miRNAs regulating vascular smooth muscle cell phenotype
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More than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\\n\\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\\n\\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\\n\\nAdditionally, each book published by IntechOpen contains original content and research findings.
\\n\\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\\n\\n\\n\\n
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'
Simba Information has released its Open Access Book Publishing 2020 - 2024 report and has again identified IntechOpen as the world’s largest Open Access book publisher by title count.
\n\nSimba Information is a leading provider for market intelligence and forecasts in the media and publishing industry. The report, published every year, provides an overview and financial outlook for the global professional e-book publishing market.
\n\nIntechOpen, De Gruyter, and Frontiers are the largest OA book publishers by title count, with IntechOpen coming in at first place with 5,101 OA books published, a good 1,782 titles ahead of the nearest competitor.
\n\nSince the first Open Access Book Publishing report published in 2016, IntechOpen has held the top stop each year.
\n\n\n\nMore than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\n\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\n\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\n\nAdditionally, each book published by IntechOpen contains original content and research findings.
\n\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\n\n\n\n
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\r\n\tOrganic synthesis has always been one of the central topics of research for the scientific community in the academic laboratories and industrial world. Many striking journal articles and remarkable reviews and books have been published in the past year describing the practicability and applications of the subject demonstrating the importance of organic synthesis. In the present book, we will be putting together the topics in organic synthesis which may include but not limited to, (1) the basic terms and concepts, (2) various organic reactions including reduction, oxidation, addition, elimination, rearrangements, and cycloadditions, (3) Total Synthesis of Natural products, (4) transition metal catalysts, organocatalysts, enzymes and biotransformations, (5) applications in medicinal chemistry and drug design and development, (6) purification methods and characterization techniques, etc. To set a limit and to increase the scope of the book, author(s) are encouraged to send the chapters that include selected examples with practical applications and good yielding reactions reported within the past decade. Older topics with significant findings or their essence to prepare the foundation may be included in the chapter are welcomed as well.
",isbn:null,printIsbn:"979-953-307-X-X",pdfIsbn:null,doi:null,price:0,priceEur:null,priceUsd:null,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"f3bbbd989d0896f142d317ccb8abcc35",bookSignature:"Dr. Prashant S Deore",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/8807.jpg",keywords:"Natural Product Synthesis, Organic Reaction Mechanism, Stereoselective synthesis, Chirality, C-H Functionalization, Cross-Coupling Reactions, Heterogeneous Catalysis, Homogeneous Catalysis, Green Synthesis, Green Solvents and Reagents, Bioorganic synthesis, Click Chemistry",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"December 10th 2018",dateEndSecondStepPublish:"January 14th 2019",dateEndThirdStepPublish:"March 15th 2019",dateEndFourthStepPublish:"May 20th 2019",dateEndFifthStepPublish:"July 19th 2019",remainingDaysToSecondStep:"2 years",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:null,coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"251769",title:"Dr.",name:"Prashant",middleName:"S",surname:"Deore",slug:"prashant-deore",fullName:"Prashant Deore",profilePictureURL:"https://mts.intechopen.com/storage/users/251769/images/system/251769.png",biography:"Dr. Prashant S. Deore was born in India. He received a Master’s degree in organic chemistry from Pune University in 2007. In the same year, he qualified with the SET and CSIR-NET (JRF) and joined in the group of Prof. Narshinha P. Argade for the doctoral studies in National Chemical Laboratory, India. In 2014, he awarded with a Ph. D. in Chemistry and was a recipient of the 2nd prize in “2014 Eli Lilly and Company Asia Outstanding Thesis Awards”. In July 2014 he moved to Canada and joined as a postdoctoral researcher in the group of Prof. Richard Manderville at the University of Guelph, Canada. Presently, Dr. Deore is working on the collaborative project between the University of Guelph and Aterica health Inc., and providing consulting to the company. His research interest includes organic synthesis, fluorescent probes development, nucleic acid synthesis and modifications, and aptasensor development for proteins and food toxins.",institutionString:"University of Guelph",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:null}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"8",title:"Chemistry",slug:"chemistry"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"270935",firstName:"Rozmari",lastName:"Marijan",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/270935/images/7974_n.png",email:"rozmari@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. 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Only about 2% of the eukaryotic genome sequence codes for protein encoding genes and the remaining so called “junk” DNA are thought to have no functional significance [3, 4]. Based on large scale studies of human and other eukaryotic genomes it is estimated that about 98 % of the transcriptional output of their genomes is RNA that does not encode protein implying that the genomes are gorged with either inept RNA transcripts or with ncRNA transcripts that exhibit unanticipated functions in eukaryotic biology. However, recent development of new technologies in molecular biology and human genetics such as genome tiling [4,5], microarrays, and next generation RNA-sequencing (RNA-Seq) [6,7] have enabled the discovery of different types of ncRNAs that do not code for protein product [8-10]. Even though ncRNAs do not encode proteins, they play pivotal roles in the complex networks that are necessary to regulate cellular functions via transcriptional and translational regulation of protein coding genes that are crucial to normal development and physiology, and to disease [11]. Moreover, many of the ncRNAs are highly conserved and susceptible to epigenetic and genetic defects that affect normal development and disease process significantly [12-15].
There are copious non-coding transcripts that participate principally in regulating cellular protein synthesis, which are grouped into different classes based on their size, function and association with transcription start site [1, 12, 16-18]. According to their size, ncRNAs are categorized into: small ncRNAs, 20 to 200 nucleotides long, which includes microRNAs (miRNAs), PIWI-interacting RNAs (piRNAs) and small nucleolar RNAs (snoRNAs); long ncRNAs (lncRNAs) that are longer than 200 nucleotides; and macro ncRNAs, longer than 200 nucleotides that can reach 100 kilobases (kb) longer without being processed into small ncRNAs [1,7,12,18]. Based on where they are derived from within the genome, lncRNAs can be distinguished from each other. There are intronic lncRNAs (transcribed between exons of genes), intergenic lncRNAs (transcribed from the space between two genes) and lncRNAs that are derived from the regions that overlap both exon and intron of a coding gene. Furthermore, each of these ncRNAs may also be in the sense or in the antisense direction. According to functional significance, ncRNAs can be divided into: (1) housekeeping ncRNAs and (2) regulatory ncRNAs. Housekeeping ncRNAs include constitutively expressed ncRNAs that are crucial for the normal function and cellular viability, which include transfer RNAs, ribosomal RNAs, small nuclear RNAs, and snoRNAs [18]. On the contrary, regulatory ncRNAs or riboregulators include ncRNAs such as miRNAs and lncRNAs that are expressed in response to external signals, during different cellular states such as cellular differentiation or at certain stages of development, influencing the expression of other genes at transcription and translational levels [1, 7, 12, 18]. Regarding ncRNAs that are associated with transcription start sites of genes, there are different classes of ncRNAs such as promoter-associated small RNAs (PASRs) [16], transcription start site-associated RNAs (TSSa-RNAs) [19], promoter upstream transcripts (PROMPTs) [20] and transcription initiation RNAs (tiRNAs) [21]. Even though their functional roles are poorly delineated, perhaps they have a regulatory role in transcription.
Among the ncRNAs, the most widely studied and comparatively well delineated regarding their functional relevance to normal development and physiology, and to pathogenesis of disease are, small microRNAs [1, 12, 22-25]. miRNA deficiencies or surpluses have been correlated with diverse clinically important diseases including various types of cancers, neurological diseases, metabolic diseases, cardiovascular diseases, and many others [22, 25-32]. Here, we provide an overview of the current knowledge of miRNAs that participate in the regulation of vascular smooth muscle cells (VSMC) phenotypic modulation and present the potential opportunities for miRNA-based therapeutic and diagnostic approaches for vascular proliferative diseases due to atherosclerosis and restenosis. Finally, we briefly describe our preliminary unpublished data on miRNA expression profile of VSMC in response to butyrate, a histone deacetylase (HDAC) inhibitor.
Vascular cell activation and remodeling are the principle events in vascular pathologies such as atherosclerosis, transplant vasculopathy, post angioplasty restenosis, in-stent restenosis and bypass graft failure [33, 34]. It is realized that injury to vessel wall by various atherogenic insults sets-off inflammatory response causing endothelial cell dysfunction. Following endothelial cell dysfunction, VSMC in the media that are quiescent and contractile in nature, migrate to intima in response to local inflammation and become proliferative cells. VSMC are highly specialized cells whose principal function is to regulate the attributes of blood vessels in the body by appropriately responding to changes in the volume of blood vessels and the local blood pressure to facilitate distribution of oxygenated blood to different parts of the body. In adult vessels, VSMC proliferate at very low rate; display reduced synthetic activity; and express a unique compilation of proteins that is characteristic of contractile phenotype such as contractile proteins, ion channels, and signaling molecules. Yet, they still maintain remarkable plasticity and retain the ability to undergo extreme and reversible changes in phenotype in response to their local environmental signals, especially during vascular development, and in response to vascular injury as a key mechanism in wound healing. It is recognized vascular injury provoked by various atherogenic insults such as mechanical, chemical and immunological injuries triggered by different disease risk factors promote VSMC activation, migration and proliferation, which are precursors to the development of atherosclerosis and neointimal hyperplasia [34, 35]. VSMC also undergo phenotypic modification from contractile to proliferative or synthetic phenotype in conjunction with vessel remodeling by altering the cell number and composition of vessel wall as the primary pathophysiological mechanism in different clinical pathologies such as postangioplasty restenosis, in-stent restenosis, and vein bypass graft failure and transplant vasculopathy [34-37]. However, the molecular mechanisms involved in VSMC phenotypic control are still vague.
During the last few years there is an upsurge in ncRNA research specifically pertaining to a novel class of small miRNAs because of their role in various biological functions. In a variety of eukaryotic organisms miRNAs have been demonstrated to play key roles in various cellular processes including proliferation, differentiation, and apoptosis [38-40], which are central to normal development and physiology, and pathogenesis of diseases. As such, dysregulation of miRNAs has been linked to different diseases, including different cancers, neurological, cardiovascular and other diseases [22, 25-32]. Because of their effects on cellular processes as gene expression regulators, impairment of miRNAs as evidenced in many cancers, suggest involvement of miRNAs in the phenotypic modulation of VSMC both in normal and disease states. Here we briefly describe miRNAs, their biogenesis and mechanism of action and then summarize the recent progress in the functional significance of miRNAs in VSMC phenotypic modulation and response to injury.
miRNAs are endogenous, well conserved, small ncRNAs, usually 20 to 26 nucleotides, that mediate posttranscriptional gene silencing by complimentary binding to the 3’-untranslated region (3’-UTR) of their target mRNA, leading to direct target mRNA degradation or translational repression, a key phenomenon for controlling gene expression in a tissue- and development-specific manner [1, 38-40]. They were first detected in Caenorhabditis elegans as regulators of development in 1993 [41] and since then they have been found in many species of plants and animals. There are several differences between plants and eukaryotic mRNAs. In plants, transcriptional repressions require a perfect or near-perfect target match, whereas mismatched target can cause gene silencing at the translational level in eukaryotes. In eukaryotes, miRNA complementarity typically includes the 5’ bases 2-7 of the miRNAs, which is referred as miRNA “seed” region, Furthermore, one miRNA can target many different sites on the same mRNA or many different mRNAs, and a single mRNA can be under stringent but redundant control of several miRNAs. Another difference is the location of target sites on mRNAs. In eukaryotes miRNA target sites are in the 3’-UTRs of the mRNAs. In plants, target sites are normally in the coding region but they can be present in the 3’-UTRs.
miRNAs are predicted to target about 60% of protein coding transcripts [12, 42, 43]. At present the number of miRNA sequences deposited in miRBase (Release 16) include over 15,000 miRNA loci, expressing over 17,000 distinct mature miRNA sequences from 142 species [44]. Moreover, recent appreciation in miRNA research in eukaryotes implicates that these key gene expression regulators control various biological processes as diverse as cell proliferation, cell differentiation, apoptosis, and stem cell division particularly in mammalian development [38-40, 45]. In spite of tremendous advances in miRNA research, the role of miRNAs in physiological and pathophysiological processes is just emerging. Recent miRNA expression studies demonstrate miRNAs in cardiovascular development [46], brain development [47], viral infection [48], metabolism [29], different types cancer, neurologic and cardiovascular diseases [22, 25-32] suggesting link between miRNAs and wide range of tissue development and diseases. In effect, miRNAs are considered as trans-acting gene regulatory molecules, similar to and as important as transcription factors in the control of gene expression [49]. Although miRNAs are considered to act as intracellular RNAs to control gene expression at posttranscriptional level, recent studies have detected miRNAs in circulating blood and in cell culture medium indicating they may be useful as biomarkers of disease [50, 51].
The transcription of miRNAs depends on their location within the genome. Most of the miRNA genes are located throughout the genome in introns, exons and intergenic regions with many miRNAs produced from clusters of coexpressed genes. Some miRNA transcription depends on same RNA polymerase II promoters that drive the transcription of mRNAs. miRNA genes located in intronic regions that includes half of known miRNAs genes often depend on the expression of host gene [52, 53]. Some miRNA genes with independent promoters are transcribed from their own RNA polymerase II promoters. Additionally a small number of miRNAs genes are transcribed by RNA polymerase III. Those miRNAs organized in clusters for example, miRNA-17-92-family, share the same transcriptional regulation and are grouped together in one cluster on a single unprocessed transcript and expressed together [54].
The process of miRNA biogenesis starts in the nucleus as depicted in the following Figure [12, 31, 32]. miRNAs are transcribed as hundreds or thousands of base long large primary miRNA species (pri-miRNA) by RNA polymerase II or RNA polymerase III. These pri-miRNA transcripts fold into a stem loop or hairpin structures with capped 5’ end and polyadenylated (poly A) tail on 3’ end [55]. Following transcription by RNA polymerase II/III, pri-miRNA transcripts are trimmed to about 60 to 100 nucleotide hairpin structures with ~2 nucleotide 3’ overhang to form precursor miRNAs (pre-miRNAs) by the action of nuclear microprocessor complex. Microprocessor complexes are formed of Drosha (RNASEN), a nuclear ribonuclease RNase III enzyme and its partner DGCR8 (DiGeorge critical region 8) also called as Pasha (Partner of Drosha). The pre-miRNA transcripts are then shuttled to cytoplasm for further processing via Exportin5 and Ran-GTP6. Pre-miRNAs are processed further in the cytoplasm by the action of Dicer, another RNase III enzyme, with the assistance of double-stranded RNA binding proteins (dsRBPs) including TRBP (tar RNA binding protein), resulting in the cleavage of hairpin loop of pre-miRNAs leading to formation of ~22 nucleotide mature miRNA duplexes. Mature duplex is composed of a matured miRNA strand referred as guide strand and a complimentary strand referred as the passenger strand. The gene silencing capability depends on Dicer-mediated loading of one of the miRNA strands, usually guide strand, in the RNA-induced silencing complex (RISC) together with Argonaute (Ago) protein. The RISC guides the miRNA to bind to its complementary sequence within the 3’-UTR of its target mRNA. The degree of complementarity between the seed sequence of the miRNA and the 3’-UTR of its target mRNA determines whether to mediate mRNA degradation or to disrupt translation.
miRNAs are relatively new regulatory molecules that are identified about a decade ago and demonstrated to have regulatory role in every organism and in every biological functions influencing normal biology and disease process. Once again, oncology research is in the leading position in understanding miRNA involvement in human diseases. Although most of the miRNA knowledge is coming from cancer research, during the past few years their role in other systems and diseases are emerging and rapidly being evaluated with new technologies such as deep sequencing. It is not surprising that interest in miRNA is also on the raise in cardiovascular research field. Literature on the roles and functions of miRNAs in normal cardiovascular development and in vascular pathologies is escalating [32, 46, 56-60]. Furthermore, importance of miRNAs in the regulation of VSMC development and phenotypic modification, and response to injury is swiftly being explored because VSMC proliferation and migration are important events in vascular proliferative diseases. Here we will summarize recent updates on the significance of miRNAs in VSMCs and their role in phenotypic modulation of VSMC, thus to vascular proliferative diseases [32, 57-60]. Most of the knowledge of VSMC miRNAs is coming from culture cells, animal models and blood samples of cardiovascular disease patients.
Biogenesis of miRNA and gene silencing pathway. The miRNA synthesis starts in the nucleus where pri-miRNA transcript is cleaved by Drosha/ DGCR8 to form ~60-100 nucleotides long hairpin loop pre-miRNA. Pre-miRNA is then transported to cytoplasm through the mediation of Exportin5 and Ran-GTP6 where it is further processed by RNase activity of Dicer to ~22 nucleotides mature miRNA duplex. The miRNA duplex then loads onto Ago in the RISC complex and undergoes strand separation. The guide strand of the miRNA mediates gene silencing by degrading the target mRNA or interfering with translational process. The passenger strand gets degraded.
Because activity of Dicer is essential for the miRNA processing, loss of Dicer activity should result in global loss of miRNAs. Importance of miRNAs for VSMC development and biology can be validated by knocking out the miRNA processing enzyme Dicer in VSMC. To demonstrate the importance of miRNAs in VSMC development and function, a smooth muscle restricted -Dicer knockout model, SM-Dicer KO mice, is investigated recently [59,61]. Outcomes of the study indicate deletion of Dicer causes embryonic lethality due to decreased VSMC proliferation and differentiation resulting in thinner vessel walls, impaired contractility and hemorrhage as well as reduced expression of VSMC-specific genes and proteins [59, 61]. Overall, these observations suggest that Dicer-generated miRNAs are crucial for normal VSMC development, differentiation and contractile function.
VSMC exhibit remarkable plasticity by adapting to local conditions via phenotypic modulation. Phenotypic modulation of VSMC is a highly complex process regulated by transcription factors and other gene products and multiple pathways that are still vaguely understood. Recently several reports have demonstrated the involvement of miRNA-mediated gene silencing in the regulation of VSMC proliferation, migration and differentiation in normal vascular development and in vascular pathologies. A list of a few selected miRNAs that regulate VSMC proliferation and differentiation in cell cultures and animal models with angioplasty is shown in Table 1 along with factors that regulate miRNA expression, their validated target proteins and function of the target proteins. While some of these miRNAs promote VSMC proliferation, others stimulate differentiation.
\n\t\t\t\tmicroRNA\n\t\t\t | \n\t\t\t\n\t\t\t\tInducer/ Regulator\n\t\t\t | \n\t\t\t\n\t\t\t\tTarget Proteins\n\t\t\t | \n\t\t\t\n\t\t\t\tCellular Functions of Target Proteins\n\t\t\t | \n\t\t\t\n\t\t\t\tReferences\n\t\t\t | \n\t\t
\n\t\t\t\tmiRNA 21\n\t\t\t | \n\t\t\tVascular injury | \n\t\t\tPTEN, Bcl2 | \n\t\t\tIncrease proliferation, apoptosis | \n\t\t\t62 | \n\t\t
\n\t\t\t\tmiRNA 221/222\n\t\t\t | \n\t\t\tInjury, PDGF | \n\t\t\tp27kip1, p57kip2 | \n\t\t\tIncrease proliferation | \n\t\t\t63 | \n\t\t
\n\t\t\t\tmiRNA -146a\n\t\t\t | \n\t\t\tKLF5 | \n\t\t\tKLF4 | \n\t\t\tIncrease proliferation | \n\t\t\t64 | \n\t\t
\n\t\t\t\tmiRNA 26a\n\t\t\t | \n\t\t\tSerum deprivation | \n\t\t\tSmad 1, Smad 4 | \n\t\t\tDecrease proliferation | \n\t\t\t68 | \n\t\t
\n\t\t\t\tmiRNA 143\n\t\t\t | \n\t\t\tp53, SRF/ Myocardin | \n\t\t\tPDGFR, Elk1 | \n\t\t\tDecrease proliferation, stimulate differentiation | \n\t\t\t58 | \n\t\t
\n\t\t\t\tmiRNA 145\n\t\t\t | \n\t\t\tSRF/ Myocardin | \n\t\t\tCamKIIδ, KLF4, KLF5 | \n\t\t\tDecrease proliferation stimulate differentiation | \n\t\t\t58,65 | \n\t\t
miRNAs regulating vascular smooth muscle cell phenotype
Some miRNAs, such as miR-21, miRNA-221, miRNA-222 and 146a are demonstrated to promote VSMC proliferation in balloon-injured rat carotid arteries and cultured rat VSMC by silencing their target proteins (Table 1). Among these, miRNA-21 is the first miRNA that is recognized to regulate VSMC growth and survival by silencing phosphatase and tensin homolog (PTEN), a tumor suppressor protein and increasing B-cell lymphoma 2 (Bcl-2), which increased VSMC proliferation and survival [32,59-62]. Interestingly, this same miRNA is shown to regulate features of both proliferative and contractile phenotype by separate mechanisms. Through the regulation of processing of the miRNA-21 primary transcript to the mature miRNA -21 transcript, transforming growth factor-β (TGF-β) and bone morphogenetic proteins (BMPs) increased the miRNA-21. This increased miRNA-21 is shown to promote VSMC differentiation by upregulating VSMC restricted contractile proteins by silencing programmed cell death 4, a tumor suppressor protein [63].
Other miRNAs that stimulated proliferative phenotype include miRNA-221 and -222. Their proliferative effect on VSMC is mediated through silencing of their target proteins, p27kip1 and p57kip2, respectively, both of which are negative regulators of cell cycle progression [32, 64]. miRNA-146a is shown to directly target Krupple-like factor-4 (KLF-4) and promote VSMC proliferation in cultured rat VSMC and vascular neointimal hyperplasia [32, 60, 65]. KLF-4 and miRNA-146a appear to exhibit a feedback relationship regulating each other’s expression. While miRNA-146a inhibits KLF-4 expression by targeting the 3’-UTR region of KLF-4, KLF-4 inhibits miRNA-146a at the transcriptional level. KLF-5, another member of KLF family promoted the transcription of miRNA-146a. It appears these molecules form a regulatory control to appropriately modulate VSMC proliferation [32, 60].
Certain miRNAs including miRNA-143, miRNA-145 and miRNA-26a alter VSMC phenotype by causing suppression of VSMC proliferation (Table 1). Among these miRNAs, miRNA-143 and -145 are considered master regulators of contractile phenotype by promoting contractile protein expression [32, 58, 60]. Moreover, miRNA-145 not only stimulates differentiation of adult VSMC, but also promotes differentiation of multipotent neural crest stem cells into VSMC [57]. In normal vessel walls the miRNA-143/145 cluster is lavishly expressed. However, both miRNAs are dramatically reduced not only in injured carotid arteries following angioplasty [32, 58, 60, 66] but also downregulated in different cancer cell lines [67]. Further studies proved that miRNA-145 is a critical modulator of VSMC differentiation via its target gene KLF-5. Consistent with this, while the use of miRNA-145 oligonucleotide mimics upregulated the expression of VSMC differentiation marker genes such as SM α-actin, calponin, and SM-MHC, both at gene and protein levels, overexpression of KLF-5 reduced the gene expression of SM α-actin implicating a relationship between miRNA-145 and KLF-5 gene in VSMC differentiation.
Analysis of growth arrested human aortic VSMC by miRNA array screening identified upregulation of miRNA-26a in differentiated VSMC, which is associated with reduction in SMAD activity [59, 60, 68]. This miRNA is dramatically downregulated in two murine models of aneurysm.
Embryonic stem cells are known to differentiate to VSMC and one of the factors that induces VSMC differentiation is all trans retinoic acid, which in addition to regulating a wide variety of protein coding genes it also regulates expression of miRNAs that affect smooth muscle cell differentiation. It is found that expression of miRNA-10a contributes to retinoic acid-induced VSMC differentiation by negatively regulating its target histone deacetylase 4 [69]. Involvement of miRNAs in stem cell and vessel wall progenitor cell differentiation has significant implications in the pathogenesis of atherosclerosis, the response to vascular injury and vascular remodeling.
Recently presence of miRNAs is demonstrated in circulating blood, which may be useful as biomarkers for diseases [51]. Analysis of serum or plasma for circulating levels of miRNAs in normal individuals and in patients with coronary artery disease revealed circulating levels of angiogenesis-related miRNA-126 and miRNA-92a, the inflammation-associated miRNA-155; and VSMC-enriched miRNA-145 and miRNA-17 are significantly reduced in patients with coronary artery disease compared to normal individuals [51]. Whereas cardiac muscle-enriched miRNAs, miRNA-133a and -208a are elevated in patients with disease. These observations suggest that circulating miRNAs can be used as biomarkers for diagnosis of cardiovascular diseases.
Although roles of various miRNAs and their participation in biological processes have been recognized in various cultured cells or animal models, and expression profiles of circulating miRNAs in patients of cardiovascular diseases [50, 51], involvement of miRNAs in human atherosclerotic plaques has received little attention. However, one of the recent studies investigated miRNA/mRNA expression profiles of human atherosclerotic plaques from peripheral arteries in comparison to nonatherosclerotic left internal thoracic arteries to determine the relationship between miRNA/mRNA expression profiles and biological processes in atherosclerosis [70]. Results of this study revealed significant amounts of miRNA-21,-34a, -146a, -146b-5p, and -210 expressions in atherosclerotic lesions. Consistent with this there was downregulation of several predicted targets of these miRNAs in atherosclerotic plaques. According to the combination of miRNA/mRNA profiles and bioinformatic analysis, nine KEGG pathways including immunodeficiency, metabolism, p53 and cell proliferation signaling pathways enriched with predicted targets were significantly upregulated. On the contrary, VSMC contraction and purine metabolism were downregulated.
Role of miRNAs in restenosis is mainly studied using the common rat carotid artery balloon injury animal model. miRNA profiles in the carotid artery is determined by using miRNA arrays [62]. One of the miRNA that was aberrantly overexpressed in injury-induced neointimal lesions is miRNA-21. miRNA-21 promotes VSMC proliferation and inhibits apoptosis of VSMC by directly targeting PTEN and programmed cell death 4, respectively [32]. Similarly miRNA-221 and -222, which are encoded by a gene cluster on X chromosome, share the same seed sequence, identical targets and similar functions were upregulated in balloon-injured carotid arteries. Consistent with their upregulation, their target genes, p27kip1 and p57kip2 were downregulated [32, 64]. Additionally, miRNA-143 and miRNA-145 that promote VSMC differentiation and expressed highly in vascular tissue, were significantly reduced in apolipoprotein E knockout mice where vascular injury was induced by hypercholesterolemic diet [71]. Cooperatively, both miRNA-143 and miRNA-145 target a network of transcription factors such as Elk1, KLF-4 and myocardin to stimulate differentiation and inhibit proliferation of VSMC. Taken together, these studies indicate significant role of miRNA-143/miRNA-145 in VSMC differentiation and vascular disease.
Butyrate, a dietary-derived epigenetic histone modifier and a histone deacetylase (HDAC) inhibitor, is a strong inhibitor of VSMC proliferation [72-75]. Butyrate elicits many cytoprotective, chemopreventive and chemotherapeutic activities mainly through inhibition of cell proliferation, induction of cell death or stimulation of cell differentiation by selectively modulating gene expression via epigenetic changes [72-75]. Incidentally, the cellular effects that are stimulated by butyrate are also regulated by miRNAs and expression of some of these miRNAs is regulated by epigenetic mechanisms including DNA methylation and histone modification [76, 77]. Because butyrate is an established epigenetic histone modifier it is possible that butyrate may alter expression of some of the miRNAs in butyrate arrested VSMC proliferation. To explore this possibility, we recently examined expression profile of 650 miRNAs in butyrate inhibited rat VSMC proliferation by qRT-PCR array platform. Our preliminary unpublished data indicates differential expression of about 60 miRNAs. Among these, members of the miRNA-17-92 cluster are some of the miRNAs that are downregulated by butyrate in VSMC suggesting that antiproliferation action of butyrate is linked to downregulation of miRNAs of miRNA-17-92 cluster (Table 2). Studies have shown that the miRNAs of this cluster are not only involved in normal development of heart, lung and immune system but they also exhibit essential role in tumor formation by promoting cell proliferation and suppressing apoptosis [78].
miRNA-17-92 clustermature miRNAs | \n\t\t\t\n\t\t\t\tFold change *\n\t\t\t | \n\t\t
\n\t\t\t\trno-miR-17-1-3p\n\t\t\t | \n\t\t\t-2.77 | \n\t\t
\n\t\t\t\trno-miR-17-2-3p\n\t\t\t | \n\t\t\t-2.65 | \n\t\t
\n\t\t\t\trno-miR-17-5p\n\t\t\t | \n\t\t\t-2.15 | \n\t\t
\n\t\t\t\trno-miR-18a*\n\t\t\t | \n\t\t\t-1.80 | \n\t\t
\n\t\t\t\trno-miR-19a\n\t\t\t | \n\t\t\t-2.26 | \n\t\t
\n\t\t\t\trno-miR-19a*\n\t\t\t | \n\t\t\t-2.31 | \n\t\t
\n\t\t\t\trno-miR-19b\n\t\t\t | \n\t\t\t-2.32 | \n\t\t
\n\t\t\t\trno-miR-19b-1*\n\t\t\t | \n\t\t\t-2.84 | \n\t\t
\n\t\t\t\trno-miR-20a*\n\t\t\t | \n\t\t\t-2.40 | \n\t\t
\n\t\t\t\trno-miR-92a\n\t\t\t | \n\t\t\t-2.45 | \n\t\t
\n\t\t\t\trno-miR-92a-1*\n\t\t\t | \n\t\t\t-8.62 | \n\t\t
Changes in miRNA-17-92 cluster mature miRNAs levels in butyrate treated rat VSMC
*Values represent fold changes relative to untreated rat VSMC.
The miRNA-17-92 cluster is a polycistronic miRNA gene, which is titled as oncomir-1 in humans because of their oncogenic properties and overexpression in different cancers [79]. The miRNA-17-92 primary transcript encodes six mature miRNAs: miRNA-17,-18a, 19a, 20a, 19b-1, and 92a-1 that are tightly grouped within an 800 base-pair region of human chromosome 13 [80]. For some of these members corresponding target genes have been identified, which include cell cycle inhibitor CDKN1A (p21Cip1) and pro- apoptotic PTEN and BCL2L11 (Bim). Furthermore, transcription of miRNA-17-92 has been shown to be activated by c-myc transcription factor [78]. In our earlier studies butyrate has been shown to downregulate c-myc [81] and upregulate CDKN1A (p21Cip1) [72-75] in proliferation inhibited VSMC. Based on these observations, it appears by downregulating c-myc expression potentially via epigenetic modification, butyrate inhibits expression of miRNA-17-92 cluster with a corresponding increase in miRNA-17-92 target genes such as CDKN1A (p21Cip1). Taken together, our preliminary miRNA expression data emphasizes role of miRNAs in antiproliferative and chemoprotective effects of butyrate in VSMC. Further studies are under investigation to confirm the role of miRNA-17-92 cluster in the regulation of VSMC proliferation by investigating the effects of miRNA mimics of miRNA-17-92 cluster in reversing the effect of butyrate on VSMC proliferation and on decreasing the levels of their target proteins. Utilization of this information is beneficial in targeting miRNAs aimed to decrease the level of pathogenic/aberrantly expressed miRNAs or to increase miRNAs with valuable functions in the intervention of occlusive vascular proliferative diseases.
Despite the substantial progress in understanding the etiology and clinical management of vascular proliferative diseases, they are still life threatening diseases responsible for the global burden of cardiovascular diseases. Clinically, medications and surgical procedures are the only methods of treatment for patients with atherosclerotic disease. Atherosclerotic patients are generally treated by angioplasty with stent replacement but it commonly leads to restenosis in significant number of angioplasty patients. Phenotypic modification of VSMC from contractile differentiated state to proliferative dedifferentiation state is the primary pathophysiological mechanism in the development of atherosclerosis and in different clinical pathologies such as postangioplasty restenosis, in-stent restenosis, vein bypass graft failure and transplant vasculopathy [33,34]. Therefore, understanding the molecular mechanisms of VSMC proliferation may offer novel insights into disease pathogenesis leading to targeted therapies. Vascular phenotypic modulation is a multifactorial process involving multiple pathways and multiple genes. Based on the current understanding of the roles of miRNAs in the normal development and in disease pathogenesis, it appears miRNA-based therapy has a potential in vascular proliferative diseases, particularly because one endogenous miRNA can target its multiple target genes. Moreover, demonstration of changes in expression of certain miRNAs that is specifically associated with particular VSMC phenotype in different models of studies, as depicted in this article, clearly suggests that expression analysis of miRNA will provide insights into vascular proliferative disease mechanisms and possibly identifies novel targets for future vascular therapy. This information is important in targeting miRNAs aimed to decrease the level of abnormally expressed miRNAs and/or to increase miRNAs with valuable functions in the intervention of occlusive vascular proliferative diseases.
The recent demonstration that changes in expression of certain miRNAs in neointimal lesions, particularly upregulation of miRNA-21 and miRNA-221/-222 and downregulation of miRNA-145 support proliferative phenotype of VSMC suggests targeting miRNAs may represent a new form of therapy for vascular proliferative diseases [62, 64]. Furthermore, silencing of miRNA-21 and miRNA-221/222 by the local delivery of chemically engineered oligonucleotide-based miRNA inhibitors referred as “antigomirs” are efficient and specific silencers targeted for miRNA-21 and miRNA-221/222 was shown to reduce neointima formation [62, 64]. Similarly, use of an antagomir against miRNA -122, specifically silenced miRNA-122 expression in the liver, lung, intestine, heart, skin and bone marrow for more than a week after one intravenous injection [82]. In another method, silencing of mir-145 or miRNA- 143 was achieved by adenovirus-mediated delivery of these miRNAs to vascular lesion, which appears to restore miRNA profile of vascular lesion that resembles normal tissue [66, 71]. Although these studies suggest that targeting miRNAs may represent a new therapy for vascular proliferative diseases, the miRNA-based technology is still long way from being translated to clinical therapy.
Exploring the microRNAome that controls VSMC phenotype and analysis of their targets have greater possibilities for unraveling unforeseen regulatory pathways and disease mechanisms, development of novel therapeutic approaches. miRNAs in cardiovascular research are a newly emerging powerful biomolecules, which demonstrate several unique opportunities for microRNAs-based therapeutics. Although some of the studies appear to indicate targeting certain miRNAs presents a potential therapy for atherosclerosis, knowledge of full scope of miRNAs in vascular pathogenesis is limited. With 1,000 or more microRNAs encoded by the human genome, only a few of which have been analyzed appear to be linked to vascular proliferative diseases. Considering the complexity of the multifactorial vascular proliferative diseases including atherosclerosis and restenosis, there may be several miRNAs and even several clusters of miRNAs, similar to miRNA-17-92 cluster, which impact the development of vascular pathogenesis. Therefore, several issues have to be addressed prior to use of miRNA-based technology can be translated to clinical therapy such as: profile of miRNAs responsible for vascular proliferative diseases needs to be determined; detailed effects of these miRNAs in the prevention and treatment of vascular proliferative diseases requires investigation; procedures for in vivo miRNA silencing needs to be improved to minimize off-target effects; technology for miRNA upregulation in arterial vessel wall requires development; and potential toxicity of miRNA-based therapy should be determined. Developing miRNAs into therapeutics reveals other significant challenges, such as methods of delivery and duration of action. Methods for local delivery to the arteries via catheters or coated stents may avert these challenges and should minimize off-target effects on other tissues. Besides their therapeutic potential, identification of circulating miRNAs released from injured tissues or highly expressed in patients with cardiovascular diseases suggest miRNAs can also be useful as potential biomarkers for clinical diagnosis of cardiovascular disease patients.
Neurofeedback [1, 2] is a smart biofeedback platform which provides real-time feedback to individuals about their neurophysiological signals in order to achieve brain activity associated with therapeutic benefit. Brain activity of an individual is measured continuously using an EEG system during the course of neurofeedback training and parameters describing neurophysiological signals such as alpha power or peak alpha frequency are calculated in real-time [3]. These calculated features of ongoing brain activity are then presented to the individual either in an audio or visual form [3]. The idea behind this is that through repeated provision of such feedback, the individual gains an awareness of their current brain state and can identify different mental strategies which help them achieve the desired brain state [4]. Once the individual identifies strategies which work for them, they can keep practicing them over the course of multiple sessions with the final aim of being able to implement these strategies independent of a neurofeedback session.
Neurofeedback has already been investigated extensively for the management of several neuropsychiatric conditions [5] such as Attention Deficit Hyperactivity Disorder (ADHD) [6], depression and anxiety [7], cognition [8] and stroke rehabilitation [9] for example. Being able to target brain signals through neurofeedback can be of great benefit in conditions such as chronic pain. This is because the perception of chronic pain depends on how multiple regions of the brain process the ascending pain signals [10, 11]. Such central processing of incoming pain signals has been shown to be different in chronic pain patients compared to healthy participants by a number of studies [12, 13, 14]. Considering the brain plays such an important in the development and maintenance of chronic pain state, being able to target changes in the neurophysiological signal which reflect such brain activity using a novel therapy such as neurofeedback is of great interest.
The field of neurofeedback therapy for chronic pain is rapidly developing. Several studies have been performed on a range of medical conditions over the last decade [15]. The current studies are highly heterogenous with a number of variations in neurofeedback protocol and delivery [15, 16]. This chapter aims to give an overview of the neurophysiological changes observed in chronic pain and how these have been targeted by different neurofeedback studies. We also discuss the different aspects of neurofeedback protocols which have been used so far and the outcomes of these studies in terms of reduction in pain and pain associated symptoms.
Our understanding of the neuroscience underlying pain has evolved significantly over time. Neural pathways involved in pain perception have been shown in Figure 1. One of the earliest theories explaining pain was the “specificity theory” (Figure 1: Red pathway). According to this theory, pain is experienced when an injury to a particular part of the body leads to signals being relayed via nociceptive neurons to the “pain center” [17]. The brain was considered to be a “passive recipient of sensory information” [17].
Neural pathways underlying pain perception proposed by different pain theories.
One of the landmark theories which was highly influential in changing this prior understanding of pain was the Gate Control Theory by Melzack and Wall (1965) [18] (Figure 1: Blue pathway). This theory proposed that several neurons in the spinal cord, such as large fibers carrying touch and vibration sensations as well as interneurons in substantia gelatinosa of the dorsal horn, modulate the incoming signals from the site of pain, thereby influencing the final signal which is transmitted to the brain for processing.
Since then, advances in neuroimaging has revealed that in addition to neural pathways in the spinal cord, several cortical structures are also involved in modulating pain perception [19, 20] (Figure 1: Purple pathway). Some of the areas which have been reported to be involved include anterior cingulate gyrus, somatosensory cortex, insular cortex, thalamus and prefrontal cortex [19]. These findings suggest that there is not a single “pain centre”. Instead, pain is processed by a “pain matrix” connecting different parts of the brain, thereby, reinforcing the idea that pain perception is a result of several sensory, affective and cognitive processes [10, 11]. Therefore, pain experienced by an individual is an integration of the current information about the painful sensory stimulation and prior information from previous experiences which influence the emotions, anxiety, attention and expectations of the individual about the pain [21].
Different areas of the cortex constituting the pain matrix project onto the hypothalamus and amygdala, which then give rise to both descending inhibitory pathways and descending facilitatory pathways [21, 22]. These descending pathways directly project onto the dorsal horn of the spinal cord where gating of pain is occurring, therefore, influence the signals which are relayed up the ascending pathways [21, 22]. This process is known as top-down modulation of pain [23].
In summary, the pain perceived by an individual is an integration of how different parts of the cortex process the ascending pain signals as well as how the activity of these cortical and subcortical structures influence the ascending pain signals via descending pathways [17, 21, 24]. With the discovery of these higher-order processes which influence pain perception, several neuromodulatory therapies such as neurofeedback (NFB), hypnosis and meditation, have been explored with the potential of controlling pain by influencing this supraspinal cortical processing of pain [25].
Generally, the EEG oscillations are categorized based on their frequency into theta (4–7 Hz), alpha (8–12 Hz), low beta or beta1 (15–20 Hz) and high beta or beta2 (22–30 Hz) [26, 27, 28, 29]. Another oscillation which is widely investigated in the field of neuromodulation is sensorimotor rhythm (SMR). SMR refers to oscillations in the 12–15 Hz range which appear in spindle-like pattern over the sensorimotor cortex during idling of the motor cortex [30, 31]. Motor execution or motor imagery which activates the motor cortex leads to a decrease in the SMR activity [31].
Each of these brain rhythms is associated with a specific cognitive state. For instance, whilst alpha waves have been associated with a relaxed state, beta waves are associated with wakefulness and a state of engagement in task. Theta waves have been associated with drowsiness [27, 32].
Patients with chronic pain have differences in their resting-state brain (EEG) oscillations from healthy individuals. An example of a chronic pain condition which has been extensively investigated for identification of EEG correlates of chronic pain has been spinal cord injury (SCI). A study by Sarnthein et al. [12] showed that SCI patients with central neuropathic pain had increased activity of theta and beta oscillations compared to healthy individuals. These findings were confirmed by another study [13] which observed similar increases in theta and beta activity, but in addition, also identified lower levels of alpha activity in this patient population. This association between chronic pain and EEG changes was further strengthened when Jensen et al. [33] demonstrated that even within a group of patients with spinal cord injury, individuals with central neuropathic pain had higher theta and lower alpha activity than patients with spinal cord injury but no chronic pain.
These patterns of EEG have also been reported in other chronic pain conditions. For instance, patients with migraine have higher theta and delta power compared to healthy controls [14]. Patients with fibromyalgia have been shown to have higher theta activity with sources estimated to be in the left dorsolateral prefrontal and orbitofrontal cortex, higher beta and gamma activity with sources estimated to be in the insular, primary motor and primary and secondary somatosensory cortices and slowing of the dominant alpha peak [34].
Identification of such neurophysiological correlates of chronic pain is important as it not only provides the necessary feedback signal to increase voluntary control in therapies such as neurofeedback, but also allows monitoring the efficacy of the therapy in modulating the neurophysiological processes targeted by the therapy.
There are two key modalities which have been used to provide neurofeedback – EEG neurofeedback and fMRI neurofeedback. Whilst EEG neurofeedback provides feedback based on the neurophysiological signals recorded through an EEG system, fMRI neurofeedback provides feedback based on the degree of activation of a particular region of the brain detected using fMRI imaging in real time [35]. Hence it is inevitable that there is some lag between the activation and signal detection in fMRI neurofeedback which happens almost instantaneously in EEG neurofeedback [35].
Evidence regarding efficacy of fMRI neurofeedback in pain is limited understandably due to the increased difficulties and expenses associated with this form. The common region of interest which has been targeted in fMRI studies has been rostral anterior cingulate gyrus (rACC), whereby increased activity of rACC, measured through detecting an increase in blood oxygen level dependent signal from the region, has been associated with pain reduction [36, 37]. However, these studies have been severely limited in terms of number of sessions [37, 38], therefore the full benefit of the neurofeedback which occurs over the course of several sessions has not been explored yet in fMRI neurofeedback for chronic pain.
A number of brain rhythms have been targeted by EEG neurofeedback in order to increase resilience to pain (Table 1). The commonly targeted rhythms include theta (4–7 Hz), alpha (8–13 Hz), beta (14–30 Hz) and sensorimotor (12–15 Hz over the sensorimotor area) [17]. However, the change desired in each of these rhythms varies. Whilst pain reduction has been associated with an increase in the power of alpha and sensorimotor rhythms, contrastingly, a decrease in theta and beta rhythms have been associated with pain relief [17]. However, very few studies target these signals in isolation [20, 39]. More often studies target multiple signals at the same time, whereby patients are either shown each rhythm individually at the same time or they are shown feedback based on the ratio of two such signals [40, 41, 42, 43].
Brain rhythm | Frequency | Desired change |
---|---|---|
Theta | 4–7 Hz | Decrease in power |
Alpha | 8–13 Hz | Increase in power |
Beta | 14–30 Hz | Decrease in power |
Sensorimotor rhythm | 12–15 Hz Over sensorimotor cortex | Increase in power |
Neurofeedback targets [17].
In general, neurofeedback sessions tend to be 30–45 minutes long and patients are offered 20–40 sessions [15]. The frequency of these sessions ranges from one to five times a week, but studies which administered more frequent sessions have reported greater pain relief. Commonly used electrodes for providing feedback include C3, C4, Cz, T3, T4, FP1, P3 and P4 [15].
Feedback has been provided in a range of ways. Auditory feedback has been mainly in the form of changing volume of sound, whereby, achievement of signal has been associated with an increase in the volume heard [44]. Visual feedback used has been more varied (Figure 2). Some studies use simple bars to show the feedback, whereby the height of the bar is proportional to the intensity of the signal [45]. Other studies have changed the color of the bar on achievement of signal such that when the threshold is met, the color turns green, otherwise it remains red [43]. Some studies have tried to engage the users through the idea of games whereby the width of a river increases as the intensity of signal increases for instance [41, 46]. Therefore, feedback has been provided in a range of ways. Another form of stimulation which can be explored in the context of neurofeedback is tactile stimulation. Some studies have even combined two forms of stimuli such as visual and auditory whereby patient is shown an angry and shouting patient [36]. In order to calm the patient, the individual has to achieve the desired changes in the brain rhythms.
Schematic representation of visual stimulus provided in different neurofeedback studies.
Several neurofeedback studies have shown pain reduction following neurofeedback. Key randomized controlled trials in the field have been summarized in Table 2. Reduction in pain has been reported across several pain conditions such as Fibromyalgia [27, 29, 36, 41], Central Neuropathic Pain in Paraplegic patients [28, 43, 47, 48, 49], Traumatic Brain Injury [39, 50], Chemotherapy-Induced Peripheral Neuropathy [51], Primary Headache [52], Complex Regional Pain Syndrome Type I [53], Post-Herpetic Neuralgia [37] and chronic lower back pain [54]. There is a wide range of pain reduction reported which can range from an average of 6–82% reduction in pain intensity [15]. A recent systematic review published showed that ten out of twenty-one studies published in the field reported a pain reduction of greater than 30% which is considered to be clinically significant reduction [15].
Study | Chronic pain condition | Target brain oscillation | % Pain reduction | Pain associated symptoms reported to improve following NFB |
---|---|---|---|---|
Goldway et al. (2019) [36] | Fibromyalgia | ↓Amygdala activation (fMRI) | 7% | REM latency Sleep quality |
Prinsloo et al. (2018) [50] | Chemotherapy-induced peripheral neuropathy | ↑Alpha ↓Beta | 45% | Fatigue Cancer-related symptoms Physical functioning Quality of life |
Guan et al. (2015) [37] | Post-herpetic Neuralgia | ↓rACC activity (fMRI) | 64% | None studied |
Farahani et al. (2014) [45] | Primary headache | ↑SMR ↓Theta ↓Beta | 19% | None studied |
Caro et al. (2011) [29] | Fibromyalgia | ↑SMR ↓Theta ↓Beta | 39% | Fatigue |
Kayiran et al. (2010) [40] | Fibromyalgia | ↑SMR ↓Theta ↓Beta | 82% | Fatigue Depression Anxiety Social functioning Physical functioning |
Randomized controlled trials investigating role of neurofeedback in chronic pain conditions.
Such variability in the degree of pain reduction could be due to a number of aspects of the neurofeedback protocol ranging from number of sessions, frequency of sessions, target frequencies and electrodes used for feedback, for example. The neurofeedback studies conducted so far have been highly variable on more than one of these aspects [15, 16], making comparison of results across studies impossible. Therefore, it is difficult to determine which of these parameters is responsible for the difference or how to best optimize each of these aspects of the training.
Most of the neurofeedback studies have measured changes in pain immediately following neurofeedback [39, 43, 52, 55, 56]. Furthermore, pain reduction has been reported to be sustained even at follow up of 3–6 months after completion of neurofeedback training [28, 36, 41, 49, 50, 51, 54]. However, these studies do not report whether the corresponding change in brain rhythm which were measured following completion of training were also sustained at long-term follow-up. We do not know the length of time for which the effect of neurofeedback on brain rhythms is sustained. Interestingly, one study reported that although pain reduction did not occur immediately following completion of the training course, there was improvement in pain at follow-up [36]. This could suggest that perhaps NFB could lead to changes in the underlying brain networks which occurs over a longer period of time but can be sustained for longer duration. These results provide the preliminary evidence for potential of neurofeedback for providing analgesia in chronic pain.
It has been shown that neurofeedback not only leads to reduction in pain but leads to improvement in a number of pain associated symptoms such as depression [27, 39, 41, 54, 57, 58, 59, 60], anxiety [27, 41, 54, 57, 59], fatigue [27, 29, 41, 49, 51], and sleep [36, 39, 49, 50, 51, 57]. These symptoms have been known to co-exist with pain in chronic pain conditions and also known to exacerbate the individual’s pain on a day-to-day basis [61, 62, 63]. Therefore, by being able to target these symptoms along with pain, neurofeedback has the potential to holistically improve the well-being of these individuals. A summary of different symptoms which have been shown to improve following neurofeedback have been shown in Figure 3.
Schematic representation of pain and pain associated symptoms in chronic pain syndromes.
Current neurofeedback studies have a number of limitations. There are currently only seven controlled trials in the field [29, 41, 47, 51, 52, 64, 65], of which only one trial is of high quality [65]. Most of the trials lack appropriate blinding as the control group are often patients on other pain medications [29, 66]. This makes the blinding of patient difficult and could lead to patient’s belief in treatment affecting the results. Only two studies have implemented sham neurofeedback [36, 37].
The best sham treatment to offer is debatable. One would argue that patients could be shown the feedback signal from another region of the brain. But this might not be best as it might be the case that another region which is used for feedback might be the undiscovered part of the pain matrix. Another way to provide sham feedback would be to show the individual the recording from another participant or their own recording in a reverse order. Whilst this might be a true sham condition as the feedback shown to the individual would be independent of the individual’s brain activity, it might mean that the patients find no relief of symptoms and discover that it is a sham treatment. Either way, such sham neurofeedback needs to be implemented by more studies in order to truly understand whether the pain reduction reported in these individuals is due to underlying changes in neuronal networks.
Whilst we have learnt a lot about neurofeedback over the past decade, there is still a lot which is unknown about this technique. Neurofeedback differs from other neuromodulatory techniques such entrainment and transcranial magnetic stimulation in that neurofeedback involves active involvement of the individuals in changing the brain oscillations, as opposed to passive reception of stimulation [5]. We do not know which of these is a more efficient technique to alter brain oscillations yet. Furthermore, it is also unknown what mental strategies in particular are associated with changes in brain oscillations seen in the studies so far. Some of the common instructions given to patients undergoing training involve asking them to stay relaxed, imagining happy moments, revisiting happy memories and thinking about favorite family member or friends. However, none of the studies so far document which of these strategies actual work for the patients. Therefore, further qualitative studies are required to see what patients have been using to actively change their brain oscillations during neurofeedback in order to provide more focused instructions to patients undergoing training. Furthermore, studies should aim to analyze the correlation between neurophysiological signal and pain reduction rather than solely focusing on the behavioral outcomes [29, 41, 47, 51, 52, 64, 65]. Establishing such correlation between behavioral change and changes in neurophysiological signal is key to understanding whether the pain relief is truly due to neurofeedback.
In addition to this, there is also a possibility that once the patients have been able to identify the mental strategy which allows them to achieve the desired brain state and practice in the neurofeedback setting for a number a sessions, they might be able to implement such mental strategies without the ongoing EEG signal feedback. It is not clear if this possible or how long it might take for an individual to become independent of the EEG feedback and still receive pain relief.
The current neurofeedback studies are highly heterogenous. It is unclear which brain regions, oscillations, feedback form or training length is required to optimize the improvement in pain. More studies are required comparing one aspect of the neurofeedback training program at once in order to determine which of these parameters provide the most therapeutic benefit.
Another area of uncertainty is the efficacy of neurofeedback in different pain conditions. Studies so far have shown that all chronic pain condition report pain reduction to some degree following neurofeedback. However, it is not known whether neurofeedback is better for some chronic pain conditions than others. It might be the case that neuronal changes seen following neurofeedback is linked to central sensitization only, in which case several chronic pain conditions may benefit from it equally as many pain conditions have this as the underlying pathology. However, we do not know whether it is equally as good at treating nociceptive pain as seen in conditions such as arthritis.
Furthermore, the role that neurofeedback will play in pain management in the future is not clear [16]. It is not clear whether it has the true potential to substitute pharmacological agents completely. It might be the case that it might reduce the escalation of opioid usage in this patient cohort. Hence further studies are needed to determine the maximum potential of this form of therapy.
In general, neurofeedback is well tolerated with a minority of patients experiencing mild adverse events. These adverse events are often self-limiting and tend to be controlled by decreasing the frequency of training [43, 48]. Adverse events seen in neurofeedback studies seem to be more common in certain patient groups than others. For instance, some individuals with spinal cord injury and central neuropathic pain have reported some hypersensitivity of soles of the feet due to recovery of proprioception or spasms of the lower limb, [28, 48]. Patients with traumatic brain injury have reported an increase in nausea and the intensity of their headaches [39, 67]. It is difficult to confirm that these side-effects are due to NFB as these reported symptoms are often seen in these conditions irrespective of provision of neurofeedback therapy. Overall, NFB is safe and well-tolerated in majority of patients in most clinical studies.
Neurofeedback has also been delivered in the home setting by a few recent studies [43, 48]. This can be achieved through the use of a headset which records activity from one single electrode, such as C4 [43, 48] or FP1 [39] and makes use of an app on tablets to analyze and showcase feedback to the individual [28, 48]. Such systems have been implemented in patients with central neuropathic pain [43, 48] as well as traumatic brain injury [39]. Patients could practice neurofeedback for 5- or 10-minutes sessions as and when they wanted.
These studies have shown some promising results. With further expansion of this technology, it might be possible for individuals to benefit from neurofeedback at their home as and when required as patients have on average used neurofeedback 3–40 times over the course of 2–3 months in these studies [43, 48]. Two of these studies have reported around 33% reduction in pain [43, 48] whereas one of them reported 16% reduction in pain [39] on average in participants who tried these home-based systems.
One of these studies also performed qualitative research on user experience following such home-based systems [43]. Overall, it was reported that the patient satisfaction score was high when measured using QUESB (Quebec User Evaluation of Satisfaction Questionnaire). According to the patients, the key factors which affected the frequency of their use of the home-based device were their health state, availability of free time and their intensity of pain. Patients also put effectiveness, ease of use and comfort as their main priority when using any such home-based device. Hence whilst the current home-based technology used in this study showed that it could record the data with decent quality, it also highlighted that patients wanted technology which was able to provide neurofeedback wirelessly using headset and smart device as well as collect information from the scalp without the use of gel to connect electrodes.
Being able to do this on a regular basis would also increase the efficacy of the therapy and patients might be able to use neurofeedback in addition to or instead of commonly used pharmacological agents which are associated with significant adverse effect profiles. Therefore, home-based neurofeedback can act as a novel treatment option to provide pain relief to patients with much fewer side effects than current pharmacological agents [68].
Neurofeedback is a newly emerging technique which can be used to achieve brain states associated with increased resilience to pain. The results so far have been very promising not only in terms of improvement in chronic pain, where as many as half of the studies in the field have shown clinically significant reduction in clinical pain following neurofeedback, but also in terms of improvement in pain associated symptoms such as fatigue, depression, anxiety and sleep which have also been reported to improve with neurofeedback. Being able to target all of these co-morbidities holistically using neurofeedback is key for the overall improvement in the well-being of chronic pain patients because these factors are often interlinked and aggravate each other.
There is still a lot of work that needs to be done. Different aspects of training protocols, such as target signal, number of sessions, length of sessions and scalp region of interest, need to be optimized in order to identify parameters which lead not only to successful modulation of the brain activity but also a corresponding change in pain signals. Currently, it is not clear what neurofeedback protocol brings about maximum pain relief for patients.
Furthermore, identification of mental strategies which enable individuals to reach therapeutic brain states is also required, with the aim being that eventually individuals will be able to practice these strategies independent of the feedback system after an initial course of training sessions. Whilst, there is a lot of work to do, the results so far have been promising, opening window of opportunity to manage a number of chronic pain conditions at low cost and without the side effects associated with the currently available pharmacological agents.
The authors have no conflict of interest to declare.
IntechOpen implements a robust policy to minimize and deal with instances of fraud or misconduct. As part of our general commitment to transparency and openness, and in order to maintain high scientific standards, we have a well-defined editorial policy regarding Retractions and Corrections.
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\\n\\n3.1. ERRATUM
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\\n\\nA published Erratum will adhere to the Retraction Notice publishing guidelines outlined above.
\\n\\n3.2. CORRIGENDUM
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\\n\\n4. FINAL REMARKS
\\n\\nIntechOpen wishes to emphasize that the final decision on whether a Retraction, Statement of Concern, or a Correction will be issued rests with the Academic Editor. The publisher is obliged to act upon any reports of scientific misconduct in its publications and to make a reasonable effort to facilitate any subsequent investigation of such claims.
\\n\\nIn the case of Retraction or removal of the Work, the publisher will be under no obligation to refund the APC.
\\n\\nThe general principles set out above apply to Retractions and Corrections issued in all IntechOpen publications.
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\\n\\nPolicy last updated: 2017-09-11
\\n"}]'},components:[{type:"htmlEditorComponent",content:'IntechOpen’s Retraction and Correction Policy has been developed in accordance with the Committee on Publication Ethics (COPE) publication guidelines relating to scientific misconduct and research ethics:
\n\n1. RETRACTIONS
\n\nA Retraction of a Chapter will be issued by the Academic Editor, either following an Author’s request to do so or when there is a 3rd party report of scientific misconduct. Upon receipt of a report by a 3rd party, the Academic Editor will investigate any allegations of scientific misconduct, working in cooperation with the Author(s) and their institution(s).
\n\nA formal Retraction will be issued when there is clear and conclusive evidence of any of the following:
\n\nPublishing of a Retraction Notice will adhere to the following guidelines:
\n\n1.2. REMOVALS AND CANCELLATIONS
\n\n2. STATEMENTS OF CONCERN
\n\nA Statement of Concern detailing alleged misconduct will be issued by the Academic Editor or publisher following a 3rd party report of scientific misconduct when:
\n\nIntechOpen believes that the number of occasions on which a Statement of Concern is issued will be very few in number. In all cases when such a decision has been taken by the Academic Editor the decision will be reviewed by another editor to whom the author can make representations.
\n\n3. CORRECTIONS
\n\nA Correction will be issued by the Academic Editor when:
\n\n3.1. ERRATUM
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\n\nA published Erratum will adhere to the Retraction Notice publishing guidelines outlined above.
\n\n3.2. CORRIGENDUM
\n\nA Corrigendum will be issued by the Academic Editor when it is determined that a mistake in a Chapter is a result of an Author’s miscalculation or oversight. A published Corrigendum will adhere to the Retraction Notice publishing guidelines outlined above.
\n\n4. FINAL REMARKS
\n\nIntechOpen wishes to emphasize that the final decision on whether a Retraction, Statement of Concern, or a Correction will be issued rests with the Academic Editor. The publisher is obliged to act upon any reports of scientific misconduct in its publications and to make a reasonable effort to facilitate any subsequent investigation of such claims.
\n\nIn the case of Retraction or removal of the Work, the publisher will be under no obligation to refund the APC.
\n\nThe general principles set out above apply to Retractions and Corrections issued in all IntechOpen publications.
\n\nAny suggestions or comments on this Policy are welcome and may be sent to permissions@intechopen.com.
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