG and then leveled out for some time, (3) depression remained a bit higher 6 months and more after CABG. Patients’ longitudinal psychological conditions would have been influenced by not only invasive cardiovascular surgery but also life events. The nonpharmacology intervention would have improved patients’ psychological conditions. Further research is needed to clarify the long-term psychological outcome and to develop the effective intervention programs toward patients with cardiovascular surgery.",signatures:"Yuko Okamoto and Noboru Motomura",downloadPdfUrl:"/chapter/pdf-download/53855",previewPdfUrl:"/chapter/pdf-preview/53855",authors:[{id:"49017",title:"Prof.",name:"Noboru",surname:"Motomura",slug:"noboru-motomura",fullName:"Noboru Motomura"},{id:"193513",title:"Dr.",name:"Yuko",surname:"Okamoto",slug:"yuko-okamoto",fullName:"Yuko Okamoto"}],corrections:null},{id:"53777",title:"Chronic Pain and Depression",doi:"10.5772/66671",slug:"chronic-pain-and-depression",totalDownloads:2389,totalCrossrefCites:1,totalDimensionsCites:2,hasAltmetrics:1,abstract:"Today, it is clear that chronic pain and depression are closely related. Depression can cause pain, and chronic pain can cause depression too. According to the American Pain Foundation, about 32 million people in the U.S. report have had pain lasting longer than 1 year. Statistical international data prove that more than half of the patients with pain are depressed or have mood swings, and on average, 65% of depressed people also complain of pain. Patients simultaneously suffering of chronic pain and limited independence are especially vulnerable. Fibromyalgia (FM) is one of the most common chronic pain syndromes, affecting 15 up to 5% of world population, is characterized as diffuse widespread body pain, with definite tender points and clinical features, and also triggers the development of depression. Depression severity in patients with FM worsens severity of pain. Depressive disorders are observed in approximately 90% of patients with FM. Pain triggers development of depressive conditions in patients with chronic character of pain, and time course of disease shows certain pattern of increasing of severity of depression and worsens long term outcomes. Patients with chronic pain must be evaluated for depression, and successful management of pain must include treatment of depressive mood too.",signatures:"Aleksandra A. Karapetyan and Hovhannes M. Manvelyan",downloadPdfUrl:"/chapter/pdf-download/53777",previewPdfUrl:"/chapter/pdf-preview/53777",authors:[{id:"71210",title:"Prof.",name:"Hovhannes",surname:"Manvelyan",slug:"hovhannes-manvelyan",fullName:"Hovhannes Manvelyan"},{id:"193854",title:"Dr.",name:"Aleksandra",surname:"Karapetyan",slug:"aleksandra-karapetyan",fullName:"Aleksandra Karapetyan"}],corrections:null},{id:"53680",title:"Investigating the Relationship between Depression, Negative Automatic Thoughts, Life Satisfaction and Symptom Interpretation in Turkish Young Adults",doi:"10.5772/66622",slug:"investigating-the-relationship-between-depression-negative-automatic-thoughts-life-satisfaction-and-",totalDownloads:1695,totalCrossrefCites:4,totalDimensionsCites:6,hasAltmetrics:0,abstract:"The purpose of this study is to examine the relationship between depression, negative automatic thoughts, life satisfaction, number of symptoms, psychologizing, somatizing and normalizing in young adults. The mediator role of life satisfaction in the relationship between negative automatic thoughts and depression especially is the major question of this study. Participants are composed of 115 volunteer teacher candidates from an urban Turkish university. Their ages vary between 21 and 29. The data are collected through Beck Depression Inventory, Life Satisfaction Scale, Automatic Thoughts Scale, Symptom Interpretation Questionnaire and Personal Information Form. As a result, it is seen that the depression scores of young adults do not differ according to gender and according to whether they encountered an event causing stress in the past 3 months or not. Another finding is that five variables (negative automatic thoughts, life satisfaction, number of symptoms, psychologizing and normalizing) are significant predictors in explaining the depression level of young adults. Together, these five variables explain 52% of the young adults’ depression. Another finding of the study is that negative automatic thoughts of young adults make them negatively assess quality of life and this causes the depression levels to increase.",signatures:"Yasemin Yavuzer and Zeynep Karataş",downloadPdfUrl:"/chapter/pdf-download/53680",previewPdfUrl:"/chapter/pdf-preview/53680",authors:[{id:"193985",title:"Associate Prof.",name:"Yasemin",surname:"Yavuzer",slug:"yasemin-yavuzer",fullName:"Yasemin Yavuzer"},{id:"196063",title:"Dr.",name:"Zeynep",surname:"Karataş",slug:"zeynep-karatas",fullName:"Zeynep Karataş"}],corrections:null},{id:"53669",title:"Body-Mind Connectedness: Integrative Body-Mind-Spirit Group Work for Depressed Persons with Salient Somatic Disturbances",doi:"10.5772/66960",slug:"body-mind-connectedness-integrative-body-mind-spirit-group-work-for-depressed-persons-with-salient-s",totalDownloads:1417,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:1,abstract:"Globally, depression frequently comorbid with a variety of physical illnesses, which exert substantial mental and somatic distresses on patients. Sleep disturbance is one of the common conditions reported by individuals with either, mental or physical illnesses. Complex interaction among depression, sleep and physical illnesses highlighted the essential mind‐body connection in the planning of integrative care and other clinical services. A number of eastern mind‐body practices, such as Qigong, acupuncture and meditation, have been frequently studied indicating the efficacy of mind‐body connection in complementary therapies. This chapter will introduce the integrative body‐mind‐spirit (I‐BMS) group work, which has been found effective in addressing comorbid depressed mood and somatic afflictions, especially sleep disturbances among Hong Kong Chinese adults.",signatures:"Sylvia Hong Yao, Jane Xiao-Wen Ji, Celia Hoi Yan Chan and Cecilia\nLai Wan Chan",downloadPdfUrl:"/chapter/pdf-download/53669",previewPdfUrl:"/chapter/pdf-preview/53669",authors:[{id:"194033",title:"Ms.",name:"Hong",surname:"Yao",slug:"hong-yao",fullName:"Hong Yao"},{id:"194041",title:"Ms.",name:"Xiaowen",surname:"Ji",slug:"xiaowen-ji",fullName:"Xiaowen Ji"},{id:"194042",title:"Prof.",name:"Lai Wan",surname:"Chan",slug:"lai-wan-chan",fullName:"Lai Wan Chan"},{id:"195960",title:"Dr.",name:"Celia Hoi Yan",surname:"Chan",slug:"celia-hoi-yan-chan",fullName:"Celia Hoi Yan Chan"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited 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The extracellular matrix (ECM) is the cell structural environment in tissues and organs. The ECM is a dynamic structure that it is constantly remodelled. It contributes to tissue integrity and mechanical properties. It is also essential for maintaining tissue homeostasis, morphogenesis and differentiation, which it does, through specific interactions with cells. The ECM is composed of a mixture of water and macromolecules classified into four main categories: collagens, proteoglycans, elastic proteins, and non-collagenous glycoproteins (also called adhesive glycoproteins). The nature, concentration and ratio of the different ECM components are all important factors in the regulation of the assembly of complex tissue-specific networks tuned to meet mechanical and biological requirements of tissues.
Collagens form a superfamily of 28 trimeric proteins, distinguishable from the other ECM components by their particular abundance in tissues (collagens represent up to 80-90% of total proteins in skin, tendon and bones) and their capacity to self-assemble into supramolecular organized structures (the best known being the banded fibers). The collagen superfamily is highly complex and shows a remarkable diversity in structure, tissue distribution and function (Ricard-Blum and Ruggiero, 2005).
The importance of collagens has been illustrated by the wide range of mutations in collagen genes that result in minor and severe human diseases. Various mutations (point, null or structural mutations, insertions, exon skipping, deletions) in genes encoding collagens are known to be responsible for a large spectrum of human disorders (
The aim of this chapter is to describe the use of targeted mutagenesis in the understanding of the physiopathology of inherited connective tissue disorders. Specifically we are concerned with mutations in collagen genes. We will focus on the use of site-directed mutagenesis to analyze the causative effects of human-identified collagen gene mutations. Recombinant molecules were used to analyze the effects of these mutations on collagen structure, biosynthesis, posttranslational modifications and interactions with binding partners and cells. This work has considerably improved our knowledge in development and in human disorders. These results will then be compared with the limited information about the introduction of subtle targeted mutations into murine collagen genes.
The 28 members of the collagen superfamily exhibit considerable complexity and diversity in structure, assembly and function. However, collagens also share common features. (i) All members are modular proteins composed of collagenous (COL) domains flanked by non collagenous (NC) domains or linker regions. (ii) They are trimeric molecules formed by the association of three identical or different α-chains, which are characterized by repetitions of the G-x-y tripeptide (with the x and y positions often occupied by proline and hydroxyproline, respectively). (Abbreviations and single-letter codes for amino acids are given in Table 1 of the chapter by Figurski
Based on their structure and supramolecular organization, collagens have been divided into several subfamilies (Myllyharju and Kivirikko, 2001). They are (i) the fibril-forming collagens I, II, III, V, XI, XXIV and XVII, which share the capacity to assemble into organized fibrils; (ii) the network-forming collagens IV, VIII and X and the FACIT (Fibril-Associated Collagen with Interrupted Triple-helix collagens) collagens IX, XII, XIV, XVI, XIX, XX, XI and XXII, which are known to mediate protein-protein interactions; (iii) the basement membrane multiplexin (multiple triple-helix domains and interruptions) collagens XV and XVIII; (iv) the transmembrane collagens, including the neuronal XXV collagen and types XIII, XVII, XXIII; and finally (v) other unconventional collagens, such as the anchoring fibrils collagen VII and the ubiquitous collagen VI, which assembles into characteristic beaded filaments (Table 1).
The length of the triple helical domains varies noticeably among different collagen types. Fibril-forming collagens consist of a long central COL domain with about 1000 amino acids (330 G-x-y tripeptide repeats), flanked by small terminal globular extensions (NC domains). After proteolytic processing of the N and C-terminal extensions, the mature molecules aggregate into highly ordered fibrils with a banded pattern observable by transmission electron microscopy. In other collagens, the COL domains are shorter and/or contain interruptions. The NC domains can represent the main part of the molecule, as for the FACIT collagen XII. Most, if not all, collagen types are recognized by specific cell receptors, such as the major ECM integrin receptors, collagen-specific discoidin domain receptors (DDR) and the transmembrane proteoglycan syndecans (Humphries et al., 2006; Xian et al., 2010; Leitinger et al., 2007). Through various interactions with these cell receptors, collagens can induce intracellular pathways directly or indirectly and regulate cell functions, such as migration, proliferation and differentiation. Certain collagens can also bind to growth factors and control their bioavailability by acting as reservoirs. The controlled release of growth factors by proteolytic activity or expression of a splice variant that does not contain the binding site controls morphogenesis, as described for the cartilage collagen II (Zhu et al., 1999).
A myriad of mutations has been characterized in collagen genes (Table 1). The function of the gene product and its tissue localization are criteria that lead to a number of inherited connective tissues disorders (reviewed in Bruckner-Tuderman and Bruckner, 1998; Bateman et al., 2009). Typically mutations in collagen genes are null-mutations,
The presence of a glycine in every third position is critical for triple-helix formation, since only glycine, the smallest amino acid, fits into the center of the triple helix. The majority of dominant-negative mutations in collagen genes are due to replacements of one of the glycines in the collagenous domains of the α-chains with a larger amino acid. Glycine substitution mutations in collagen genes underlie heritable connective tissue diseases, such as osteogenesis imperfecta (OI), chondrodysplasias, certain subtypes of Ehlers-Danlos syndrome (EDS), or Alport’s syndrome (reviewed in Bruckner-Tuderman and Bruckner, 1998; Bateman et al., 2009). Since a non-glycine amino acid does not easily fit into the interior space of the triple helix, helix formation is distorted, thereby affecting its structure and stability and impeding fibrillogenesis. Delay in triple-helix formation can result in over-modification and may affect collagen function.
Osteogenesis imperfecta (OI), also known as brittle bone disease, is caused by mutations in genes for collagen I, the most abundant collagen in organisms. OI is characterized by fragile bones that break easily and reduced bone mass. Most OI cases are believed to be associated with glycine substitution mutations in the
Collagen VII, encoded by
Mutations in the
Collagen V is a quantitatively minor fibril-forming collagen that co-polymerizes with collagen I to form heterotypic fibrils (Fichard et al., 1995). Co-polymerisation has a critical role in the nucleation and growth of fibrils in tissues. A collagen V feature is to retain in the mature molecule a major part of the α1(V) N-propeptide which projects beyond the surface of collagen fibrils. This domain was proposed to limit heterotypic fibril growth by steric hindrance and electrostatic interactions (Linsenmayer et al., 1993). Skin biopsies revealed abnormalities in fibril formation (altered diameter, contour, or shape of dermal fibrils). However, abnormalities of fibril structure affected less than 5% of fibrils (reviewed in Fichard et al., 2003). Moreover, the clinical phenotype of classical EDS supports an important role of collagen V in the biomechanical integrity of the skin, tendon and ligaments, although collagen V is only a minor component of the affected tissues. Thus, collagen V may be involved in functions other than the control of fibril growth in classical EDS. A likely hypothesis is that collagen V might be involved in the physiopathology of EDS through interactions with other fibril-associated components and/or with cell receptors. Along this line, it has been shown that mutations in the genes for the collagen V-binding partners, tenascin-X (
Although mutant gene products are thought to impair matrix structure and assembly that eventually alters tissue function, growing evidence links ER stress and the unfolded protein response (UPR) to the initiation and progression of a broad repertoire of connective tissue disorders, including those caused by collagen gene mutations. Some mutant chains cannot be incorporated into procollagen molecules, consequently causing protein degradation with important downstream effects. Misfolded or slowly folding collagens are retained within the endoplasmic reticulum (ER) and ultimately targeted for degradation by a mechanism initially called “protein suicide.” Because connective-tissue cells typically produce large quantities of collagens, the contribution of ER stress induced by misfolded collagens in disease pathogenesis has certainly been underrated. The current knowledge on the implications of unfolded protein response and ER stress in connective tissue diseases has been recently reviewed, and readers are referred to these reviews for further reading (Boot-Handford and Briggs, 2010; Tsang et al., 2010). Notably, mutations in genes encoding collagen I (
Collagen types, associated-diseases and mouse models.
Schematic diagram illustrating the biological consequences of point mutations or small deletions in collagen genes on chain synthesis, protein folding and subsequent fibril assembly in the extracellular matrix.
Mutations in the three major collagen VI genes (
The paucity of evidence-based data regarding correlations of genotype and phenotype is in part due to the large spectrum of mutations reported for the collagen genes [
A powerful approach to study the biochemical consequences of mutation and the protein structure/function relationship is to engineer a specific mutation into a functional domain of the molecule. Targeted mutagenesis approaches, including the use of alanine-scanning mutagenesis techniques, have led to important insights into the effects of collagen mutations on protein structure and function. A major limitation of mutagenesis strategies to investigate collagens is the large number of collagen gene mutations to be investigated in order to have a better understanding of the molecular mechanisms of “collagenopathies.” Knowledge about the impact of collagen mutations has also been hampered by the technical difficulty of introducing targeted mutations of very large collagen genes into mice.
Production of a recombinant collagen gene represents a powerful technique to introduce a human mutation into the gene of interest by site-directed mutagenesis. It allows one to analyze the impact of the mutation on collagen assembly and secretion. Collagen biosynthesis is a complex multistep process that takes place in the intracellular and extracellular space and includes various post-translationnal modifications, such as prolyl- and lysyl-hydroxylation, glycosylation, trimerization, proteolytic processing, polymerization and cross-links. Because of recombinant technology, these large multimeric proteins have been produced in large amounts in almost all existing expression systems (Ruggiero and Koch, 2008). This technological breakthrough enabled researchers to analyze in detail the effects of collagen mutations on biosynthesis, molecular and cell interactions, processing and, in some cases, self-assembly. Researchers can also address the question of the correlation of genotype, protein structure and function.
Mutations occurring in collagen I genes are the most extensively studied mutations among all collagen types. A first set of experiments substituted glycine 859 of the proα1(I) chain with cysteine or arginine by site-directed mutagenesis to reproduce two mutations identified in OI patients. In order to study the expression of the mutant molecule in the presence or absence of the wild-type proα1(I) chain, the mutated constructs were transfected into normal fibroblasts to look for a dominant-negative effect in the presence of the wild-type gene or in fibroblasts isolated from Mov13 homozygous mice (referred to as Mov13 fibroblasts hereafter), whose cells carry a provirus that prevents transcription initiation of the natural proα1(I) gene (Schnieke et al., 1987). In agreement with observations of collagen I in OI patients, the mutated collagens were poorly secreted from the cells and exhibited reduced thermal stability and increased sensitivity to degradation. This supported the idea that the strict preservation of the G-x-y triplets is absolutely required for proper formation of the triple helix.
The integrity of the C-propeptide is pivotal for the trimerization of all fibril-forming collagens. The C-propeptides of the proα1(I) and proα2(I) chains contain an Asn-Ile-Thr sequence. That sequence fits a consensus sequence for the addition of N-linked oligosaccharides. To analyze the role of this post-translational modification, the asparagine residue of the proα1(I) chain was changed to glycine by site-directed mutagenesis. The expression of the corresponding molecule was analyzed in transfected normal and Mov13 fibroblasts (Lamandé and Bateman, 1995). The mutation did not impair heterotrimeric assembly and secretion of hybrid procollagen I into the extracelllular space. Only a slight effect on C-proteinase cleavage efficiency was observed with the unglycosylated molecule. To circumvent the difficulty of producing a large repertoire of full-length mutated collagens I in order to undertake a genotype/phenotype analysis, a recombinant trimeric mini-collagen I was recently expressed in an
Human collagen IV mutations, thought to affect the biosynthesis of this basement membrane collagen, were extensively investigated. These mutations were known to cause Alport syndrome, a severe renal disease leading eventually to kidney failure. Collagen IV chains, α1(IV)-α6(IV), are encoded by 6 genes,
Collagens undergo a great variety of proteolytic modifications. The fate and functions of the released fragments derived from collagens are still under intensive investigation, but the consequences of mutations in the coding regions for the cleavage sites on collagen structure, self-assembly and function have not been investigated in detail. A large repertoire of proteinases is responsible for these processing interactions. Included among such enzymes are the ADAMTS (a disintegrin and metalloprotease with thrombospondin motifs) and the BMP-1/tolloid families of metalloproteinases and more recently the furin-like proprotein convertases (Ricard-Blum and Ruggiero, 2005). To investigate collagen processing, fastidious extraction and purification steps were often necessary to obtain limited amounts of unprocessed proteins and enzymes with full activity in order to undertake
In most cases, the gene of interest was disrupted and knock-out mice were preferably generated. Few transgenic mice harbouring point mutations or small deletion in collagen genes have been generated (Table 1). Naturally occurring mutations in mice disrupting collagen genes have also been identified and characterized. The
Another example concerns collagen V deficiency/dysfunction, which is responsible for Ehlers-Danlos syndrome (EDS). In the absence of the
Site-directed mutagenesis has been extensively used in collagen engineering and has shed light on collagen structure, expression, folding, secretion, interactions and self-assembly in the extracellular space. It also opened the way for the analysis of specific functional domains. It allowed the study of the wide variety of collagen types, including those expressed in trace amounts in tissues but nevertheless display pivotal functions. While it is true that site-directed mutagenesis has yielded important information on the functional consequences of a range of collagen mutations responsible for human diseases, only few studies have approached the consequences of collagen gene mutations on cell adaptation to ER stress. Collagen gene mutations affect protein synthesis, folding and secretion imbalance, which eventually induces ER stress.
Mouse models are particularly useful for analysing the biological significance of collagens in pathological situations. Knock-out mice often lead to embryonic lethality, which hampers in-depth analysis of the phenotype. A few knock-in mice have been created with subtle mutations or small deletions that reproduce human mutations. The major reason for the paucity of knock-in mice is certainly that collagen genes are very large. Thus, they are difficult to manipulate. The introduction of a small deletion or a single point mutation in murine collagen genes still represents a considerable challenge. Nevertheless, the few examples of knock-in mouse lines tend to prove that mouse models can bring new information about
It is estimated that 1 in 59 children in the United States has a diagnosis of Autism Spectrum Disorder (ASD) [1], which is characterized by life-long social communication deficits and the presence of restricted interests and/or repetitive behaviors [2]. Though all individuals with ASD meet common diagnostic criteria, they display a wide spectrum of behavioral manifestations, thus producing a wide array of heterogeneous phenotypes. As such, a multitude of behavioral interventions exist to address common symptoms of ASD, many of which have been tailored to address the heterogeneity of the disorder. Behavioral interventions are currently one of the most effective methods for improving social-communication skills, as no medications have been approved to “treat” social communication behaviors in ASD.
In the current chapter, we propose that administering the neuropeptide oxytocin in conjunction with evidence-based behavioral interventions may lead to improved outcomes in social-communication for children with ASD. Specifically, we propose that oxytocin administration may “prime” social reward circuitry in the brain, allowing behavioral interventions designed to increase social motivation/initiation to be more effective. This theoretical model draws from the following research: (1) the social motivation hypothesis of ASD, (2) animal and human literature related to oxytocin, (3) studies of oxytocin levels in children with ASD, (4) behavioral changes after oxytocin administration in children with ASD, (5) neural changes after oxytocin administration in children with ASD, and (6) neural changes after behavioral interventions in children with ASD.
Subsequent sections will briefly review these research areas. We propose that taken together, the aforementioned literature provides a theoretical basis for combining oxytocin administration with behavioral interventions to improve social-communicative outcomes for children with ASD.
The social motivation hypothesis posits that early impairments in social attention (due to social stimuli being less rewarding for individuals with ASD compared to their neurotypical peers) set a series of negative developmental consequences in motion. Initial impairments in social attention--which often manifest as decreased orienting to one’s own name, diminished eye contact, and decreased social initiations in early life--lead to fewer opportunities for social learning, which in turn lead to deficits in social communication, social skills, and social-cognitive development [3, 4]. The proposed neural mechanisms underlying the social motivation hypothesis are the reward centers in the brain including the amygdala, ventral striatum, and orbito-frontal cortex [4]. Importantly, social motivation is thought to involve both oxytocin and the dopaminergic reward pathways [5, 6]. Given the hypothesized role of oxytocin in social motivation, it is not surprising that oxytocin has been considered as a potential mechanism for understanding social deficits in ASD--and that oxytocin administration has been considered as a potential therapeutic agent.
Oxytocin is a neuropeptide produced in the hypothalamus [7]. Colloquially referred to as the “love hormone,” oxytocin has been implicated in the formation of pair bonds in a variety of species, including rats and prairie voles [8, 9, 10]. As such, oxytocin has been extensively studied and utilized for its effects on social cognition and prosocial behaviors [11, 12, 13]. It has been hypothesized that interactions between oxytocin and the dopaminergic reward system support social affiliative behaviors and social bonds [14]. Further evidence of the connection between oxytocin and the dopamine reward system comes from overlap in locations of receptor binding sites and neuronal fibers [15]. Furthermore, oxytocin cells in the hypothalamus have been found to express dopamine receptors [16]. Importantly for neurodevelopmental disorders such as ASD, oxytocin is developmentally regulated and its receptors are malleable, particularly in response to parent-child interactions [17, 18].
In contrast to other conditions in which both behavioral and medical treatments are supported by empirical evidence, no medication is currently approved to improve core symptoms of ASD. Although two pharmaceutical medications, risperidone and aripiprazole, have been approved by the Federal Drug Administration for use in ASD, they do not address core symptoms. Rather, they have been approved to treat ancillary symptoms of ASD, such as aggression and irritability [19]. Due to the lack of pharmacological interventions to address the core symptoms of ASD, there has been a focus on compounds that directly address social communication symptoms. Given oxytocin’s role in prosocial behaviors, exogenous administration of the neuropeptide has been considered as a potential therapeutic agent in ASD.
Modahl and colleagues [20, 21] were the first to provide evidence of reduced levels of oxytocin in children with ASD. Specifically, the authors found that compared to their neurotypical peers, oxytocin does not increase prior to the onset of puberty in individuals with ASD. This suggests that oxytocin is less available to individuals with ASD during development [21]. Our understanding of oxytocin in individuals with ASD has since been shaped by research that suggests deficits in oxytocin may reveal the pathogenesis of ASD. No known mechanistic pathway exists to form a substantial link between the neuropeptide and development of ASD, but studies support the idea that lower concentrations of oxytocin are strongly related to social impairments [22].
Early studies of the endocrine system have found that oxytocin release occurs differently in children with ASD compared to their neurotypical peers, suggesting that oxytocin may be disrupted early in development in children with ASD [23]. Oxytocin blood plasma levels increase throughout neurotypical development, while children with ASD exhibit lower levels of plasma oxytocin [24] that are stable over time [21]. Therefore, disruptions of the oxytocin system may possibly occur early in life in individuals with ASD, resulting in cascading consequences.
To our knowledge, eight studies have been conducted to measure behavioral results of oxytocin administration for children with ASD [22, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33]. Though the current chapter focuses on children, see the meta-analysis by Ooi and colleagues [32] for a review of randomized control trials of oxytocin administration in both children and adults. See Table 1.
Authors | Study Design & Participants | Oxytocin Administration and Dosage | Primary Outcomes |
---|---|---|---|
Guastella et al. [25] | Double-blind placebo-controlled design. 16 ASD (all male)
| A single dose of oxytocin and a placebo nasal spray 1 week apart. (a) OXT nasal spray and (b) placebo containing all ingredients except active oxytocin puff per nostril contained 3 IU. Older participants (aged 16 –19, n = 5) received a dose of 24 IU (4 puffs per nostril, 3 IU per puff). Those aged 12 to 15 years n = 11 received 75% dose of the adult dose at 18 IU (3 puffs per nostril, 3 IU per puff). | Oxytocin improved performance on the REMET (particularly on “easy” items) compared to placebo. |
Tachibana et al. [26] | Open label, single arm long-term design. 8 ASD (all male)
| Intranasal oxytocin twice a day for approximately 7 months; dosage was increased in a stepwise fashion every 2 months (from an initial dose of 8 IU to 24 IU). Placebo was inserted between the dosing steps as a washout period. Concentration of OXT in the nasal spray was changed so that a total of 6 puffs/dose twice a day was maintained throughout the protocol. | Communication and social interaction scores on ADOS-G were significantly improved after oxytocin administration. |
Anagnostou et al. [27] | Single arm, open label design. 15 ASD (11 male, 4 female)
| Twice per day (morning and night) for 12 weeks; 24 IU total a day | Improvements on the following measures: ABC; SRS, BASC social skills and functional communication subscales, Let’s Face It! Skills Battery, Irony and Empathy Task, Strange Stories Task, CASI, RBS-R, and C-YBOCS |
Dadds et al. [28] | Double-blind, placebo controlled randomized controlled design. 38 ASD (all male). 19 in OXT group; 19 in placebo group
| Treatment group: intranasal spray contained: oxytocin, mannitol, glycerine, methyl parraben, propyl, parraben and purified water. Placebo contained all ingredients except the active oxytocin and mannitol. 5-day trial. Each nostril received a 12 IU dose (6 IU per puff) for a total of 24 IU/day. | No significant benefit of oxytocin versus placebo on SSRS, SRS, or an emotion recognition task. |
Guastella et al. [29] | Double-blind placebo-controlled design. 50 ASD (all male); 26 in OXT group, 24 in placebo
| Intranasal oxytocin or placebo, 2 times per day for 8 weeks. Older participants (aged 16 –19, n = 5 in each group) received a dose of 24 IU. Those aged 12 to 15 years received 75% of the adult dose at 18 IU. | No improvements related to oxytocin were observed on primary outcome measures (SRS or CGI-Improvement scale). |
Yatawara et al. [30] | Double-blind, randomized, placebo-controlled crossover (A/B, B/A) design. 31 ASD (27 male, 4 female).15 in OXT then placebo group; 16 in placebo then OXT group
| Intranasal oxytocin or placebo twice per day for 5 weeks, followed by a 4 week wash-out period, and then received either oxytocin or placebo (whichever they did not receive in the first phase) twice per day for 5 weeks. 24 IU total per day; 12 IU in morning and 12 IU at night. | Social-communication skills (SRS) improved significantly after oxytocin versus placebo. Ratings on the CGI were significantly better after oxytocin versus placebo. |
Parker et al. [22] | Double-blind, randomized, placebo-controlled design. 32 ASD (27 males, 5 females). 13 in OXT group; 14 in placebo group
| Treatment group: Syntocinon nasal spray; Placebo group: placebo solution consisted of all the ingredients used in the active solution except the oxytocin compound. Participants’ parents then were provided with a 4-week drug supply and were responsible for their child’s continued twice daily dosing (24 IU per dose, 4 IU per puff, 48 IU/day) at home. | ASD participants who received oxytocin had greater improvements on the SRS compared to ASD participants who received the placebo. Pre-treatment plasma oxytocin negatively predicted the magnitude of improvement on the SRS (i.e., participants who had lower concentrations of oxytocin pre-treatment demonstrated the largest improvements in SRS scores). |
Strathearn et al. [31] | Randomized, double-blind, placebo-controlled crossover design. 16 ASD
| One nasal solution (oxytocin or placebo) on Visit 1 and the alternate solution on Visit 2. Participants 16 years and older received 24 IU oxytocin (10 puffs alternating between nostrils 2.4 IU). Participants aged 12–15 years received 7 puffs (16.8 IU), and participants aged 8–11 years received 5 puffs (12 IU total). | After nasal oxytocin was administered to ASD participants, differences in visual preference for structured/systemized images between ASD and TD participants was eliminated. |
Behavioral results of oxytocin administration in children with ASD.
In 2010, Guastella and colleagues [25] completed a double-blind placebo-controlled study with 16 adolescent boys with ASD (ages 12-19). 45 minutes after oxytocin (or placebo) administration, participants completed the Reading the Mind in the Eyes Task, or RMET [33]. Compared to placebo, oxytocin improved performance on the REMET for 60% of participants. When the authors split REMET items into “easy” and “hard” categories, the effect of oxytocin was particularly significant for “easy” items. This was the first investigation of the results of oxytocin administration to children/adolescents, and suggested that oxytocin improves emotion recognition in a group of males with ASD.
Tachibana and colleagues [26] measured behavioral changes associated with an open label (participants knew they were receiving oxytocin), single arm (no placebo condition) long-term oxytocin administration in 8 boys with ASD (ages 10-14). Participants received intranasal oxytocin twice a day for approximately 7 months. Oxytocin dosage was increased in a stepwise fashion every 2 months (from an initial dose of 8 IU to 24 IU). Outcome measures were scores on the Autism Diagnostic Observation Schedule—Generic (ADOS-G; [34]), Aberrant Behavior Checklist (ABC; [35]), and Child Behavior Checklist (CBCL; [36]). ADOS-G scores for items comprising the “communication,” and “social interaction” sub-scales and the sum of both sub-scales were significantly improved after oxytocin administration. No change in ADOS-G scores related to play/imagination of restrictive/repetitive behaviors (RRBs) were observed. No significant changes were observed for the ABC or CBCL after oxytocin administration though some scores improved at a trend level. The authors note that oxytocin administration appeared to specifically affect social communication and interaction, but did not affect RRBs or play. However, the study was open label, single arm. Therefore, caution is needed when interpreting these findings.
Anagnostou and colleagues [27] administered intranasal oxytocin to 15 male and female adolescents (ages 10-17) twice per day for 12 weeks in a single arm, open label design. Participants completed a follow-up session 12 weeks after discontinuation of oxytocin administration. Though the authors measured change on a variety of behavioral measures related to social function, social cognition, anxiety, and repetitive behaviors, the aim of the study was to measure the safety of varying dose levels of oxytocin in this population. Safety results suggested that .4 IU/kg twice per day for 12 weeks produced no serious or severe adverse events. Using the Clinical Global Improvement-Social (CGI), almost half of the sample were classified as “responders” at 12 weeks, and most responders at 12 weeks maintained improvements 12 weeks after the end of the study (e.g. 24 weeks from the beginning of the study). At 12 weeks, significant improvements were observed for the following measures: ABC [35], Social Responsiveness Scale (SRS; [37]), Behavioral Assessment System for Children (BASC; [38]) social skills and functional communication subscales, Let’s Face It! Skills Battery (LFI; [39]), Irony and Empathy Task [40], Strange Stories Task [41], Child and Adolescent Symptom Inventory (CASI; [42]), Repetitive Behavior Scale-Revised (RBS-R; [43]), Child Yale-Brown Obsessive-Compulsive Scale (C-YBOCS; [44]). At 24 weeks, significant improvements were observed for the following measures: BASC functional communication T-Score, RMET [33]--difficult items, Irony and Empathy Task, and C-YBOCS. The authors note that not all children demonstrated behavioral improvements in response to oxytocin administration, and that more information is needed about individual differences in response to oxytocin. Nevertheless, a broad array of measures was, on average, shown to increase after oxytocin administration.
Dadds and colleagues [28] completed a 5-day double-blind, placebo controlled, randomized controlled trial with 38 boys with ASD (ages 7-16). This study is unique as it combined oxytocin administration with consecutive parent-child interaction training sessions over a period of 4 days. The authors did follow-up testing 3 months after the completion of the 5-day intervention. The parent-child interaction training consisted of emotion recognition training using the Mindreading (MR) program [45], and short video clips demonstrating successful client interactions (e.g. eye contact, body language, responsiveness). Outcomes included parent-child interaction tasks (free play, emotion talk, and an “I love you” task in which a parent expresses positive emotions and the child’s response is recorded), and parent-questionnaire measures (Social Skills Rating Scale, or SSRS, [46]; SRS, [37]), and an emotion recognition task (UNSW Facial Emotion Task, [28]). Analysis of the parent-child interaction tasks, parent rating scales, and emotion recognition tasks indicated behavioral improvements over time in both the placebo and oxytocin groups, but no significant benefit of oxytocin versus placebo. We note that although this study combined oxytocin and behavioral intervention, the intervention was not one previously validated for improving core symptoms of ASD, and the study timeline was short (5 days).
Guastella and colleagues [29] completed a double-blind placebo-controlled trial with 50 male participants with ASD (ages 12-18). Participants received either placebo or oxytocin nasal spray twice a day for 8 weeks. Participants were assessed again 3 months after completion of the study. Primary outcome measures were the SRS [37] and clinician ratings on the Clinical Global Impressions--Improvement scale (CGI-Improvement). Secondary outcome measures included the Developmental Behaviour Checklist, or DBC [47] and Repetitive Behavior Scale-Revised, or RBS [43], RMET [33], the Diagnostic analysis of nonverbal accuracy, or DANVA [48], and Biological Motion [49]. No improvements related to oxytocin were observed on the primary or secondary outcome measures.
Yatawara and colleagues [30] completed a double-blind, randomized, placebo-controlled crossover (A/B, B/A) design trial in 31 children with ASD (ages 3-8). Children received intranasal oxytocin or placebo twice per day for 5 weeks, completed a 4-week wash-out period, and then received either oxytocin or placebo (whichever they did not receive in the first phase) twice per day for 5 weeks. Primary outcome measures were scores on the SRS [37], and scores on the RBS-R [43]. Secondary outcome measures were changes in ADOS scores, scores on the DBC [50], clinician-rated clinical global impressions-improvement scale [51], and the Caregiver Strain Questionnaire [52]. Results indicated that parent-rated social-communication skills (SRS) improved significantly after oxytocin versus placebo. Ratings on the CGI were significantly better after oxytocin versus placebo. To our knowledge, this study includes the youngest sample of children with ASD to receive oxytocin versus placebo in a randomized, double-blind trial. This work provides behavioral evidence of symptom reduction in ASD in response to prolonged oxytocin administration.
Parker and colleagues [22] completed a double-blind, randomized, placebo-controlled trial with 32 children with ASD (ages 6-12). Children received either intranasal oxytocin or placebo twice per day for 4 weeks. The primary outcome measure was scores on the SRS [37]. Secondary outcome measures included scores on the RBS-R [43] and Spence Children’s Anxiety Scale [53]. Additionally, authors measured plasma oxytocin concentrations both before and after participation in the trial, as well as expression of genes related to oxytocin receptors (Oxytocin Receptor Gene, OXTR, and Vasopressin Receptor 1a; V1AR). Results suggested that children who received oxytocin demonstrated greater improvements on the SRS compared to those receiving placebo. Additionally, pre-treatment plasma oxytocin negatively predicted the magnitude of improvement on the SRS. That is, individuals who had the lowest concentrations of oxytocin pre-treatment demonstrated the largest improvements. The authors hypothesized conflicting findings of previous oxytocin trials may be attributable to variability in pre-treatment concentrations of oxytocin. That is, previous trials did not measure pre-treatment oxytocin concentrations which may have reduced their ability to accurately measure improvement. When the authors did not include pre-treatment oxytocin, concentration findings were non-significant. In fact, inclusion of these pre-treatment “biomarkers” improved the statistical models by 43%, which underscores the importance of measuring individual variability in pre-post measurement designs.
Strathearn and colleagues [31] completed a double-blind, placebo-controlled crossover study with 16 children with ASD and 16 neurotypical children (ages 8-19). Participants completed an eye tracking paradigm on two occasions: once after receiving oxytocin and the other after receiving a placebo nasal spray. The authors measured participants’ eye gaze while viewing images that varied on how organized or structured they were. The authors’ primary focus was whether or not oxytocin affected eye gaze patterns when viewing stimuli that varied on levels of systemization. Results demonstrated that after oxytocin administration, children and adolescents with ASD displayed a decreased preference for highly systemized stimuli, whereas neurotypical children and adolescents displayed increased preference for systemized images. Overall, when participants received placebo, children and adolescents with ASD displayed more of a preference for systemized stimuli compared to their neurotypical peers. After both groups received oxytocin this difference was no longer significant (e.g. participants with ASD looked more similar to their neurotypical peers, and neurotypical children and teens looked more similar to their peers with ASD). The authors concluded that oxytocin administration may have differential effects on individuals with and without ASD, but that oxytocin appears to decrease preference for highly organized (e.g. systemized) stimuli in ASD.
Overall, studies of the behavioral effects of oxytocin in children in ASD are mixed, with some investigations observing significant behavioral changes [22, 25, 26, 27, 30, 31], whereas others find no evidence for change as a function of oxytocin versus placebo administration [28, 29]. A likely explanation for these disparate findings is outlined by Parker and colleagues [22]. The authors noted that measuring participant’s plasma oxytocin levels provided a critical “biomarker” for predicting a given individual’s response to oxytocin administration. Most studies do not measure oxytocin concentration prior to administration and therefore may miss individual differences which significantly impact outcomes. Parker and colleagues [22] noted that without the addition of pre-administration plasma oxytocin concentration into their predictive models, their results would have indicated no difference between oxytocin and placebo. When pre-administration oxytocin levels were included, their models were improved by 43%. This underscores why it is critical to consider biological differences in individuals
To our knowledge, only 3 studies have investigated the effects of oxytocin on brain activity in children with ASD [54, 55, 56]; see [57] for a review. See Table 2.
Authors | Participants and Oxytocin Administration | Design and Stimuli/Paradigm | Major Findings |
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Gordon et al. [54] | 21 ASD (3 females; 18 males)
Older participants (16 – 19 yrs.) received a dose of 24 IU (4 puffs per nostril); 15 yr olds received 18 IU (3 puffs per nostril); Younger participants (7 - 11 yrs.) received 12 IUs, (1 puff per nostril); or placebo. Testing was repeated on consecutive study visits. Order was randomized. | Randomized, double-blind, cross-over design. fMRI. Reading the Mind in the Eyes Test (RMET). Participants were instructed to label the mental state of each facial picture, or label the category of automobile images. | Social condition: Enhanced activity in the dorsal and ventral striatum, premotor cortex, posterior cingulate, inferior parietal lobule, and posterior STS in response to oxytocin compared to placebo. |
Gordon et al. [55] | 20 ASD (3 females)
Older participants (16 – 19 yrs.) received a dose of 24 IU (4 puffs per nostril); 15 yr olds received 18 IU (3 puffs per nostril). Younger participants (7 - 11 yrs.) received 12 IUs, (1 puff per nostril); or placebo. Testing was repeated on consecutive study visits. Placebo or oxytocin was randomized at the first visit and participants received the opposite nasal spray at the second visit. | Randomized, double blind, placebo-controlled crossover design. fMRI. Participants passively viewed a biological motion paradigm (human motion and scrambled motion) and listened to a vocal affect perception paradigm (angry voices and happy voices). | Biological motion condition: enhanced response in the right posterior superior temporal sulcus (pSTS) after oxytocin compared to placebo administration. Negative vocal affect condition: Enhanced activation in right brainstem and right amygdala after oxytocin versus placebo administration. |
Greene et al. [56] | 28 ASD (2 females, 26 males)
3 puffs per nostril (Syntocinon), each puff contained 4 IU of oxytocin, for a total of 24 IU, or placebo containing the same inactive ingredients. Nostrils were alternated between puffs over the course of several minutes. Two scan sessions were scheduled at least 72 hours apart from one another. Order of oxytocin and placebo were counter-balanced. | Placebo-controlled double-blind design. fMRI. Participants completed an incentive delay task with nonsocial (money) or social rewards (smiling face). | Anticipation of nonsocial reward: Increased activity in right nucleus accumbens (NAcc), right frontal pole, left ACC, left superior frontal cortex, bilateral orbital frontal cortex (OFC) after oxytocin versus placebo administration. Increased functional connectivity during nonsocial reward anticipation (between the right NAcc and the right FP) after oxytocin versus placebo. Nonsocial reward outcome: Decreased frontostriatal functional connectivity between left ACC, bilateral postcentral gyrus, left inferior front gyrus, left precentral gyrus, and left medial frontal gyrus after oxytocin vs placebo administration. |
Neuroscience results after oxytocin administration in children with ASD.
Gordon and colleagues [54] used functional magnetic resonance imaging (fMRI) to measure brain activity after oxytocin versus placebo in 17 children and adolescents with ASD (ages 8-16.5) using a randomized, double-blind, crossover design. Forty-five minutes after administration of either oxytocin or placebo, participants completed an fMRI emotion recognition task based on the RMET [33]. In a control fMRI condition, participants were asked to label the category of automobile presented in pictures. Findings suggested enhanced brain activity after oxytocin administration in brain areas hypothesized to be critical to reward (dorsal and ventral striatum), social attention and cognition (posterior cingulate, inferior parietal lobule, posterior superior temporal sulcus), and reasoning about mental states (medial prefrontal cortex). In addition, several brain regions were less active during nonsocial judgements after oxytocin administration. Interestingly, the effect of oxytocin on brain activity in response to social judgements differed as a function of symptom severity. Children with ASD with less severe symptoms (measured with the SRS) exhibited more ‘typical’ brain activity after oxytocin administration compared to children with ASD with more severe symptoms. Taken together, the authors hypothesized that oxytocin may increase the reward value and/or salience of social stimuli for children with ASD while simultaneously decreasing the salience of nonsocial information.
Gordon and colleagues [55] employed a randomized, double-blind, placebo-controlled crossover design with 20 children with ASD (ages 8-16.5). Participants completed an fMRI scan twice: once receiving oxytocin and the other after receiving placebo nasal spray. The authors measured participants’ brain activity in response to two social perception tasks: a biological motion task and an affective voices task. The authors’ primary aim was to measure whether oxytocin increased brain activity in areas related to the reward system and the connections between reward and social brain regions (e.g. mesocorticolimbic pathways and communication between this pathway and socially-relevant brain regions) compared to placebo. Results were consistent with the author’s hypotheses: oxytocin enhanced neural responses to biological versus random motion in the posterior superior temporal sulcus (pSTS), and in the amygdala and hippocampus in response to angry versus happy voices. Across both fMRI tasks, oxytocin increased neural connectivity both within reward regions and between the reward pathway and regions associated with social perception. The authors concluded that oxytocin administration appeared to enhance salience/reward of social stimuli (as measured in the biological motion task), but also increased the salience of negative social stimuli (as measured by the affective voices task).
Greene and colleagues [56] conducted a placebo-controlled, double-blind study with 28 children and adolescents with ASD (ages 10-17). Participants completed an fMRI incentive delay task on two occasions: once after receiving oxytocin, and once after receiving a placebo nasal spray. The fMRI task involved both social and non-social reward conditions so the authors could compare the effects of oxytocin versus placebo on brain activity related to both social and nonsocial rewards. Results demonstrated that compared to placebo, oxytocin increased brain activity in the caudate nucleus, left anterior cingulate cortex, frontal pole, insular cortex, and orbito-frontal cortex in the nonsocial reward versus social reward condition. Additionally, the authors found a positive relationship between symptom severity (measured using the SRS; [37]) and activation in the frontal pole and anterior cingulate during nonsocial reward anticipation, and between symptom severity and activation in the precentral gyrus and left caudate during nonsocial reward processing. Interestingly, these findings do not support the hypothesis that oxytocin selectively enhances reward-related brain activity to social stimuli, but rather may be associated with increased reward anticipation and processing for nonsocial stimuli. The authors hypothesize that reward-related effects of oxytocin may be sensitive to task-specific features, and noted that their findings strengthen the body of evidence that oxytocin acts on the brain’s reward system.
Taken together, these findings provide further evidence that intranasal oxytocin administration appears to act on the neural reward system. However, evidence is mixed regarding whether oxytocin specifically acts on the social reward system [54, 55] or the reward system more broadly [56]. It is likely that differences in neuroscience tasks, as well as differences in regions of interest, and participant sample characteristics may explain disparate findings. Importantly for our theoretical framework, intranasal oxytocin administration appears to impact the reward system in children with ASD. This provides an empirical basis for our hypothesis that combining a pharmacological agent with behavioral interventions that act on similar brain regions/networks may improve outcomes related to social initiation and communication.
Given the heterogeneous behavioral manifestations of ASD, it is not surprising that multiple behavioral interventions have been developed to improve social communication and decrease challenging behaviors [58, 59, 60]. Multiple systematic reviews have been published on the success of behavioral interventions for children with ASD (e.g. [61, 62, 63, 64]), and an extensive review is beyond the scope of the current chapter. Of primary relevance to the current chapter are behavioral interventions designed to increase the salience, relevance, and reward value of social interactions in order to improve social-communicative symptoms.
This section will briefly review two of these behavioral interventions, specifically the Early Start Denver Model (ESDM) and Pivotal Response Training (PRT) as both of these interventions are based on principles of Applied Behavioral Analysis (ABA) but emphasize naturalistic teaching strategies to promote generalization. Note, however, that there are other naturalistic interventions grounded in ABA principles (e.g. Incidental Teaching [65]; Reciprocal Imitation Training, or RIT [66, 67]; Parent-training programs, such as Project ImPACT [68]; Joint attention Interventions, such as JASPER [69, 70], and others).
ESDM is an empirically validated, manualized intensive early intervention program designed for children between the ages of 1-4 [60, 71]. ESDM uses teaching strategies including: interpersonal exchange and positive affect, engagement with real-world activities and materials, adult responsivity and sensitivity, and focus on both verbal and nonverbal communication. These strategies are grounded in ABA principles including operant conditioning, shaping, and chaining. Importantly, ESDM is not conceptualized as a behavioral intervention that must occur in a table-top or structured situation, nor is it a “one size fits all” approach. Each child’s program is individualized, and parent’s roles are emphasized. Parents are taught ESDM strategies and encouraged to utilize them during daily activities (e.g. feeding, bath time, play). In a 2010 randomized controlled trial, Dawson and colleagues compared the efficacy of ESDM versus treatment as usual (TAU) over a 2-year period [60]. Results found significant improvements in cognitive abilities in the ESDM group compared to TAU. These group differences appeared driven by improvements in both expressive and receptive language in the ESDM group. Additionally, significant group differences were observed in adaptive behaviors. Whereas children in the ESDM group remained steady in their adaptive behaviors across time, children in the TAU group exhibited lower scores across time when compared to their neurotypical peers. This difference appeared driven by increasing gaps between the TAU group and their neurotypical peers in a variety of adaptive skills, whereas children in the ESDM group displayed improvement in their communication abilities. A recent meta-analysis corroborates the efficacy of ESDM in improving cognition and language for children with ASD [72].
Pivotal response training (PRT), sometimes referred to as Pivotal Response Teaching or Pivotal Response Therapy, is a naturalistic behavior intervention based on principles of ABA. The underlying assumption of PRT is that children’s challenges can be improved with behavioral and environmental manipulations including reinforcement, contingencies, consequences, and extinction [73]. The term “pivotal” is important as it refers to pivotal behaviors that, when targeted, can lead to improvements in other areas of behavior not specifically targeted. The behaviors/function areas most commonly targeted in PRT are: motivation, initiation, responding to multiple cues, and self-management [74, 75]. To increase motivation, teaching strategies include: following the child’s lead, offering choices, providing clear opportunities for response, varying tasks, including both maintenance and acquisition tasks, contingent and natural reinforcement, and reinforcing all attempts at target skills [73, 74]. Similar to ESDM, PRT emphasizes the importance of implementing the intervention in the child’s natural environment and the involvement of parents and other caregivers in the intervention [73]. Results of a systematic review indicate that PRT is largely effective at increasing self-initiation and improving language, communication, and play skills in children with ASD [76]. A 2016 meta-analysis concluded that PRT is effective at teaching behaviors to children with ASD [77].
Despite a wealth of research examining the behavioral utility of empirically-based interventions for children with ASD, there is a relative paucity of literature utilizing neuroscience as an outcome measure or predictor of behavioral intervention response (see [78] for a review). To our knowledge, seven studies have been published using neuroscience as either an outcome measure or predictor of response for an empirically supported behavioral intervention designed to help with core symptoms of ASD. See Table 3.
Authors | Participants | Intervention, Neuroscience Methodology, & Task | Neuroscientific Findings |
---|---|---|---|
Dawson et al. [79] | 15 ASD in ESDM group
| ESDM; 2 for years; 20 hours/week ERP Participants viewed images of faces and toys. | Faster Nc and increased cortical activation to faces vs. objects in the EDSM group. Faster Nc and increased cortical activation to objects vs. faces in the TAU group. |
Voos et al. [80] | 2 ASD (1 male, 1 female), each 5 years old | PRT; 16 weeks; 8– 10 hours/week fMRI Participants viewed biological motion clips and scrambled motion clips. | During biological motion: Participant 1 (female): Increased activity in the fusiform gyrus (FG) and dorsolateral prefrontal cortex (dlPFC). Participant 2 (male): Increased activity in the posterior superior temporal sulcus (pSTS), ventrolateral prefrontal cortex (vlPFC), and FG. |
Ventola et al. [82] | 10 ASD (8 male, 2 female) Hypoactive group (3 male, 2 female):
| PRT; 16 weeks; 7 hours/week fMRI Participants viewed biological motion clips and scrambled motion clips. | During biological motion: Initially hypoactive group: increased activation in the ventral striatum (VS) and right posterior superior temporal sulcus (pSTS) Initially hyperactive group: decreased activation in right pSTS, amygdala, thalamus, and hippocampus. |
Van Hecke et al. [83] | 28 ASD in the immediate treatment group (22 male, 6 female)
| PEERS; 14 weeks; 1.5 hours/week EEG Continuous resting EEG | Immediate treatment: Increased left-dominant gamma asymmetry during resting state EEG after intervention vs. pre-intervention (more similar to TD). WLC: no change. |
Venkataraman et al. [88] | 19 ASD (13 males, 6 females)
| PRT; 16 weeks; 7 hours/week fMRI Participants viewed biological motion clips and scrambled motion clips. | During biological motion, reduction in connectivity between the posterior cingulate cortex (PCC) and orbital frontal cortex and an increase in connectivity between the PCC and regions of ventral occipital temporal extrastriate cortex. |
Yang et al. [89] | 20 ASD (13 male, 7 female)
| PRT; 16 weeks; 7 hours/week fMRI Participants viewed biological motion clips and scrambled motion clips. | Pre-intervention brain activity in the following areas while viewing biological motion predicted behavioral improvements on the SRS from pre- to post-intervention. (1) social perception (fusiform gyrus, inferior temporal gyrus, middle temporal gyrus), (2) social attention (inferior parietal gyrus, superior parietal lobule), (3) emotion regulation and reward (orbitofrontal cortex, ventrolateral prefrontal cortex, anterior insula), and (4) social reward (putamen, pallidum, amygdala, hippocampus, ventral striatum) |
Baker et al., [90] | 7 ASD (6 male, 1 female)
| PEERS; 16 weeks; 1.5 hours/week ERP Participants completed a reward task with feedback that was social (face) or nonsocial (arrow) with correct or incorrect feedback (face: smile vs frown; arrow: upward vs downward). | Increased neural sensitivity to both social and nonsocial rewards (RewP amplitude) after versus before intervention. |
Neuroscience outcome measures of behavioral interventions in children with ASD.
The first published paper using neuroscience as an outcome measure was Dawson and colleagues in 2012 [79]. 29 children with ASD (ages 48-77 months) participated in the study and were randomly assigned to either receive two years of ESDM intervention or two years of treatment as usual, TAU. Compared to toddlers in the community intervention, those who received ESDM demonstrated faster neural signatures of attention (the Nc ERP component) when viewing faces versus objects. Interestingly, when brain activity patterns of the two groups of toddlers with ASD were compared to brain activity of neurotypical (TD) toddlers, the ESDM and TD groups exhibited increased cortical activation when viewing faces versus objects, whereas toddlers in the TAU group evidenced more cortical activation when viewing objects vs. faces. The authors concluded that participation in ESDM appeared to lead to “normalization” of attention to faces. However, the authors did not include measures of brain activity prior to intervention, so they were unable to directly infer whether participation in ESDM significantly changed brain activity from pre to post intervention.
Voos and colleagues [80] used fMRI to measure brain activity in two five-year-olds with ASD before and after four months of PRT. The fMRI paradigm involved watching point-light displays that were either attached to an adult who performed actions (e.g. biological motion) or scrambled light displays created with random selections of light points (scrambled motion). When measuring brain activity from brain areas implicated in ASD from previous research [81], the authors found that one participant had increased brain activity after intervention in the left fusiform gyrus and left dorsal prefrontal cortex, and the other participant had greater activation in the left ventrolateral prefrontal cortex, right posterior superior temporal sulcus, and fusiform gyrus. All of these brain regions have been previously implicated as relevant to processing social stimuli and biological motion. Despite the small sample size, the results suggest that PRT can increase brain activity in important regions associated with social stimuli.
Ventola and colleagues [82] also measured brain activity before and after participation in PRT. 10 children with ASD (aged 4-7) completed an fMRI biological motion task both before and after 16 weeks of PRT. 5 neurotypical children were tested twice (once at “baseline” and once 16 weeks later) but they did not receive PRT. Based on activity in the parietal temporal sulcus (pSTS) at baseline compared to neurotypical participants, children with ASD were separated into two groups: hypo- and hyper-active. Children with hypo-activation were hypothesized to have decreased social motivation (evidenced by hypoactivity in the pSTS compared to neurotypical children), and children with hyper-activation were hypothesized to be hypersensitive to stimuli (evidenced by hyperactivity in the pSTS compared to neurotypical children). After PRT, children in the hypo-active group had increased brain activity in the pSTS and ventral striatum when viewing biological motion, and decreased ventral striatum activity in response to scrambled motion. Children in the hyperactive group evidenced decreased brain activity in the pSTS, amygdala, thalamus, and hippocampus when viewing biological motion. The authors’ hypothesized that participation in PRT differentially affected brain activity of children depending on their baseline characteristics (e.g. children who displayed too little brain activity in response to social stimuli evidenced increased brain activity after intervention, whereas children who displayed too much brain activity in response to social stimuli evidenced decreased activity after intervention).
Van Hecke and colleagues [83] used electrophysiology (EEG) to measure brain activity before and after participation in a randomized control trial of the Program for the Education and Enrichment of Relational Skills (PEERS; [84, 85]) versus a waitlist control (WLC) condition. PEERS is an empirically validated, manualized program which focuses on making and keeping friends for adolescents with ASD [86]. 35 adolescents (13-14 years old) with ASD were randomly assigned to receive PEERS, 31 were randomly assigned to WLC, and 30 neurotypical (TD) adolescents were assessed prior to the intervention for comparison purposes. The authors measured brain activity patterns during “resting state” during which adolescents were instructed to focus on a fixation point for three minutes. Of particular interest was patterns of brain activity in the right versus left hemispheres as previous research suggests that individuals who have left-hemisphere dominance have higher approach motivation and positive affect compared to those with right-hemisphere dominance who are often characterized as withdrawn [87]. Prior to intervention, the two groups of teens with ASD evidenced less left-dominant asymmetry compared to the TD group. When comparing post-intervention brain activity of teens who received PEERS to brain activity in the TD group, differences in left-hemispheric dominance were no longer observed. Differences between the WLC group and the TD group were still observed after the 14-week intervention period (during which the WLC group did not receive intervention). These findings suggest that participation in PEERS (compared to a waitlist condition) significantly changed patterns of brain activity to be increasingly left-hemisphere dominant, which is more similar to patterns observed in neurotypical teens.
Venkataraman and colleagues [88] used a Bayesian probabilistic model to characterize fMRI activity in 19 children with ASD (mean age 5.87 years) before and after 16 weeks of PRT. Similar to Ventola et al. [82], the fMRI paradigm involved watching two types of light displays: biological motion and scrambled motion. The probabilistic model allowed the authors to measure PRT-induced changes in neural connectivity between neural regions of interest. Results indicated both reduced connectivity between the posterior cingulate cortex (PCC) and orbitofrontal cortex and increased connectivity between the PCC and areas of the ventral occipital temporal extrastriate cortex. These results are interesting given that the PCC is known for its role in social cognitive processes, the orbitofrontal cortex has been implicated in reward processes, and the ventral occipital and temporal cortices play a role in processing socially meaningful stimuli (including biological motion). These findings suggest that PRT causes a shift, in which connectivity between the PCC and orbitofrontal cortex is decreased while PCC and the ventral occipital-temporal cortex connection is strengthened.
Yang and colleagues [89] utilized fMRI as a pre-intervention predictor of intervention response in 20 children with ASD (mean age 5.90 years). The authors measured brain activity during a biological motion paradigm prior to 16 weeks of PRT. Results demonstrated that pre-intervention brain activity in areas implicated in: (1) social perception (fusiform gyrus, inferior temporal gyrus, middle temporal gyrus), (2) social attention (inferior parietal gyrus, superior parietal lobule), (3) emotion regulation and reward (orbitofrontal cortex, ventrolateral prefrontal cortex, anterior insula), and (4) social reward (putamen, pallidum, amygdala, hippocampus, ventral striatum) while viewing biological motion predicted behavioral improvements on the SRS from pre- to post-intervention. For all 4 regions, greater levels of pre-intervention brain activity were associated with increased behavioral improvements from pre- to post- intervention. Results from this study suggest that neuroscience methods may be able to predict which children are most likely to benefit from a specific intervention, as well as underscoring the importance of brain regions associated with social perception, emotion regulation, and reward for understanding how interventions may affect brain circuitry in ASD.
Baker and colleagues [90] used event-related potentials (ERP) to measure brain response to reward in ASD adolescents before and after participation in the PEERS program compared to a typically developing sample. Response to social and nonsocial rewards were measured using the reward-related positive component (RewP) in seven adolescents with ASD and seven TD adolescents, aged 10 to 17 years. Prior to intervention, patterns of reward-related brain activity (RewP mean amplitude) did not differ between groups. However, after intervention the ASD group demonstrated an enhanced sensitivity to rewards, regardless of social or nonsocial condition, compared to the TD group. Additionally, ASD participants with less robust responses to social rewards prior to the start of the PEERS intervention demonstrated the most gains in social behaviors (as measured via SRS-2 [91]; Social Skills Improvement System, [92]. Findings from this study suggest an enhancement of the neural response to rewards after teens with ASD receive training in social skills and additionally that teens with attenuated responses to social rewards may gain the most benefit from intervention.
Taken together, these seven studies provide evidence for two critical concepts: (1)
Although there are no published studies (to our knowledge) that have conducted double-blind, placebo-controlled trials combining oxytocin administration with an empirically validated behavioral intervention in ASD, two trials are currently underway and recorded on ClinicalTrials.Gov (identifiers NCT02918864 and NCT03370510). We also note that a large-scale multi-site trial of the behavioral effects of oxytocin versus placebo is underway by the Study of Oxytocin in Autism to Improve Reciprocal Social Behaviors (SOARS-B; clinical trial identifier NCT01944046). One paper describing the rationale and methods for the trial has been published [93].
As noted above, we hypothesize that empirically based behavioral interventions designed to increase social-communication skills such as social initiation/motivation are more likely to be enhanced by oxytocin administration than interventions focused on other aspects of ASD (e.g. disruptive behaviors, anxiety). Such interventions are typically aimed towards young children (i.e. ESDM was developed for children ages 1-4) due to the targeted skills. We hypothesize that age is likely to play an important role in the efficacy of combining oxytocin with behavioral interventions such that younger children are more likely to benefit due to: (a) Early interventions in ASD often focus on improving social motivation and initiation, whereas interventions for older children are less likely to have such an emphasis. As oxytocin has been shown to affect the reward system, behavioral interventions designed to increase the reward value of social stimuli are likely to be the best candidates for this framework. (b) Increased neural plasticity in younger ages and the negative neuro-developmental sequelae described in the social motivation hypothesis. That is, young children have been hypothesized to benefit more from early intervention for ASD compared to older children due to neural plasticity, and the social motivation hypothesis posits that decreased reward value of social stimuli early in life leads to a negative cascade of developmental consequences [5, 94]. It therefore seems likely that younger children are best positioned to benefit from combining behavioral intervention with oxytocin because early interventions may disrupt this negative developmental cascade and help children move back towards a typical trajectory. (c) Accumulating evidence that interventions for ASD are likely to be more effective if started earlier in life [94, 95, 96]. It is unclear, however, exactly how age will affect our theoretical model. Future research should pay close attention to how and if age is a predictor when measuring outcomes of combining oxytocin and behavioral intervention in ASD.
Taken together, considering extant research findings from behavioral and neural effects of oxytocin administration along with those on brain activity in response to behavioral interventions in children with ASD suggests that both oxytocin and behavioral interventions lead to measurable changes in regions of the “social brain” and reward network. These findings, combined with those suggesting that oxytocin administration may improve social-communication in children with ASD, provide the empirical basis of our hypothesis [57] that combining oxytocin administration with behavioral interventions may improve outcomes related to social-communication. We hypothesize that the administration of oxytocin prior to each session of an intervention may “prime” the neural reward system to be maximally responsive to the behavioral skills taught during the intervention session. Due to the central role of the reward system in our theoretical model we hypothesize that this combined approach may be most effective for social-communicative skills requiring social motivation (e.g. social initiation/approach) and be maximally beneficial for young children. See Figure 1 for hypothesized neural mechanisms underlying the efficacy of combining interventions with oxytocin to improve outcomes.
It is important to note, however, that this approach is unlikely to be equally effective in all children with ASD. As with all interventions, there does not appear to be any “one size fits all” approach to help children with ASD. It will be critical to measure and characterize individual differences that may explain variability in treatment efficacy from
"Open access contributes to scientific excellence and integrity. It opens up research results to wider analysis. It allows research results to be reused for new discoveries. And it enables the multi-disciplinary research that is needed to solve global 21st century problems. Open access connects science with society. It allows the public to engage with research. To go behind the headlines. And look at the scientific evidence. And it enables policy makers to draw on innovative solutions to societal challenges".
\n\nCarlos Moedas, the European Commissioner for Research Science and Innovation at the STM Annual Frankfurt Conference, October 2016.
",metaTitle:"About Open Access",metaDescription:"Open access contributes to scientific excellence and integrity. It opens up research results to wider analysis. It allows research results to be reused for new discoveries. And it enables the multi-disciplinary research that is needed to solve global 21st century problems. Open access connects science with society. It allows the public to engage with research. To go behind the headlines. And look at the scientific evidence. And it enables policy makers to draw on innovative solutions to societal challenges.\n\nCarlos Moedas, the European Commissioner for Research Science and Innovation at the STM Annual Frankfurt Conference, October 2016.",metaKeywords:null,canonicalURL:"about-open-access",contentRaw:'[{"type":"htmlEditorComponent","content":"The Open Access publishing movement started in the early 2000s when academic leaders from around the world participated in the formation of the Budapest Initiative. They developed recommendations for an Open Access publishing process, “which has worked for the past decade to provide the public with unrestricted, free access to scholarly research—much of which is publicly funded. Making the research publicly available to everyone—free of charge and without most copyright and licensing restrictions—will accelerate scientific research efforts and allow authors to reach a larger number of readers” (reference: http://www.budapestopenaccessinitiative.org)
\\n\\nIntechOpen’s co-founders, both scientists themselves, created the company while undertaking research in robotics at Vienna University. Their goal was to spread research freely “for scientists, by scientists’ to the rest of the world via the Open Access publishing model. The company soon became a signatory of the Budapest Initiative, which currently has more than 1000 supporting organizations worldwide, ranging from universities to funders.
\\n\\nAt IntechOpen today, we are still as committed to working with organizations and people who care about scientific discovery, to putting the academic needs of the scientific community first, and to providing an Open Access environment where scientists can maximize their contribution to scientific advancement. By opening up access to the world’s scientific research articles and book chapters, we aim to facilitate greater opportunity for collaboration, scientific discovery and progress. We subscribe wholeheartedly to the Open Access definition:
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\\n\\nBook chapters published in edited volumes are distributed under the Creative Commons Attribution 3.0 Unported License (CC BY 3.0). IntechOpen upholds a very flexible Copyright Policy. There is no copyright transfer to the publisher and Authors retain exclusive copyright to their work. All Monographs/Compacts are distributed under the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). Read more
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\\n\\nDigital Archiving Policy
\\n\\nIntechOpen is committed to ensuring the long-term preservation and the availability of all scholarly research we publish. We employ a variety of means to enable us to deliver on our commitments to the scientific community. Apart from preservation by the Croatian National Library (for publications prior to April 18, 2018) and the British Library (for publications after April 18, 2018), our entire catalogue is preserved in the CLOCKSS archive.
\\n\\nOpen Science is transparent and accessible knowledge that is shared and developed through collaborative networks.
\\n\\nOpen Science is about increased rigour, accountability, and reproducibility for research. It is based on the principles of inclusion, fairness, equity, and sharing, and ultimately seeks to change the way research is done, who is involved and how it is valued. It aims to make research more open to participation, review/refutation, improvement and (re)use for the world to benefit.
\\n\\nOpen Science refers to doing traditional science with more transparency involved at various stages, for example by openly sharing code and data. It implies a growing set of practices - within different disciplines - aiming at:
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The Open Access publishing movement started in the early 2000s when academic leaders from around the world participated in the formation of the Budapest Initiative. They developed recommendations for an Open Access publishing process, “which has worked for the past decade to provide the public with unrestricted, free access to scholarly research—much of which is publicly funded. Making the research publicly available to everyone—free of charge and without most copyright and licensing restrictions—will accelerate scientific research efforts and allow authors to reach a larger number of readers” (reference: http://www.budapestopenaccessinitiative.org)
\n\nIntechOpen’s co-founders, both scientists themselves, created the company while undertaking research in robotics at Vienna University. Their goal was to spread research freely “for scientists, by scientists’ to the rest of the world via the Open Access publishing model. The company soon became a signatory of the Budapest Initiative, which currently has more than 1000 supporting organizations worldwide, ranging from universities to funders.
\n\nAt IntechOpen today, we are still as committed to working with organizations and people who care about scientific discovery, to putting the academic needs of the scientific community first, and to providing an Open Access environment where scientists can maximize their contribution to scientific advancement. By opening up access to the world’s scientific research articles and book chapters, we aim to facilitate greater opportunity for collaboration, scientific discovery and progress. We subscribe wholeheartedly to the Open Access definition:
\n\n“By “open access” to [peer-reviewed research literature], we mean its free availability on the public internet, permitting any users to read, download, copy, distribute, print, search, or link to the full texts of these articles, crawl them for indexing, pass them as data to software, or use them for any other lawful purpose, without financial, legal, or technical barriers other than those inseparable from gaining access to the internet itself. The only constraint on reproduction and distribution, and the only role for copyright in this domain, should be to give authors control over the integrity of their work and the right to be properly acknowledged and cited” (reference: http://www.budapestopenaccessinitiative.org)
\n\nOAI-PMH
\n\nAs a firm believer in the wider dissemination of knowledge, IntechOpen supports the Open Access Initiative Protocol for Metadata Harvesting (OAI-PMH Version 2.0). Read more
\n\nLicense
\n\nBook chapters published in edited volumes are distributed under the Creative Commons Attribution 3.0 Unported License (CC BY 3.0). IntechOpen upholds a very flexible Copyright Policy. There is no copyright transfer to the publisher and Authors retain exclusive copyright to their work. All Monographs/Compacts are distributed under the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). Read more
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\n\nOA Publishing Fees
\n\nThe Open Access publishing model employed by IntechOpen eliminates subscription charges and pay-per-view fees, enabling readers to access research at no cost. In order to sustain operations and keep our publications freely accessible we levy an Open Access Publishing Fee for manuscripts, which helps us cover the costs of editorial work and the production of books. Read more
\n\nDigital Archiving Policy
\n\nIntechOpen is committed to ensuring the long-term preservation and the availability of all scholarly research we publish. We employ a variety of means to enable us to deliver on our commitments to the scientific community. Apart from preservation by the Croatian National Library (for publications prior to April 18, 2018) and the British Library (for publications after April 18, 2018), our entire catalogue is preserved in the CLOCKSS archive.
\n\nOpen Science is transparent and accessible knowledge that is shared and developed through collaborative networks.
\n\nOpen Science is about increased rigour, accountability, and reproducibility for research. It is based on the principles of inclusion, fairness, equity, and sharing, and ultimately seeks to change the way research is done, who is involved and how it is valued. It aims to make research more open to participation, review/refutation, improvement and (re)use for the world to benefit.
\n\nOpen Science refers to doing traditional science with more transparency involved at various stages, for example by openly sharing code and data. It implies a growing set of practices - within different disciplines - aiming at:
\n\nWe aim at improving the quality and availability of scholarly communication by promoting and practicing:
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His studies in robotics lead him not only to a PhD degree but also inspired him to co-found and build the International Journal of Advanced Robotic Systems - world's first Open Access journal in the field of robotics.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"441",title:"Ph.D.",name:"Jaekyu",middleName:null,surname:"Park",slug:"jaekyu-park",fullName:"Jaekyu Park",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/441/images/1881_n.jpg",biography:null,institutionString:null,institution:{name:"LG Corporation (South Korea)",country:{name:"Korea, South"}}},{id:"465",title:"Dr.",name:"Christian",middleName:null,surname:"Martens",slug:"christian-martens",fullName:"Christian Martens",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Rheinmetall (Germany)",country:{name:"Germany"}}},{id:"479",title:"Dr.",name:"Valentina",middleName:null,surname:"Colla",slug:"valentina-colla",fullName:"Valentina Colla",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/479/images/358_n.jpg",biography:null,institutionString:null,institution:{name:"Sant'Anna School of Advanced Studies",country:{name:"Italy"}}},{id:"494",title:"PhD",name:"Loris",middleName:null,surname:"Nanni",slug:"loris-nanni",fullName:"Loris Nanni",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/494/images/system/494.jpg",biography:"Loris Nanni received his Master Degree cum laude on June-2002 from the University of Bologna, and the April 26th 2006 he received his Ph.D. in Computer Engineering at DEIS, University of Bologna. On September, 29th 2006 he has won a post PhD fellowship from the university of Bologna (from October 2006 to October 2008), at the competitive examination he was ranked first in the industrial engineering area. He extensively served as referee for several international journals. He is author/coauthor of more than 100 research papers. He has been involved in some projects supported by MURST and European Community. His research interests include pattern recognition, bioinformatics, and biometric systems (fingerprint classification and recognition, signature verification, face recognition).",institutionString:null,institution:null},{id:"496",title:"Dr.",name:"Carlos",middleName:null,surname:"Leon",slug:"carlos-leon",fullName:"Carlos Leon",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Seville",country:{name:"Spain"}}},{id:"512",title:"Dr.",name:"Dayang",middleName:null,surname:"Jawawi",slug:"dayang-jawawi",fullName:"Dayang Jawawi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Technology Malaysia",country:{name:"Malaysia"}}},{id:"528",title:"Dr.",name:"Kresimir",middleName:null,surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/528/images/system/528.jpg",biography:"K. 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L. Sukiman, X. Zhou, N. Birbilis, A.E. Hughes, J. M. C. Mol, S. J. Garcia, X. Zhou and G. E. Thompson",authors:[{id:"43567",title:"Prof.",name:"Nick",middleName:null,surname:"Birbilis",slug:"nick-birbilis",fullName:"Nick Birbilis"}]},{id:"24059",doi:"10.5772/18766",title:"High Strength Al-Alloys: Microstructure, Corrosion and Principles of Protection",slug:"high-strength-al-alloys-microstructure-corrosion-and-principles-of-protection",totalDownloads:6897,totalCrossrefCites:10,totalDimensionsCites:57,abstract:null,book:{id:"217",slug:"recent-trends-in-processing-and-degradation-of-aluminium-alloys",title:"Recent Trends in Processing and Degradation of Aluminium Alloys",fullTitle:"Recent Trends in Processing and Degradation of Aluminium Alloys"},signatures:"Anthony E. Hughes, Nick Birbilis, Johannes M.C. Mol, Santiago J. Garcia, Xiaorong Zhou and George E. 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Dobrzański, Tomasz Tański, Szymon Malara, Mariusz Król and Justyna Domagała-dubiel",authors:[{id:"15700",title:"Prof.",name:"Tomasz Arkadiusz",middleName:null,surname:"Tański",slug:"tomasz-arkadiusz-tanski",fullName:"Tomasz Arkadiusz Tański"},{id:"15880",title:"Prof.",name:"Leszek A.",middleName:null,surname:"Dobrzański",slug:"leszek-a.-dobrzanski",fullName:"Leszek A. 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The freezing pattern of the liquid melt decides the feeding of the mould which is instrumental in producing a complete and compact casting. For pure metals and even in case of alloys with a narrow freezing range a well defined solid–liquid macro-interface exists. Here feeding of the solidifying casting is the easiest, by the common lowering of the liquid metal surface in the mould. However, in many instances, a well defined interface is not witnessed. The solid–liquid interface could be discrete and not continuous. Here process of feeding the solidification sites that witness considerable shrinkages, may become complicated. On grounds of above it is implied, the process of solidification constitutes an important aspects in the production of a defect free casting.",book:{id:"10432",slug:"casting-processes-and-modelling-of-metallic-materials",title:"Casting Processes and Modelling of Metallic Materials",fullTitle:"Casting Processes and Modelling of Metallic Materials"},signatures:"Upendra Kumar Mohanty and Hrushikesh Sarangi",authors:[{id:"328540",title:"Prof.",name:"Hrushikesh",middleName:null,surname:"Sarangi",slug:"hrushikesh-sarangi",fullName:"Hrushikesh Sarangi"},{id:"328543",title:"Prof.",name:"Upendra Kumar",middleName:null,surname:"Mohanty",slug:"upendra-kumar-mohanty",fullName:"Upendra Kumar Mohanty"}]},{id:"48856",title:"Silicon Carbide in Microsystem Technology — Thin Film Versus Bulk Material",slug:"silicon-carbide-in-microsystem-technology-thin-film-versus-bulk-material",totalDownloads:2887,totalCrossrefCites:4,totalDimensionsCites:10,abstract:"This chapter looks at the role of silicon carbide (SiC) in microsystem technology. It starts with an introduction into the wide bandgap (WBG) materials and the properties that make them potential candidates to enable the development of harsh environment microsystems. The future commercial success of WBG microsystems depends mainly on the availability of high-quality materials, well-established microfabrication processes, and economic viability. In such aspects SiC platform, in relation to other WBG materials, provides a clear and competitive advantage. The reasons for this will be detailed. Furthermore, the current status of the SiC thin film and bulk material technologies will also be discussed. Both SiC material forms have played important roles in different microsystem types.",book:{id:"4721",slug:"advanced-silicon-carbide-devices-and-processing",title:"Advanced Silicon Carbide Devices and Processing",fullTitle:"Advanced Silicon Carbide Devices and Processing"},signatures:"Mariana Amorim Fraga, Matteo Bosi and Marco Negri",authors:[{id:"9292",title:"Dr.",name:"matteo",middleName:null,surname:"bosi",slug:"matteo-bosi",fullName:"matteo bosi"},{id:"38456",title:"Dr.",name:"Mariana",middleName:null,surname:"Amorim Fraga",slug:"mariana-amorim-fraga",fullName:"Mariana Amorim Fraga"},{id:"175671",title:"MSc.",name:"Marco",middleName:null,surname:"Negri",slug:"marco-negri",fullName:"Marco Negri"}]},{id:"46237",title:"Corrosion Resistance Through the Application of Anti- Corrosion Coatings",slug:"corrosion-resistance-through-the-application-of-anti-corrosion-coatings",totalDownloads:7398,totalCrossrefCites:11,totalDimensionsCites:32,abstract:null,book:{id:"3817",slug:"developments-in-corrosion-protection",title:"Developments in Corrosion Protection",fullTitle:"Developments in Corrosion Protection"},signatures:"Api Popoola, OE Olorunniwo and OO Ige",authors:[{id:"169258",title:"Dr.",name:"Patricia",middleName:null,surname:"Popoola",slug:"patricia-popoola",fullName:"Patricia Popoola"}]},{id:"46235",title:"Corrosion Detection for Automated Visual Inspection",slug:"corrosion-detection-for-automated-visual-inspection",totalDownloads:3578,totalCrossrefCites:18,totalDimensionsCites:32,abstract:null,book:{id:"3817",slug:"developments-in-corrosion-protection",title:"Developments in Corrosion Protection",fullTitle:"Developments in Corrosion Protection"},signatures:"Francisco Bonnin-Pascual and Alberto Ortiz",authors:[{id:"124589",title:"Prof.",name:"Alberto",middleName:null,surname:"Ortiz",slug:"alberto-ortiz",fullName:"Alberto Ortiz"},{id:"169256",title:"Ph.D. Student",name:"Francisco",middleName:null,surname:"Bonnin-Pascual",slug:"francisco-bonnin-pascual",fullName:"Francisco Bonnin-Pascual"}]}],onlineFirstChaptersFilter:{topicId:"944",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"82118",title:"Surface Hardening of Stainless Steel",slug:"surface-hardening-of-stainless-steel",totalDownloads:24,totalDimensionsCites:0,doi:"10.5772/intechopen.105036",abstract:"The addition of nitrogen to stainless steel improves mechanical and corrosion properties. Nitrogen-bearing stainless steel (HNSS) is a new corrosion-resistant alloy class exhibiting better tribological properties. High-pressure and powder metallurgy techniques were developed for the fabrication of HNSS. Solid-state routes allow nitrogen introduction through thermochemical, implantation, or plasma surface treatments. High-temperature gas nitriding (HTGN), carried out in an N2 atmosphere in the 1000°C range, allows N uptake, obtaining thick, ~0.5–1.0 wt.% N austenitic cases. HTGN is different from conventional nitriding, performed in the 500°C range, where intense CrxNy precipitation occurs, impairing the corrosion resistance. Low-temperature plasma nitriding (LTPN) introduces more N in solution, and colossal supersaturated expanded phases (~45 at.%N) are formed. N supersaturation and compressive stresses increase the hardness of the surface layer to 10–14 GPa. Ferritic, martensitic, duplex, and precipitation-hardened stainless steels can be surface-treated by LTPN, obtaining expanded ferrite and martensite. However, single LTPN stainless steel may prematurely fail when submitted to high loading, as the thin and hard expanded layers collapse due to lack of load-bearing capacity. Duplex-nitriding treatment (HTGN + LTPN) results in a thick nitrogen-rich hardened austenite substrate layer, granting mechanical support and adhesion to the expanded austenite layer.",book:{id:"11076",title:"Stainless Steels",coverURL:"https://cdn.intechopen.com/books/images_new/11076.jpg"},signatures:"André Paulo Tschiptschin and Carlos Eduardo Pinedo"},{id:"81579",title:"Welding Based Additive Manufacturing: Fundamentals",slug:"welding-based-additive-manufacturing-fundamentals",totalDownloads:31,totalDimensionsCites:0,doi:"10.5772/intechopen.104768",abstract:"Additive Manufacturing (AM) has drawn abundant attention over the past decades in the manufacturing and fabrication industries, especially to make part models and prototypes. This chapter introduces a potential welding based AM process called Wire Arc Additive Manufacturing (WAAM) for the fabrication of near-net shaped metal components including stainless steel components. To start with traditional AM processes, various fundamental traditional AM for the fabrication of components have been presented. Wire Arc Additive Manufacturing (WAAM) has been explained with its variants, synonyms, different welding processes to suit WAAM particularly to weld stainless steel metal; primary process selections for working with WAAM, important metals, and alloys that could be used in WAAM have been elaborated. A case study for WAAM fabrication of AISI 316 L stainless steel plate is included to introduce the fabrication of metal components using WAAM. Further, the most common defects which possibly play a vital role in WAAM components fabrication and a few of the future challenges regarding WAAM development are discussed. Fundamental information covered in this chapter could be more beneficial to beginners for the understanding of WAAM process generally including stainless steel component fabrication in a lucid tactic.",book:{id:"11076",title:"Stainless Steels",coverURL:"https://cdn.intechopen.com/books/images_new/11076.jpg"},signatures:"Maruthasalam Sowrirajan, Selvaraj Vijayan and Munusamy Arulraj"},{id:"80664",title:"Dependence of Corrosion Resistance of Austenitic Chromium-Nickel Steels on the Magnetic State of Austenite",slug:"dependence-of-corrosion-resistance-of-austenitic-chromium-nickel-steels-on-the-magnetic-state-of-aus",totalDownloads:59,totalDimensionsCites:0,doi:"10.5772/intechopen.102388",abstract:"Corrosive behavior of austenitic chromium-nickel steels from the magnetic state (parameter χ0) of austenite, pre-formed to interact with aggressive media are research. Correlation between the rate K of pitting corrosion and the specific magnetic susceptibility χ0 of austenite was experimentally established. It is experimentally established that the corrosion resistance of austenitic steels AISI304, 08Cr18Ni10, AISI 321, 08Cr18Ni10Тi (containing a low amount of δ-ferrite ∼0.005…0.5%) depends on the magnetic state of austenite: the corrosion rate of steel decreases with increases χ0 austenite. The tendency of change in the corrosion rate of austenitic alloy with a high nickel content 06Crh28NiMoCuTi (not contain δ-ferrite) has the opposite character: with increasing χ0, the corrosion rate of the alloy increases is revealed. For austenitic chromium-nickel steels, the corrosion rates of the individual (austenite (A), δ-ferrite (F), strain-induced α′-martensite (M)) and total (A + F, A + M and A + F + M) phases are determined. It is proposed to predict corrosion according to the specific magnetic susceptibility χ0 of austenite and the amount δ-ferrite.",book:{id:"11076",title:"Stainless Steels",coverURL:"https://cdn.intechopen.com/books/images_new/11076.jpg"},signatures:"Gennadii Snizhnoi"},{id:"80199",title:"The Evaluation of the Comparative Corrosion Behaviour of Conventional and Low-Nickel Austenitic Stainless Steel: Hercules™ Alloy",slug:"the-evaluation-of-the-comparative-corrosion-behaviour-of-conventional-and-low-nickel-austenitic-stai",totalDownloads:55,totalDimensionsCites:0,doi:"10.5772/intechopen.102381",abstract:"Austenitic stainless steels require approximately 8% Ni to maintain austenitic microstructure at room temperature for alloys such as 304 stainless steel (304SS). Ni contributes approximately 60% of the total material cost and its price fluctuates, making the cost of austenitic stainless steel unpredictable. The use of low-nickel austenitic stainless steels as a substitute has been considered in order to remedy costs associated with Ni price fluctuations. Alloying elements such as Mn and N have been considered, however they have been found to reduce corrosion resistance. A new alloy namely Hercules™ has been developed with reduced Ni content (1.8–2% Ni). This chapter presents a comparative study of the corrosion behavior of Hercules™ and 304SS in different solutions. The alloys were evaluated using cyclic polarisation technique and immersion tests. The results demonstrated that the corrosion resistance of Hercules™ is comparable to that of 304SS. This presents the alloys as potential industrial substitutes of each other.",book:{id:"11076",title:"Stainless Steels",coverURL:"https://cdn.intechopen.com/books/images_new/11076.jpg"},signatures:"Duduzile Nkomo and Nomsombuluko Masia"},{id:"80346",title:"Nitrogen Supersaturation of AISI316 Base Stainless Steels at 673 K and 623 K for Hardening and Microstructure Control",slug:"nitrogen-supersaturation-of-aisi316-base-stainless-steels-at-673-k-and-623-k-for-hardening-and-micro",totalDownloads:59,totalDimensionsCites:1,doi:"10.5772/intechopen.102387",abstract:"The high-density plasma nitriding at 673 K and 623 K was employed to make 10% of nitrogen supersaturation on AISI316 base austenitic stainless steels. The processing parameters and nitrogen-hydrogen gas flow ratio were optimized to increase the yield of N2+ ion and NH-radical for efficient nitriding. The nitrided AISI316 specimens were prepared for multidimensional analysis to describe the fundamental features of low-temperature plasma nitriding. First, macroscopic evaluation revealed that nitrogen supersaturation induced the γ-lattice expansion and the higher nitrogen content than 4% of mass in depth. The mesoscopic analysis describes the holding temperature and initial grain-size effects on the microstructure changes. Plastic straining, grain-size refinement, and nitrogen zone-boundary diffusion processes advance with nitrogen supersaturation to drive the inner nitriding behavior. The microscopic analysis explains the microstructure refinement, the two-phase structuring, and the microstructure modification. Through this multi-dimensional analysis, the essential characteristics of the low-temperature plasma nitriding of 316 austenitic stainless steels were precisely understood to extend the engineering treatise on the bulk nitrogen stainless steels for surface modification and treatment of stainless steels by nitriding. This plasma nitriding was applied to strengthen and harden the AISI316 wire surfaces toward its application on surgery wires.",book:{id:"11076",title:"Stainless Steels",coverURL:"https://cdn.intechopen.com/books/images_new/11076.jpg"},signatures:"Tatsuhiko Aizawa, Tomomi Shiratori, Tomoaki Yoshino, Yohei Suzuki and Takafumi Komatsu"},{id:"79904",title:"Corrosion Resistance, Evaluation Methods, and Surface Treatments of Stainless Steels",slug:"corrosion-resistance-evaluation-methods-and-surface-treatments-of-stainless-steels",totalDownloads:106,totalDimensionsCites:1,doi:"10.5772/intechopen.101430",abstract:"Stainless steels are widely recognized and find applications in many engineering industries and companies due to their excellent properties including high resistance to corrosion as a result of their minimum 10.5% chromium content, exceptional strength and durability, temperature resistance, high recyclability, and easy formability. In the present book chapter, the basic concepts of stainless steel including its applications, classifications, and corrosion properties will first be discussed. Thereafter, their corrosion behaviour will then be explained. 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In 1982, he presented his PhD thesis \\Gerber and Lauritzen Occlusion Analysis Techniques: Diagnosis Values,\\ at Istanbul University School of Dentistry, Department of Prosthodontics. As he was also working with Prof. Senih Çalıkkocaoğlu on The Physiology of Chewing at the same time, Gözler has written a chapter in Çalıkkocaoğlu\\'s book \\Complete Prostheses\\ entitled \\The Place of Neuromuscular Mechanism in Prosthetic Dentistry.\\ The book was published five times since by the Istanbul University Publications. Having presented in various conferences about occlusion analysis until 1998, Dr. Gözler has also decided to use the T-Scan II occlusion analysis method. Having been personally trained by Dr. Robert Kerstein on this method, Dr. Gözler has been lecturing on the T-Scan Occlusion Analysis Method in conferences both in Turkey and abroad. Dr. Gözler has various articles and presentations on Digital Occlusion Analysis methods. He is now Head of the TMD Clinic at Prosthodontic Department of Faculty of Dentistry , Istanbul Aydın University , Turkey.",institutionString:"Istanbul Aydin University",institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"256417",title:"Associate Prof.",name:"Sanaz",middleName:null,surname:"Sadry",slug:"sanaz-sadry",fullName:"Sanaz Sadry",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/256417/images/8106_n.jpg",biography:null,institutionString:null,institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"240870",title:"Ph.D.",name:"Alaa Eddin Omar",middleName:null,surname:"Al Ostwani",slug:"alaa-eddin-omar-al-ostwani",fullName:"Alaa Eddin Omar Al Ostwani",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/240870/images/system/240870.jpeg",biography:"Dr. Al Ostwani Alaa Eddin Omar received his Master in dentistry from Damascus University in 2010, and his Ph.D. in Pediatric Dentistry from Damascus University in 2014. Dr. Al Ostwani is an assistant professor and faculty member at IUST University since 2014. \nDuring his academic experience, he has received several awards including the scientific research award from the Union of Arab Universities, the Syrian gold medal and the international gold medal for invention and creativity. Dr. Al Ostwani is a Member of the International Association of Dental Traumatology and the Syrian Society for Research and Preventive Dentistry since 2017. He is also a Member of the Reviewer Board of International Journal of Dental Medicine (IJDM), and the Indian Journal of Conservative and Endodontics since 2016.",institutionString:"International University for Science and Technology.",institution:{name:"Islamic University of Science and Technology",country:{name:"India"}}},{id:"42847",title:"Dr.",name:"Belma",middleName:null,surname:"Işik Aslan",slug:"belma-isik-aslan",fullName:"Belma Işik Aslan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/42847/images/system/42847.jpg",biography:"Dr. Belma IşIk Aslan was born in 1976 in Ankara-TURKEY. After graduating from TED Ankara College in 1994, she attended to Gazi University, Faculty of Dentistry in Ankara. She completed her PhD in orthodontic education at Gazi University between 1999-2005. Dr. Işık Aslan stayed at the Providence Hospital Craniofacial Institude and Reconstructive Surgery in Michigan, USA for three months as an observer. She worked as a specialist doctor at Gazi University, Dentistry Faculty, Department of Orthodontics between 2005-2014. She was appointed as associate professor in January, 2014 and as professor in 2021. Dr. Işık Aslan still works as an instructor at the same faculty. She has published a total of 35 articles, 10 book chapters, 39 conference proceedings both internationally and nationally. Also she was the academic editor of the international book 'Current Advances in Orthodontics'. She is a member of the Turkish Orthodontic Society and Turkish Cleft Lip and Palate Society. She is married and has 2 children. Her knowledge of English is at an advanced level.",institutionString:"Gazi University Dentistry Faculty Department of Orthodontics",institution:null},{id:"202198",title:"Dr.",name:"Buket",middleName:null,surname:"Aybar",slug:"buket-aybar",fullName:"Buket Aybar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/202198/images/6955_n.jpg",biography:"Buket Aybar, DDS, PhD, was born in 1971. She graduated from Istanbul University, Faculty of Dentistry, in 1992 and completed her PhD degree on Oral and Maxillofacial Surgery in Istanbul University in 1997.\r\nDr. Aybar is currently a full-time professor in Istanbul University, Faculty of Dentistry Department of Oral and Maxillofacial Surgery. She has teaching responsibilities in graduate and postgraduate programs. Her clinical practice includes mainly dentoalveolar surgery.\r\nHer topics of interest are biomaterials science and cell culture studies. She has many articles in international and national scientific journals and chapters in books; she also has participated in several scientific projects supported by Istanbul University Research fund.",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"178412",title:"Associate Prof.",name:"Guhan",middleName:null,surname:"Dergin",slug:"guhan-dergin",fullName:"Guhan Dergin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178412/images/6954_n.jpg",biography:"Assoc. Prof. Dr. Gühan Dergin was born in 1973 in Izmit. He graduated from Marmara University Faculty of Dentistry in 1999. He completed his specialty of OMFS surgery in Marmara University Faculty of Dentistry and obtained his PhD degree in 2006. In 2005, he was invited as a visiting doctor in the Oral and Maxillofacial Surgery Department of the University of North Carolina, USA, where he went on a scholarship. Dr. Dergin still continues his academic career as an associate professor in Marmara University Faculty of Dentistry. He has many articles in international and national scientific journals and chapters in books.",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"178414",title:"Prof.",name:"Yusuf",middleName:null,surname:"Emes",slug:"yusuf-emes",fullName:"Yusuf Emes",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178414/images/6953_n.jpg",biography:"Born in Istanbul in 1974, Dr. Emes graduated from Istanbul University Faculty of Dentistry in 1997 and completed his PhD degree in Istanbul University faculty of Dentistry Department of Oral and Maxillofacial Surgery in 2005. He has papers published in international and national scientific journals, including research articles on implantology, oroantral fistulas, odontogenic cysts, and temporomandibular disorders. Dr. Emes is currently working as a full-time academic staff in Istanbul University faculty of Dentistry Department of Oral and Maxillofacial Surgery.",institutionString:null,institution:{name:"Istanbul University",country:{name:"Turkey"}}},{id:"192229",title:"Ph.D.",name:"Ana Luiza",middleName:null,surname:"De Carvalho Felippini",slug:"ana-luiza-de-carvalho-felippini",fullName:"Ana Luiza De Carvalho Felippini",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/192229/images/system/192229.jpg",biography:null,institutionString:"University of São Paulo",institution:{name:"University of Sao Paulo",country:{name:"Brazil"}}},{id:"256851",title:"Prof.",name:"Ayşe",middleName:null,surname:"Gülşen",slug:"ayse-gulsen",fullName:"Ayşe Gülşen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/256851/images/9696_n.jpg",biography:"Dr. Ayşe Gülşen graduated in 1990 from Faculty of Dentistry, University of Ankara and did a postgraduate program at University of Gazi. \nShe worked as an observer and research assistant in Craniofacial Surgery Departments in New York, Providence Hospital in Michigan and Chang Gung Memorial Hospital in Taiwan. \nShe works as Craniofacial Orthodontist in Department of Aesthetic, Plastic and Reconstructive Surgery, Faculty of Medicine, University of Gazi, Ankara Turkey since 2004.",institutionString:"Orthodontist, Assoc Prof in the Department of Aesthetic, Plastic and Reconstructive Surgery, Faculty of Medicine, University of Gazi",institution:null},{id:"255366",title:"Prof.",name:"Tosun",middleName:null,surname:"Tosun",slug:"tosun-tosun",fullName:"Tosun Tosun",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255366/images/7347_n.jpg",biography:"Graduated at the Faculty of Dentistry, University of Istanbul, Turkey in 1989;\nVisitor Assistant at the University of Padua, Italy and Branemark Osseointegration Center of Treviso, Italy between 1993-94;\nPhD thesis on oral implantology in University of Istanbul and was awarded the academic title “Dr.med.dent.”, 1997;\nHe was awarded the academic title “Doç.Dr.” (Associated Professor) in 2003;\nProficiency in Botulinum Toxin Applications, Reading-UK in 2009;\nMastership, RWTH Certificate in Laser Therapy in Dentistry, AALZ-Aachen University, Germany 2009-11;\nMaster of Science (MSc) in Laser Dentistry, University of Genoa, Italy 2013-14.\n\nDr.Tosun worked as Research Assistant in the Department of Oral Implantology, Faculty of Dentistry, University of Istanbul between 1990-2002. \nHe worked part-time as Consultant surgeon in Harvard Medical International Hospitals and John Hopkins Medicine, Istanbul between years 2007-09.\u2028He was contract Professor in the Department of Surgical and Diagnostic Sciences (DI.S.C.), Medical School, University of Genova, Italy between years 2011-16. \nSince 2015 he is visiting Professor at Medical School, University of Plovdiv, Bulgaria. \nCurrently he is Associated Prof.Dr. at the Dental School, Oral Surgery Dept., Istanbul Aydin University and since 2003 he works in his own private clinic in Istanbul, Turkey.\u2028\nDr.Tosun is reviewer in journal ‘Laser in Medical Sciences’, reviewer in journal ‘Folia Medica\\', a Fellow of the International Team for Implantology, Clinical Lecturer of DGZI German Association of Oral Implantology, Expert Lecturer of Laser&Health Academy, Country Representative of World Federation for Laser Dentistry, member of European Federation of Periodontology, member of Academy of Laser Dentistry. Dr.Tosun presents papers in international and national congresses and has scientific publications in international and national journals. He speaks english, spanish, italian and french.",institutionString:null,institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"260116",title:"Dr.",name:"Mehmet",middleName:null,surname:"Yaltirik",slug:"mehmet-yaltirik",fullName:"Mehmet Yaltirik",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/260116/images/7413_n.jpg",biography:"Birth Date 25.09.1965\r\nBirth Place Adana- Turkey\r\nSex Male\r\nMarrial Status Bachelor\r\nDriving License Acquired\r\nMother Tongue Turkish\r\n\r\nAddress:\r\nWork:University of Istanbul,Faculty of Dentistry, Department of Oral Surgery and Oral Medicine 34093 Capa,Istanbul- TURKIYE",institutionString:null,institution:{name:"Istanbul University",country:{name:"Turkey"}}},{id:"171887",title:"Prof.",name:"Zühre",middleName:null,surname:"Akarslan",slug:"zuhre-akarslan",fullName:"Zühre Akarslan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/171887/images/system/171887.jpg",biography:"Zühre Akarslan was born in 1977 in Cyprus. She graduated from Gazi University Faculty of Dentistry, Ankara, Turkey in 2000. \r\nLater she received her Ph.D. degree from the Oral Diagnosis and Radiology Department; which was recently renamed as Oral and Dentomaxillofacial Radiology, from the same university. \r\nShe is working as a full-time Associate Professor and is a lecturer and an academic researcher. \r\nHer expertise areas are dental caries, cancer, dental fear and anxiety, gag reflex in dentistry, oral medicine, and dentomaxillofacial radiology.",institutionString:"Gazi University",institution:{name:"Gazi University",country:{name:"Turkey"}}},{id:"272237",title:"Dr.",name:"Pinar",middleName:"Kiymet",surname:"Karataban",slug:"pinar-karataban",fullName:"Pinar Karataban",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/272237/images/8911_n.png",biography:"Assist.Prof.Dr.Pınar Kıymet Karataban, DDS PhD \n\nDr.Pınar Kıymet Karataban was born in Istanbul in 1975. After her graduation from Marmara University Faculty of Dentistry in 1998 she started her PhD in Paediatric Dentistry focused on children with special needs; mainly children with Cerebral Palsy. She finished her pHD thesis entitled \\'Investigation of occlusion via cast analysis and evaluation of dental caries prevalance, periodontal status and muscle dysfunctions in children with cerebral palsy” in 2008. She got her Assist. Proffessor degree in Istanbul Aydın University Paediatric Dentistry Department in 2015-2018. ın 2019 she started her new career in Bahcesehir University, Istanbul as Head of Department of Pediatric Dentistry. In 2020 she was accepted to BAU International University, Batumi as Professor of Pediatric Dentistry. She’s a lecturer in the same university meanwhile working part-time in private practice in Ege Dental Studio (https://www.egedisklinigi.com/) a multidisciplinary dental clinic in Istanbul. Her main interests are paleodontology, ancient and contemporary dentistry, oral microbiology, cerebral palsy and special care dentistry. She has national and international publications, scientific reports and is a member of IAPO (International Association for Paleodontology), IADH (International Association of Disability and Oral Health) and EAPD (European Association of Pediatric Dentistry).",institutionString:null,institution:null},{id:"172009",title:"Dr.",name:"Fatma Deniz",middleName:null,surname:"Uzuner",slug:"fatma-deniz-uzuner",fullName:"Fatma Deniz Uzuner",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/172009/images/7122_n.jpg",biography:"Dr. Deniz Uzuner was born in 1969 in Kocaeli-TURKEY. After graduating from TED Ankara College in 1986, she attended the Hacettepe University, Faculty of Dentistry in Ankara. \nIn 1993 she attended the Gazi University, Faculty of Dentistry, Department of Orthodontics for her PhD education. After finishing the PhD education, she worked as orthodontist in Ankara Dental Hospital under the Turkish Government, Ministry of Health and in a special Orthodontic Clinic till 2011. Between 2011 and 2016, Dr. Deniz Uzuner worked as a specialist in the Department of Orthodontics, Faculty of Dentistry, Gazi University in Ankara/Turkey. In 2016, she was appointed associate professor. Dr. Deniz Uzuner has authored 23 Journal Papers, 3 Book Chapters and has had 39 oral/poster presentations. She is a member of the Turkish Orthodontic Society. Her knowledge of English is at an advanced level.",institutionString:null,institution:null},{id:"332914",title:"Dr.",name:"Muhammad Saad",middleName:null,surname:"Shaikh",slug:"muhammad-saad-shaikh",fullName:"Muhammad Saad Shaikh",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Jinnah Sindh Medical University",country:{name:"Pakistan"}}},{id:"315775",title:"Dr.",name:"Feng",middleName:null,surname:"Luo",slug:"feng-luo",fullName:"Feng Luo",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Sichuan University",country:{name:"China"}}},{id:"344229",title:"Dr.",name:"Sankeshan",middleName:null,surname:"Padayachee",slug:"sankeshan-padayachee",fullName:"Sankeshan Padayachee",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of the Witwatersrand",country:{name:"South Africa"}}},{id:"315727",title:"Ms.",name:"Kelebogile A.",middleName:null,surname:"Mothupi",slug:"kelebogile-a.-mothupi",fullName:"Kelebogile A. 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