Botulinum toxin dose in spasticity [27].
\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\\n"}]',published:!0,mainMedia:{caption:"Highly Cited",originalUrl:"/media/original/117"}},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 191 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 261 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\n'}],latestNews:[{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"}]},book:{item:{type:"book",id:"10377",leadTitle:null,fullTitle:"Electric Power Conversion and Micro-Grids",title:"Electric Power Conversion and Micro-Grids",subtitle:null,reviewType:"peer-reviewed",abstract:"This edited volume is a collection of reviewed and relevant research chapters offering a comprehensive overview of recent achievements in the field of micro-grids and electric power conversion. The book comprises single chapters authored by various researchers and is edited by a group of experts in such research areas. All chapters are complete in themselves but united under a common research study topic. This publication aims at providing a thorough overview of the latest research efforts by international authors on electric power conversion, micro-grids, and their up-to-the-minute technological advances and opens new possible research paths for further novel developments.",isbn:"978-1-83969-389-2",printIsbn:"978-1-83969-388-5",pdfIsbn:"978-1-83969-390-8",doi:"10.5772/intechopen.91563",price:119,priceEur:129,priceUsd:155,slug:"electric-power-conversion-and-micro-grids",numberOfPages:178,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"9f41084eff07323bda451cd5c77dfaaf",bookSignature:"Majid Nayeripour and Mahdi Mansouri",publishedDate:"January 26th 2022",coverURL:"https://cdn.intechopen.com/books/images_new/10377.jpg",numberOfDownloads:1077,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:1,numberOfDimensionsCitationsByBook:0,hasAltmetrics:0,numberOfTotalCitations:1,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"November 27th 2020",dateEndSecondStepPublish:"December 28th 2020",dateEndThirdStepPublish:"February 23rd 2021",dateEndFourthStepPublish:"May 14th 2021",dateEndFifthStepPublish:"July 13th 2021",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6,7",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"66929",title:"Prof.",name:"Majid",middleName:null,surname:"Nayeripour",slug:"majid-nayeripour",fullName:"Majid Nayeripour",profilePictureURL:"https://mts.intechopen.com/storage/users/66929/images/system/66929.png",biography:"After 8 years of industrial experience and academic work in the electrical engineering and renewable energy fields, Prof. Majid Nayeripour was promoted to full professor in the field of micro-grids in 2016. He was given a sabbatical from Shiraz University of Technology, Iran, and was invited to Cologne University of Applied Sciences, Germany in January 2016. During his research, he gained new experiences about problems relating to high penetration levels of distributed generations and toward having 100% renewable energy in Germany, and as a result, he was awarded a fellowship program for an experienced researcher from the Alexander von Humboldt (AvH) Foundation in 2017. Currently, he is at the Cologne University of Applied Science and is involved in research on the control and dynamic investigation of interconnected micro-grids. He has published more than 120 journals and conference papers, five books, and supervised more than ten research projects.",institutionString:"Cologne University of Applied Sciences",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"5",institution:null}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:{id:"291302",title:"Dr.",name:"Mahdi",middleName:null,surname:"Mansouri",slug:"mahdi-mansouri",fullName:"Mahdi Mansouri",profilePictureURL:"https://mts.intechopen.com/storage/users/291302/images/system/291302.png",biography:"Dr. Mahdi Mansouri was born in Yazd, Iran in 1975. He received both his B.S. degree in electronic engineering and MSc degree in electronic power from the Sharif University of Technology at Power Electronics-STATCOM and his Ph.D. degree in renewable energy systems from doubly fed induction generator (DFIG)-based wind turbines from the Shiraz University of Technology. He has 20 years of experience in high-voltage transmission substations and lines as a technical engineer, a consultant, and an executive project manager. His research interests include flexible alternating current transmission system devices, power quality, and power system protection. He currently conducts power electronics, power-relay protection, and power-quality projects as a consultant and project manager.",institutionString:"Yazd University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:null},coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"756",title:"Power Electronics",slug:"power-electronics"}],chapters:[{id:"77537",title:"Design and Simulation of Low-Cost Microgrid Controller in Off-Grid Remote Areas",doi:"10.5772/intechopen.98551",slug:"design-and-simulation-of-low-cost-microgrid-controller-in-off-grid-remote-areas",totalDownloads:337,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"This study presents the microgrid controller with an energy management strategy for an off-grid microgrid, consisting of an energy storage system (ESS), photovoltaic system (PV), micro-hydro, and diesel generator. The aim is to investigate the improved electrical distribution and off-grid operation in remote areas. The off-grid microgrid model and the control algorithms developed using MATLAB Simulink and State flow. The energy management system is focusing on the state of charge of the energy storage system. The microgrid controller controls the operation mode and power generation from the distributed generations’ local controller, i.e., PV, micro-hydro, and diesel. It also controls the smart meters of the loads to be connected or disconnected to the microgrid. The simulation results show that the proposed microgrid control can control the target off-grid microgrid in given possible scenarios. The off-grid microgrid managed to meet the energy demand with the lowest power outage and the diesel generator operation’s lowest cost.",signatures:"Tapparit Bangtit",downloadPdfUrl:"/chapter/pdf-download/77537",previewPdfUrl:"/chapter/pdf-preview/77537",authors:[{id:"344060",title:"Mr.",name:"Tapparit",surname:"Bangtit",slug:"tapparit-bangtit",fullName:"Tapparit Bangtit"}],corrections:null},{id:"78818",title:"A Novel Energy Management Control Technique for PV-Battery System in DC Microgrids",doi:"10.5772/intechopen.98524",slug:"a-novel-energy-management-control-technique-for-pv-battery-system-in-dc-microgrids",totalDownloads:155,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"This paper presents a new energy management control technique for PV-Battery system used in DC microgrids. The proposed control technique is performed based on a droop control algorithm that maintains DC-bus voltage in a desirable and required range adaptively. Tightly Regulating the bus voltage In the islanded mode of operation is very challenging. However, the proposed control method by introducing a nonlinear droop profile with four adaptive parameters shows its superiority. Adaptive parameters determined by the non-linear optimal algorithms. Tightly regulating the DC bus voltage during extensive changes in demand loads/sources within a DC Micro Grid is the responsibility of the adaptive parameters. Stability of the proposed method in the whole system for a very broad range of operating conditions are proved. Simulation results along with the experimental results verify the feasibility of the proposed approach while demonstrate its superior performance compared to the conventional control method.",signatures:"Hadis Hajebrahimi, Sajjad Makhdoomi Kaviri, Suzan Eren and Alireza Bakhshai",downloadPdfUrl:"/chapter/pdf-download/78818",previewPdfUrl:"/chapter/pdf-preview/78818",authors:[{id:"344010",title:"M.Sc.",name:"Hadis",surname:"Hajebrahimi",slug:"hadis-hajebrahimi",fullName:"Hadis Hajebrahimi"}],corrections:null},{id:"77485",title:"Power Quality in Renewable Energy Microgrids Applications with Energy Storage Technologies: Issues, Challenges and Mitigations",doi:"10.5772/intechopen.98440",slug:"power-quality-in-renewable-energy-microgrids-applications-with-energy-storage-technologies-issues-ch",totalDownloads:288,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Nowadays, the electric power distribution system is undergoing a transformation. The new face of the electrical grid of the future is composed of digital technologies, renewable sources and intelligent grids of distributed generation. As we move towards the electrical grid of the future, microgrids and distributed generation systems become more important, since they are able to unify small-scale and flexible generation to clean energy and intelligent controls. The microgrids play an important role in marking electrical grids more robust in the face of disturbances, increasing their resilience. Although the microgrid concept continues in discussion in technical circles, it can be defined as an aggregation of electrical elements in low generation voltage, storage and loads (users) which are grouped in a certain bounded geographical area. The issues of a microgrid integrated with energy storage technologies has gained increasing interest and popularity worldwide as these technologies provide the reliability and availability that are required for proper operation in the system. Actual studies show that the implementation of energy storage technologies in a microgrid improves transients, capacity, increases instantaneous power and allows the introduction of renewable energy systems. However, there are still certain unsolved problems in power quality terms. This article clearly describes those problems generated by each storage technology foe microgrids applications. All the ideas in this review contribute significantly to the growing effort towards developing a cost-effective and efficient energy storage technology model with a long-life cycle for sustainable implementation in microgrids.",signatures:"Emmanuel Hernández Mayoral, Efraín Dueñas Reyes, Reynaldo Iracheta Cortez, Carlos J. Martínez Hernández, Carlos D. 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Barreto Muñoz"},{id:"420475",title:"Dr.",name:"Carlos J.",surname:"Martínez Hernández",slug:"carlos-j.-martinez-hernandez",fullName:"Carlos J. Martínez Hernández"},{id:"422336",title:"Dr.",name:"Juan D.",surname:"Rodriguez Romero",slug:"juan-d.-rodriguez-romero",fullName:"Juan D. Rodriguez Romero"}],corrections:null},{id:"79375",title:"An Overview Study of Micro-Grids for Self-Production in Renewable Energies",doi:"10.5772/intechopen.98829",slug:"an-overview-study-of-micro-grids-for-self-production-in-renewable-energies",totalDownloads:70,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Micro-grids (μ-grids) are small-scale power grids, specially designed to provide low voltage (LV) power supply to a small number of consumers. These networks include: different production units (energy resources), storage devices and local controllable loads, which have the possibility of being controlled. In this chapter, we will study in detail the constitution of an electrical micro-grid, their two operating modes (connected mode and islanded mode), and their controls. On the other hand, we will also discuss on hybrid micro-grids and their advantages. We will also discuss for the monitoring and data logging products used in micro-grids and hybrid micro-grids. Finally, at the end of this chapter we will ended with the importance of micro-grids systems.",signatures:"Hocine Sekhane",downloadPdfUrl:"/chapter/pdf-download/79375",previewPdfUrl:"/chapter/pdf-preview/79375",authors:[{id:"345906",title:"Dr.",name:"Sekhane",surname:"Hocine",slug:"sekhane-hocine",fullName:"Sekhane Hocine"}],corrections:null},{id:"76141",title:"Salp Swarm Optimization with Self-Adaptive Mechanism for Optimal Droop Control Design",doi:"10.5772/intechopen.97229",slug:"salp-swarm-optimization-with-self-adaptive-mechanism-for-optimal-droop-control-design",totalDownloads:63,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The collaboration of the various distributed generation (DG) units is required to meet the increasing electricity demand. To run parallel-connected inverters for microgrid load sharing, several control strategies have been developed. Among these methods, the droop control method was widely accepted in the research community due to the lack of important communication links between parallel-connected inverters to control the DG units within a microgrid. To help to solve the power-sharing process, keep to frequency and voltage constrained limits in islanded mode microgrid system. The parameter values must therefore be chosen accurately by using the optimization technique. Optimization techniques are a hot topic of researchers; hence This paper discusses the microgrid droop controller during islanding using the salp swarm inspired algorithm (SSIA). To obtain a better fine microgrid output reaction during islanding, SSIA-based droop control is used to optimally determine the PI gain and the coefficients of the prolapse control. The results of the simulation show that the SSIA-based droop control can control the power quality of the microgrid by ensuring that the keep to frequency and voltage constrained limits and deviation and proper power-sharing occurs during the microgrid island mode during a load change.",signatures:"Mohamed A. Ebrahim, Reham M. Abdel Fattah, Ebtisam M. Saied, Samir M. Abdel Maksoud and Hisham El Khashab",downloadPdfUrl:"/chapter/pdf-download/76141",previewPdfUrl:"/chapter/pdf-preview/76141",authors:[{id:"344676",title:"Dr.",name:"Mohamed A.",surname:"Ebrahim",slug:"mohamed-a.-ebrahim",fullName:"Mohamed A. Ebrahim"},{id:"344677",title:"Prof.",name:"Ebtisam M.",surname:"Saied",slug:"ebtisam-m.-saied",fullName:"Ebtisam M. Saied"},{id:"344678",title:"Dr.",name:"Samir M.",surname:"Abdel Maksoud",slug:"samir-m.-abdel-maksoud",fullName:"Samir M. Abdel Maksoud"},{id:"344679",title:"Dr.",name:"Reham M.",surname:"Abdel Fattah",slug:"reham-m.-abdel-fattah",fullName:"Reham M. 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Hidden losses in the technological system occur accidentally due to the appearance of defects in the equipment, erroneous actions of personnel, changes in uncontrolled external conditions. The paper considers a method of detecting and estimating hidden energy losses, based on the analysis of energy consumption precedents and building a decision support system aimed at eliminating such energy losses. Models of energy consumption precedents are formed on the basis of controlled technological parameters and their statistical estimates. In the future, local standards of efficient energy consumption are formed from individual precedents. The advantage of this method of estimating latent energy losses is the adaptation of standards of efficient energy consumption to the conditions of the consumer.",signatures:"Borys Pleskach",downloadPdfUrl:"/chapter/pdf-download/76470",previewPdfUrl:"/chapter/pdf-preview/76470",authors:[{id:"345292",title:"Ph.D.",name:"Borys",surname:"Pleskach",slug:"borys-pleskach",fullName:"Borys Pleskach"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"2023",title:"Sustainable Growth and Applications in Renewable Energy Sources",subtitle:null,isOpenForSubmission:!1,hash:"a32b4ca624cca7957ede00fcc24b834a",slug:"sustainable-growth-and-applications-in-renewable-energy-sources",bookSignature:"Majid Nayeripour and Mostafa Kheshti",coverURL:"https://cdn.intechopen.com/books/images_new/2023.jpg",editedByType:"Edited 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Such operation is straightforward when the phase modulation is a linear function of time. In this case, a standard Lock-in Amplifier (LIA) gives the required information with an optimal signal to noise ratio (SNR). Unfortunately, a number of phase modulators interesting in term of cost, achromaticity or integration offers non-linear responses, that are even sometimes coupled with unwanted amplitude modulation. A critical question that arises is “How can we extract phase and amplitude information in an optimal way when non-linear phase modulation is used?”
To solve this issue while keeping the benefits of high SNR, approaches have been proposed based on multiple lock-in detection at selected signal harmonics. These approaches were mainly employed in the case where the phase modulation is a sine function [1–6]. Such phase modulation is, for example, achieved using piezo-actuator, fiber stretchers, and other phase modulators where a sine excitation typically offers the best response. The multiple lock-in approach works fine but it is less direct and does not necessarily provide an optimal SNR or a straightforward implementation. Especially, if an amplitude modulation is present at the same frequency as that of the phase modulation. Alternately, the Generalized Lock-in Amplifier (G-LIA) technique was recently introduced [7] to solve this issue with a procedure similar to a single LIA operation. In this chapter, we first detail the principle of this method when operated in the simplest case where no amplitude modulation is present. Application is provided notably in the context of digital holography. Then we consider the case where there is an additional amplitude modulation in the signal field. The first case which is discussed is related to unbalanced interferometry where the phase modulation is achieved via a power modulation of the laser source. Finally, we also discuss the case of phase-sensitive near-field imaging.
In order to introduce the G-LIA technique, we need to provide an expression for the detected signal. We consider the simplest configuration of a 2-arm interferometer comprising a reference arm and a signal arm (cf. Figure 1). The system is illuminated by a monochromatic radiation. The detected signal intensity
Pseudo-heterodyne approach. A quasi-linear phase modulation is achieved by a sawtooth modulation of the optical path using a piezo-actuated optical mirror in the reference arm. The detected intensity exhibits a sine modulation except during the flyback time of the mirror. Any phase change in the reference arm will produce a detectable phase shift of the observed quasi-sinusoidal pattern.
where
where
From the expression of
Considering the general Eq. (2), the use of LIA is direct when Δφ(t) is linearly modulated by In this case ΔF is function of the unbalance, that is, the optical path difference.
The two unknowns (
From these two outputs, the quantities
Achieving
As can be seen, the detected intensity mimics the sinusoidal beating observed in heterodyne setups. Such approach is not widely used since errors are induced during the flyback time on the sawtooth edges, especially if the modulation is fast.
As mentioned, the use of sine modulation
Signals in the case of a sinusoidal phase modulation. (a) Top: example of detected intensity for different signal phases. Bottom: corresponding reference functions. (b) Schematic example of Fourier transform of and associated references and in the case of an arbitrary sine phase modulation and
The amplitudes of these frequency components are obtained by developing the term in
where
When only two harmonics
The main benefit of the G-LIA method is that all the weighted harmonics are used to retrieve phase and amplitude with an operation similar to that of a LIA. To introduce this method, we also remark that the interferometric term
These references contain the same frequency components than the interferometric term since
We note that in the particular case where
where
The G-LIA outputs are then similar to that of the LIA in the linear case (cf. Eqs. (4)–(5)). The difference is the presence of the additional proportionality constants
where Amplitude and phase are then determined using:
Alternately, a satisfactory solution is to filter the detected intensity to remove all DC component from the signal. In fact, such operation is easy to do and is often highly desirable to directly remove the ambient light contribution in normal conditions [12]. In this case where the signal is filtered, the G-LIA operation is:
where the An analog filter can be used. Alternately, it is possible to filter the DC component of the reference functions C(t) and S(t) only, or to filter both I and the references, with the same result. The operations A comment should also be made regarding the references C(t) and S(t). Building these references require the knowledge of
In the useful case of a sine modulation of the form
where the negative extra term in
Proportionality factors and used in a G-LIA working with a sine phase modulation as a function of the phase modulation depth. The analytical evaluations are plotted in solid lines; the markers correspond to the numerically calculated values.
In this section we review and present several results of interferometric measurements performed with the G-LIA approach described in the previous section. Results include measurement with a point detector reported elsewhere and interferometric measurement with 2D detector in the framework of holographic measurement.
Figure 4 shows measurement results adapted from the Ref. [7], where the G-LIA can be used with or without filtering to monitor an arbitrary displacement (here a triangle-shaped displacement).
Interferometric measurement with a single detector. (a) Setup for displacement measurement including capacitive sensors for comparison. (b) Displacement measurement obtained with G-LIA and the capacitive sensor.
The setup is shown on Figure 4(a). In this example, the phase modulation is a sine function
Determining the phase rather than the amplitude is known to offer potential advantage in term of sensitivity in optical sensing systems [13]. More precisely, the phase detection coupled with surface plasmon resonance (SPR) is known to improve the measurement sensitive by one to several order of magnitude depending on the exact system geometry. Many different designs on combining interferometry or heterodyne detection on Kretschmann configuration-based SPR sensor have been done [14, 15].
Figure 5 shows the demonstration setup used in [7] to demonstrate the applicability of the G-LIA for phase sensitive sensing application. The setup is similar to that of Figure 4(a), except that an
(a) Interferometric measurement with a single detector, applied to gas sensing. (b) Phase-sensitive detection of an absorption line. The obtained spectrum is adapted from Ref [
As can be seen, the phase varies more abruptly at the absorption peak center. However, the benefit of measuring the phase for monitoring a gas concentration is not clear since the amplitude has similar variation on the two sides of the absorption peak which indicates a similar sensitivity than the phase if the detection is made where the slope is maximum on the amplitude.
The interest of phase sensitive detection in SPR-based measurement is more obvious. In fact, strong plasmonic resonances can be reached by carefully adjusting the opto-geometrical parameters of the plasmonic layer in order to obtain very sharp phase variation across a resonance. One possible combination of phase sensitivity SPR bio-sensor using G-LIA for phase extraction is proposed in Figure 6, where a cuvette is put on a plasmonic chip to convey a fluid on the surface of a plasmonic chip. A coupling prism makes it possible to satisfy the Kretschmann condition for which the reflectivity of a p-polarized incident beam reaches a minimum corresponding the excitation of the plasmon-polariton surface mode. In order to have a stable phase, immune to wavelength fluctuations, the length of the two arms are made equal. Figure 6(b) presents the numerically calculated complex reflectivity as a function of the incident beam angle in the case of a glass coupling prism coated by a gold layer of thickness
Example of possible experimental setup for phase sensing based on an SPR chip. (b) Simulation of the complex reflectivity (magnitude and phase) for a light beam impinging a gold layer with a thickness
As can be seen, the phase variation across the resonance can be made very sharp by adjusting the metal thickness
If we consider a reasonable phase resolution of 10−3 rad, simple calculation show that the case
In digital holography, the holograms of a sample object are recorded on a 2D detector such as a Charge-coupled Device (CCD) or a Complementary Metal-Oxide-Semiconductor (CMOS) camera. Such system can notably be used as an optical profilometer, or for sensing applications [1, 6, 16]. Figure 7(a) presents the experimental setup of a lensless, compact, digital microscope working with the G-LIA extraction method.
(a) Lensless digital holography setup. A diaphgram may be to select the central zone of interest in the sample. (b) Amplitude and phase of a grating of straight and tilted slits made in a steel surface.
In the provided example, a metallic grid of slit is imaged in amplitude and phase. The Lead Zirconate Titanate (PZT) oscillates in the reference arm at 10 Hz to generate the phase modulation function
In this example, the raw signal
Effect of slight rotation on the holographic images. By subtracting the complex field after rotation
In some important cases, the signal field is modulated both in phase and amplitude. The modulated term
where
In interferometers having a path unbalance, a phase modulation can be efficiently induced by a wavelength modulation of the emission wavelength. For this purpose a spectrally single-mode laser diode working at a central wavelength
For modulation frequency below the MHz range, the change in wavelength is considered to be primarily due to a change of temperature that increases with the current. Therefore, using a sawtooth function to create a quasi-linear phase change is usually not an excellent choice, as the thermal inertia of the system prevents the wavelength to precisely follow the driving excitation. On the other hand, a sine power modulation will typically induce the desired sine wavelength and phase modulation. In this case, the detected intensity within an unbalanced interferometer is:
with
It is clear that in the case where the amplitude modulation is small (
where we have normalized the detected intensity by the constant laser power factor. The brackets indicate the quantity is filtered from its DC component. We see that the main issue comes from the modulated term outside the bracket which is independent from the signal We note that the cases where µ is too large to be neglected can be handled exactly without approximation but it requires to know µ in order to determine analytically or numerically all the coefficients of the G-LIA outputs (4 in this case). In general, the percentage of power modulation µ can be measured without difficulty. The condition J1(a) = 0 is still required.
Despite its advantages in term of cost, unbalanced interferometry is not currently widely used. The main reason is also related to the extreme sensitivity of the system to minute wavelengths changes. Figure 9(a) represents a compensation scheme to solve this issue. The idea is to illuminate the interferometer with a linear polarization at 45° with respect to the horizontal and vertical axis and to discriminate the two s and p polarization using polarization beam splitters. An additional signal arm is equipped with a fixed mirror in order to measure the phase fluctuation induced by any wavelength drifts in time. The light impinging on this mirror is s-polarized and is selectively detected by the photodiode PD1, using a polarization beam splitter in reflection. On the other hand, the p-polarized light impinging on the piezo-actuated mirror is reflected back onto the second photodiode (PD2). Both amplitude and phases are recorded with the above described G-LIA operation.
(a) Unbalanced interferometer with an extra arm for wavelength drifts compensation. The sine phase modulation is induced by a power modulation of the VCSEL laser source. BS: Beam splitter. (b) Actual displacement of the piezo actuated mirror (red); measured displacement without drift compensation (dotted blue); phase fluctuation induced by the intentional wavelength fluctuation (black line), and final measurement (dashed black line) obtained by subtracting the black line to the blue dotted line.
Figure 9(b) shows a controlled triangular displacement which is correctly determined despite the presence of intentional wavelength drifts. In this experiment, the wavelength of the VCSEL is driven sinusoidally at about 10 kHz to create the phase modulation. The important wavelength drifts are artificially created by adding a low frequency sine to this excitation signal. The compensation is obtained by plotting the phase of the p-polarized light minus the phase of the s-polarized light which is coming from the fixed mirror. Both signal phases are obtained by the G-LIA method with
Such system is really interesting in term of performance since VCSELs are very affordable laser sources that can be driven at very sinusoidally at very high speed. In the described experiment the phase modulation frequency was only limited by the acquisition card used to perform the G-LIA measurement.
A modulation of the amplitude at an angular frequency Ω
Phase-sensitive nanoscopy experiment based on G-LIA, where the phase modulation is
In Figure 10, the near-field head is included in the signal arm of a Michelson interferometer. Alternately the near-field microscope can be used in the signal arm of a Mach-Zhender which is well adapted to the characterization of waveguiding photonic devices as in [18–20]. Here, the sample is scanned under a nano-tip which is precisely positioned in the focus spot of an objective lens. The light backscattered by the oscillating probe operating in tapping mode contains information on the local optical properties of the sample. This backscattered light can have a rich harmonic content due to its near-field interaction with a sample. The amplitude modulation function appearing in
We note that Such case occurs when using elongated probes like tungsten probes, mounted on tuning fork working in tapping mode. The elongated shape minimizes the possible modulation of the background light, while an oscillation amplitude of few nanometers can also prevent a detectable modulation of the background light. In some other case where a Mach-Zehnder interferometer is used, only the apex of the probe can be illuminated (e.g.when imaging waveguiding structures). In general, reducing the amplitude of modulation of the probe reduces the background contributions more efficiently than the near-field contribution.
As shown in Figure 10(b), because of the interference between the probe signal and the reference field, the signal is split into sidebands at
where
First examples of phase-sensitive near-field imaging based on G-LIA can be found in Ref. [7]. In Figure 11, a simple demonstration experiment is made by using a bare tuning oscillating fork to modulate part of the signal at an angular frequency Ω
(a) Demonstration setup with
where
Figure 11(b) shows the phase determined with this method when a triangular phase modulation having a peak to peak phase modulation depth of about 2.0 rad is induced by the signal mirror. The signal phase is precisely retrieved.
The value of ψ includes the mechanical phase shift existing between the driving signal and the actual motion of the fork. In fact, in a near-field experiment, this shift can vary from one position to another on the sample depending on the material in interaction with the probe. Depending on the system, the value of ψ in
If ψ is unknown, the G-LIA can be applied twice to solve this issue with two quadrature amplitude modulation functions. In other word, we can calculate for outputs signals
The four outputs (
We have detailed the principle of the G-LIA method, first in the case of pure phase modulations then in the case where the amplitude of the signal is also modulated. For pure phase modulations, the interest of the approach was illustrated in different contexts: position monitoring, sensing, and digital holography. In these experiments, the non-linear phase modulation was achieved by mirrors mounted on sinusoidally driven piezo-actuators. In this case, the main advantage of the G-LIA is to extract amplitude and phase information directly from all the harmonic contents created by the phase modulation function. While the examples only considered sine phase modulation functions which is often the most desirable one, the G-LIA also provides a unified treatment to handle arbitrary phase modulation function.
We have also detailed the case where an amplitude modulation can be present. This is notably the case in unbalanced interferometry where a non-negligible amplitude modulation can be perceived at the same frequency than the phase modulation. Experimentally, we considered the case of unbalanced interferometers where a fast sine phase modulation is provided by a current-driven single mode laser diode. A simple yet efficient setup was described to neutralize the impact of wavelength fluctuation on the system. Such approach offers the opportunity to develop simple and cost-efficient system without sacrificing precision. Finally, we discussed the case where the signal of interest is modulated in amplitude at a frequency different from that of the phase modulation. This case was detailed in the context of phase sensitive SNOM, where the low available signal requires to exploit all the available sidebands induced by the phase modulation. Notably, the condition to cancel the effect of the unmodulated background light was presented and attention was paid to the impact of the mechanical phase of the oscillating probe.
The table (Figure 12) provides a summary of case handled by the G-LIA method.
Summary table.
At present, botulinum toxin type A is becoming the treatment of choice for a multitude of pathologies related to alterations in the biochemistry of acetylcholine [1, 2].
Since the middle of the twentieth century, many clinical trials of this type have been carried out. Botulinum toxin A is the most widely used in human therapeutic trials; some of these studies are:
Therapeutic trials were conducted by A. Scott [3]. In 1973, this author began to use botulinum toxin type A in the treatment of strabismus, initially in non-human primates and since 1980 in humans. He also described its use in endocrine orbital myopathy and lateral rectus palsy.
Therapeutic trials were conducted by Frueh et al. [4]. They described the use of toxin A in blepharospasm in 1984. In subsequent years toxin injections became the first-line treatment for blepharospasm with very good results (significant improvement in more than 80% of injected patients).
Therapeutic trials were performed by Tsui et al. [5] and Brin et al. [6]. These investigators reported results of therapeutic trials with toxin A injections for torticollis in patients who had not responded to other treatments and were severely affected.
Therapeutic trials conducted by Jankovic [7], Gelb [8], and Greene [9] between 1986 and 1991 have conducted at least five blind, placebo-controlled studies focused on toxin A for cervical dystonia. Afterward, they studied it uses in oro-mandibular, laryngeal, and limb dystonia, confirming its usefulness, particularly in the treatment of closing mandibular dystonia and laryngeal dystonia in adduction.
Botulinum toxin represents the most powerful biological toxin known at present.
This toxin is produced by an anaerobic and Gram-positive bacterium,
Various types of
These are among the most potent that exist.
One microgram contains 200,000 times the minimum lethal dose for the mice and is approximately the dose lethal for humans.
Types A, B, E, and F are the most common causing human botulism while types C and D cause botulism in poultry and cattle.
Type A is relevant to human pharmacology. It forms a complex with hemagglutinin which can be crystallized.
This is a protein with a molecular weight of 900,000 Daltons. The separation of the hemagglutinin can be carried out without the toxin losing its effectiveness.
It has a neurotoxic fraction made up of protein with a molecular weight of approximately 150,000 Daltons. It is suspected that it is made up of smaller toxic subunits [10].
Botulinum toxin interferes with the conduction of the nerve impulse, once the axonal propagation of the nerve impulse has begun.
The toxin blocks the release of acetylcholine. Therefore, botulinum toxin is an anticholinergic substance which acts as a muscle relaxant and a specific inhibitor of the release of acetylcholine, acting on the presynaptic nerve ending, preventing the action of calcium ions in the exocytosis process necessary for the release of acetylcholine, thus decreasing the plaque potential and causing muscle paralysis [1, 11].
The toxin has two subunits, one of which binds to the membrane receptor responsible for specificity, allowing the entry of the other subunit the one that blocks calcium ions.
In its therapeutic application, due to its form of administration, only neuromuscular transmission interferes at the site of application and the recovery of the nerve impulse takes place gradually as the nerve endings regenerate (Figure 1) [10].
Principal applications of botulinum toxin in recent decades.
Botox | Dysport | |
---|---|---|
Dose IU/kg/muscle | 1–6 IU/kg/muscle | 3–12 IU/kg/muscle |
Total dose | 12–14 IU/kg | 20–30 IU/kg |
Maximum dose | 300–400 IU | 750–1000 IU |
Botulinum toxin dose in spasticity [27].
When botulinum toxin is injected into the target tissue, the neurotoxin heavy chain binds to glycoproteins that are specifically found on presynaptic cholinergic nerve receptors. It penetrates the nerve ending of the motor endplate (alpha motor neuron) by endocytosis.
After its internalization, the neurotoxin light chain fragments the SNAP-25 protein, preventing the formation of the SNARE complex (NSF-anchorage protein receptors), which intervenes in the release of acetylcholine by exocytosis.
The blockage of exocytosis becomes definitive on the third day of infiltration and will last until the third month. From the 28th the neuron reacts to the blockage by creating new synaptic buttons (sprouting), restoring the original function. That is, the chemical blockage is irreversible, but the clinical effect is reversible due to the creation of new synaptic buttons [12, 13, 14, 15, 16].
Botulinum toxin diffuses locally through the muscle, preferably longitudinally. This local diffusion is dependent on the dose and the precision of the infiltration.
Hence, it is used in pathologies such as:
Dystonia: Reduced functioning of the neurotransmitter acetylcholine can reduce the excessive functioning of the muscles in different dystonia [17, 18]
Cervical dystonia (torticollis)
Blepharospasm
Apraxia of the eyelid
Oromandibular-facial lingual dystonia
Laryngeal dystonia (spasmodic dysphonia)
Dystonia of the feet, hands
Occupational cramp
Facial dystonia
Meige syndrome
Tics and stuttering
Musician dystonia
Abnormal movements: Botulinum toxin is used to control hyper functional muscular disorders such as [19, 20]
Hemifacial spasm
Tremor (head, voice, limbs)
Myoclonus (palate, spinal)
Dystonic motor tics
Myoclonus
Ophthalmological indications: Very good results have been seen when applying botulinum toxin [10]
Strabismus (esotropia/exotropia): When the botulinum toxin is injected, a transient paralysis occurs, so that when the extraocular muscle is paralyzed, it relaxes and the antagonist contracts, producing a transient overcorrection of the deviation. This causes an imbalance of forces between antagonists
Nystagmus with oscillopsia
Ptosis
Laryngeal disorders [10]
Puberphony
Granulomas of the vocal processes of the arytenoid cartilage.
Glandular and secretory cell modulation
Growth hormone (acromegaly)
Inappropriate contractions [18, 20, 21]
Spasticity (from stroke or cerebral palsy)
Radiculopathy
Muscle spasm
Stuttering
Bruxism
Smooth muscles [10]
Sphincter of oddi dysfunction
Chronic spastic bladder
Rectosphincteric dyssynergia
In disorders of the autonomic nervous system, the reduction of the neurotransmitter acetylcholine reduces the functioning of the autonomic nervous system [10, 12, 14] so that the inhibition of acetylcholine release on the postganglionic endings of the sympathetic and parasympathetic systems justifies its clinical use in these pathologies.
Hyperhidrosis: axillary, palmar, plantar and facial
Benign prostatic hiperplasia
Sialorrhea, drooling
Rhinitis
Upper esophageal sphincter achalasia/lower esophageal sphincter
Neurogenic overactive bladder
Frey’s syndrome
Anal fissures
Vaginismus/anismus
The reduction of inflammatory mediators can influence pain syndromes [12, 22, 23, 24], due to possible inhibition of the non-selective peripheral release of pain-mediating neurotransmitters (substance P). This justifies its clinical use in these pathologies
Craniofacial pain
Bruxism
Temporomandibular pain
Trigeminal neuralgia
Tension headache and chronic migraine
Myofascial pain: controversial results
Painful phantom limb syndrome
Peripheral ischemia
Postherpetic neuralgia
Joint pain: An improvement in these pathologies has been observed when treated with intra-articular injections of botulinum toxin
Osteoarthritis
Rheumatoid arthritis
Lumbar pain
Spasticity consists of “a motor disorder characterized by a speed-dependent increase in the muscle stretch reflex, also called myotatic, with exaggerated pulling on the tendons which is accompanied by hyperreflexia and hypertonia, due to neuronal hyperexcitability being one of the signs of upper motor neuron syndrome, which can be summarized as the abnormal effect of both “tonic and phasic stretch reflexes” [25] (J. Lance, Australian neurologist 1980), which results in an increase in speed-dependent tonic reflexes together with an exaggerated response of tendon (phasic) reflexes in Ref. [25].
This reflex stretching activity can be triggered during voluntary movement when a contraction with shortening of the agonist musculature occurs and is accompanied by a stretching of the antagonist musculature.
Spasticity presents in characteristic clinical patterns for different neurological etiologies. It should be noted that although the clinical patterns are similar, the response to treatment may vary depending on the etiology.
The most common forms of spasticity are:
Equine foot, equinovarus
Digital claw, hyperextension of the first toe
Thigh adduction
Hip adducts
Knee flexion/knee extension
Shoulder adduction and internal rotation
Elbow flex
Wrist flex
Claw fingers
Thumb included in the palm
The findings on the examination of spasticity:
Razor resistance (spring)
Spasticity is directly proportional to stretching speed
Hyperreflexia with polykinetic response and clonus
Presence of pyramidal release reflexes and/or spinal automatism in antigravity muscles
If we take into account the age of the patient, we can divide spasticity into two large groups:
Infantile spasticity
In childhood, the most common cause of spasticity is infantile cerebral palsy (ICP). An important difference to adult spasticity is that clinical expressiveness in children evolves with growth and causes osteoarticular deformities that interfere with normal development [25].
ICP is classically defined as a persistent movement and posture disorder caused by a non-progressive lesion or defect of the immature brain, before the age of 3–4 years. It has an incidence of 1.5–2.5 per 1000 live births.
However, the current trend is to define ICP by expressing the broad spectrum of its characteristics: ICP is a group of movement and posture disorders that cause activity limitation and is attributed to a non-progressive disorder in fetal development or infant who is frequently accompanied by sensitive, cognition, perception, communication, behavior and/or epilepsy defects.
According to this definition, the classification considers not only the topographic aspect, but also gives special meaning to the severity of the motor impairment, since the functional prognosis will depend not so much on the type of ICP but on the severity.
Motor disorders:
Nature and type (spastic, dyskinetic, ataxic, or mixed)
Motor and its severity according to GMFCS (GROSS MOTOR FUNCTION CLASSIFICATION SYSTEM). Gross motor function is a classification system levels for children with cerebral palsy between the ages of 6 and 12 years. It has five levels [26]:
Level I: Walks without restrictions; limitations in more advanced gross motor skills.
Level II: Walks without assistive devices; limitations in walking outdoors and in the community.
Level III: Walks with assistive mobility devices; limitations in walking outdoors and in the community.
Level IV: Self-mobility with limitations; children are transported or use power mobility outdoors and, in the community,
Level V: Self-mobility is severely limited even with the use of assistive technology [26]
Cause and moment of the disorder.
Location (hemiplegic, diplegic, or tetraplegic). For the diagnosis of ICP, it is essential to ensure that the causing brain alteration is not progressive.
That is, to rule out the other degenerative causes of movement disorders. It is recommended to use the guidelines and diagnostic algorithm of the AAN (American Academy of Neurology).
Spasticity in adults:
The most common causes of spasticity in adults are [25].
Acquired brain damage (ABD) caused by head trauma or cerebrovascular accident (CVA)
Spinal cord injury
The clinical characteristics of spasticity in ABD are:
Gradual development at 6–8 weeks after stroke and 2–8 weeks after head trauma
A dysregulation of motor control appears contraction, relaxation
Pain
Contraction movements
In addition to the muscle tone disorder, different patterns can be presented:
Decortication Pattern: The patient will present shoulder adduction and triple flexion of the upper extremities (elbow, wrist, fingers) and extension of the lower extremities accompanied by equinus.
Decerebration Pattern: There is a pattern in the extension of the four extremities with internal rotation of the upper extremities.
Mixed Pattern: This is a combination of the two previous patterns.
The appearance of these clinical manifestations has a global impact on the patient with ABD, who will present a decrease or loss of balance and gait, a decrease in manual ability, interference in personal hygiene and activities of daily life (ADL), as well as difficulty in communication and swallowing.
When faced with a patient with ABD, we must consider that, as well as having neuromotor deficits, the patient may also have a set of neuropsychological deficits (cognitive and sensory) therefore, the treatment must be considered in a comprehensive way.
The causes are multiple: trauma, multiple sclerosis, spinal tumors, infections of vascular origin, familial spastic paraparesis, transverse myelitis, amyotrophic lateral sclerosis and neurofibromatosis.
The incidence of spasticity in spinal cord injuries varies from 65–78% per year of evolution, decreasing to 40%.
Spasticity patterns in spinal cord injury are dependent on the level and degree of injury “classification of the American Spinal Injury Association (ASIA)”.
Spasticity in the spinal cord injury is more problematic in incomplete injuries at the cervical level (ASIA grade BCD) and is usually extension spasticity.
Spasticity is not a static phenomenon, it is long-lasting, dynamic, and changing, and there are many factors that influence it, and we must consider it when seeking treatment [27].
Spasticity evolves towards chronicity and is accompanied by static phenomena and alterations in the properties of soft tissues (elasticity, viscosity, plasticity). The alteration of these three properties leads to the establishment of fibrosis of the muscle and of the adjacent structures so that the contracture becomes fixed and retractions and osteoarticular deformities occur, which makes it important to treat as quickly as possible [25, 27].
In the evolution of spasticity, four phases appear, this will determine the treatment.
SPASTICITY PHASE: In this phase, there is an increase in muscle tone which causes it to be defined as the state of increased tension in a muscle when it is passively lengthened by exaggeration of the muscle stretch reflex.
VICIOUS ATTITUDE PHASE: This includes muscle imbalance due to the predominance of spasticity in some muscle groups, the most frequent being the plantar and varicose flexors of the foot, the adductors and hip flexors and the elbow, wrist, and finger flexors in the upper limb.
MUSCLE WITHDRAWAL PHASE: The persistence of these vicious attitudes causes uneven growth between agonist and antagonist muscle groups. This leads to the structuring of this attitude due to the lack of accommodation of the sarcomere, which is unable to achieve normal muscle growth. Understanding by muscle retraction the resistance opposed by the muscle to mobilization when it is not in contraction.
OSTEOARTICULAR DEFORMATION PHASE: When we are dealing with children in the growth phase, all the pressures and traction stimuli of the growth cartilage will be modified consecutively to the previous phases which, according to Delpech’s law, gives rise to osteoarticular deformities (Figure 2).
Delpech law.
It is important to consider that when spasticity occurs in children, it negatively influences their musculoskeletal development, which usually leads to structured deformities, problems in postural control, and limitations to spontaneous mobility [27].
A well-coordinated, multidisciplinary team will oversee guiding the spasticity treatment, seeking realistic goals that are agreed upon by the patient and the caregiver.
The objectives should be aimed at improving function, reducing pain, preventing complications, and improving hygiene, that is, improving quality of life. In the child, this allows and favors the longitudinal growth of the muscle, avoiding fixed contractures [25, 26, 27, 28].
The objectives pursued when applying the toxin on the muscle are:
Gradually decrease the potential of the drive plate.
Decrease the state of hyper contraction.
Muscle relaxation.
Facilitate extensibility.
In the case of children, facilitate the longitudinal growth of the muscle.
An improvement in function, after application in the lower limbs there will be an improvement in gait, greater comfort, balance, and a decrease in falls.
If the application is in the upper limbs there will be greater ease to find it to carry out activities of daily life such as hygiene and food preparation.
Prevent long-term complications: dislocations, osteoarticular deformities, mainly of the hip, foot, and wrist.
Improve blood circulation.
Favors the placement of orthoses and footwear.
Reduces pain associated with maintained posture.
An esthetic improvement.
Facilitate rehabilitation (Figure 3).
Objectives in the treatment with botulinum toxin.
There are different degrees of recommendation for therapeutic strategies for the treatment of spasticity, but we are going to focus on treatment with botulinum toxin.
Botulinum toxin is the treatment of choice for focal spasticity and as a complement in generalized spasticity because it can be administered in the most affected muscles, regardless of its etiology, and is part of the overall treatment.
In the case of generalized spasticity, it should be associated with treatment with intrathecal baclofen or surgery.
As we already know, botulinum toxin acts by blocking the release of acetylcholine at the neuromuscular junction which produces transient chemical denervation, as well as the inhibition of nociceptive neurotransmitters, therefore, playing an analgesic role. The result is transient functional denervation that causes paralysis, muscle atrophy, and electromyographic abnormalities. As already advised, the toxin has two subunits, in such a way that one of them binds to the membrane receptor allowing the second subunit to enter the cell where it will exert a toxic effect by inactivating specific enzymes.
This involves an ADP-riboxylation. The reaction of the toxin is believed to inactivate actin in this way.
It is recognized that only a few molecules are needed to inhibit the release of acetylcholine. The muscle weakness caused by this toxin remains restricted to the injected area, there is histological evidence that toxicity is restricted to the extrafusal muscle fibers, while the intrafusal fibers are relatively free of this affectation.
This causes an alteration in the relationship of the alpha and gamma motor neurons and consequently, there is not only a local paralysis but also an effect on the central motor control mechanisms.
Its effect is progressive, starting in 2 or 3 days, until reaching its maximum per month, maintaining its effect for 3–4 months with a variation interval of 2–6 months.
Regarding its form of presentation, the only type of botulinum toxin commercially available is type A. In the United States, it is marketed by the Californian laboratory Allergan Pharmaceuticals under the trade name “Botox”. It comes in freeze-dried and cold-dried preparations. These are ampoules that must be stored frozen at −5° C so that the toxin is reconstituted at the time of injection with sterile physiological saline (without a preservative). Its potency is expressed in units, in such a way that one unit is equivalent to the amount of toxin capable of killing 50% of a group of female Swiss-Webster mice weighing between 18 and 20 grams (LD50) [21, 26, 27, 28, 29, 30, 31, 32].
In the United States, approximately 0.4 nanograms of protein toxin equal 1 unit (or otherwise expressed 2.5 units are equivalent to 1 nanogram). In the case of European botulinum toxin type A, commercially known as “Dysport”, the potency of the preparation is different since 1 nanogram is equivalent to 40 units. Due to this divergence in potency in commercial botulinum toxin preparations, the use of doses greater than 500 units per session with the European preparation is not uncommon. The lethal dose of American botulinum toxin type A (Botox) injected into young monkeys is approximately 40 units per kilogram of weight, which, when extrapolated, represents about 50 times the average dose injected for the treatment of focal dystonia. The estimated LD50 in humans is 2500–5000 units according to some authors and closer to 5000 according to others. The diluted solution is collected in a tuberculin syringe and the toxin is injected with a 26–30 gauge needle 0.5 inches long in the superficial muscles and a 22 gauge 1.5 inches long in the muscles. Different dilutions can be prepared depending on the site to be injected, such as 2.5–5 units per 0.1 cc for cervical muscles and 1.25–2.5 units per 0.1 cc for blepharospasm or for a hemifacial spasm. The precise time for its action to appear varies between two and 3 days, reaching its maximum effect 5 or 6 days after the injection, its effect lasting a variable period that extends from 2 weeks to 8 months. (Although we have found some studies that indicate that this duration can be extended to 11 months), this is the time necessary for the toxin binding process, integration of the same, and regeneration of the neuromuscular junction. As already advised, the toxin has two subunits, in such a way that one binds to the membrane receptor allowing the entry of the second subunit into the cell where it will exert a toxic effect by inactivating specific enzymes, for which it involves an ADP reaction—riboxylation.
The toxin is believed to inactivate actin in this way. It is thought that only a few molecules are needed to inhibit the release of acetylcholine.
It is injected into large and superficial muscles, infiltrates the muscle belly by means of anatomical landmarks and palpation. Sometimes it is useful to be guided by electromyography, electrostimulation, or ultrasound. It is important to avoid venous spread.
Two toxins type A (Botox and Dysport) are marketed in Spain. Their doses are not interchangeable.
In children, the dose is calculated in international units per muscle and kilogram of weight. It is also a function of the size of the muscle and the degree of spasticity.
It is diluted in sterile 0.9% physiological saline in 1–2 ml.
The lowest effective dose should be used so that:
For Botoxr the dose is 1–6 IU/kg/muscle, with a total dose of up to 12–14 IU/kg, not being able to exceed 300–400 IU.
For Dysportr the doses are 3–12 IU/kg/muscle, with a total dose of up to 20–30 IU/kg, not being able to exceed 750–1000 IU.
The maximum dose with Botoxr per injection site is 50 U [21, 26, 27, 28, 29, 30, 31, 32].
There are some adverse effects produced by this treatment characterized by the appearance of weakness in injected and non-injected muscles or transient bladder paresis (after treatment of hip adductor spasticity), in a few patients, a generalized syndrome with tetraparesis (botulism type), It occurs after application of botulinum toxin and disappears within a period of about 4 weeks [27].
We can also find local adverse effects, which disappear in a few days, such as:
Injection site pain
Local inflammatory reaction
Appearance of flu-like picture
Diarrhea
Urinary incontinence
Allergic reaction
Fatal systemic adverse effects rarely appear, they have been described in isolated cases and with toxin doses that far exceeded the recommended dose.
The main infiltration points in the lower limb are triceps, posterior tibial, anterior tibial, abductor of the big toe, abductors, and psoas [1, 21, 31, 32, 33].
The main application has been used especially in abductor spasticity of the legs, achieving a reduction in spasticity, pain, and improved hygiene and care of the patient. It has also been used in leg extension spasticity (spastic foot drop) by applying it to the soleus, posterior tibial, and calf muscles, observing an improvement in muscle tone, gait, and foot pain with reduction of the Achilles clonus, in hip dysplasia (caused by the psoas) and of special interest because it can become dislocating. Finally, it has also been shown to be useful in spasticity of the upper extremities [1, 21, 31, 32, 33].
It should be noted that in general, the results are better in young people, in whom the joints are more dynamic. Although the use of botulinum toxin is very effective for the correction of retractions, as is the case of the Achilles tendon, it should be taken into account before saying its application is not as effective in the upper limbs as in the lower ones, as can be seen in the graph (Figure 4).
Effectiveness of botulinum toxin in different limbs.
The most effective points are [1]:
GARCIN’S SCARVED HAND: Wrist flexion with ulnar deviation, thumb adduction, and pronation. The infiltration points are found in the biceps brachii, brachialis anterior, ulnar anterior, palmar, finger flexors (especially superficial ones).
INCLUSION OF THE THUMB: Adductor pollicis on its posterior aspect because the infiltration on its anterior aspect is very painful due to the presence of many sensory receptors.
CHANDELIER PATTERN: The points of infiltration are in the common flexor of the fingers in the pronator quadratus and round, in the posterior ulnar, long supinator (its flexor component), anterior brachialis, and biceps brachii.
TRIPLE FLEXION: Hip flexion: infiltrate the rectus anterior, sartorius, tensor fascia lata, iliac psoas, pectineum, adductors, gluteus minimus and anterior fibers of the gluteus medius. Knee flexion: hamstrings, tensor fascia lata, calves and popliteus. Plantar flexion (equine): triceps, tibialis posterior, long flexor of the fingers.
SCISSOR PATTERN: Hip adduction: pectineal, adductors, internal rectus Internal rotation: adductors.
EQUINE FOOT-VARUS: Posterior tibial, triceps, intrinsic muscles of the foot.
VALGO FOOT: Lateral peroneus brevis and lateral peroneus longus muscles.
Patients allergic to the drug.
Generalized disorders of muscle function (myasthenia gravis).
Take blood thinners.
Inflammation or infection at the injection site.
Administration of high doses of aminoglycoside antibiotics (especially in patients with renal failure).
Pregnancy.
False expectation of cure.
Uncertainty of a therapeutic follow-up.
Regarding the precautions to be taken for the use of these preparations, the following should be indicated:
Caution should be exercised with children with febrile, respiratory, or swallowing processes.
It must be taken into account that its effect is enhanced by aminoglycosides because they intervene in neuromuscular transmission [1, 21, 29].
Botulinum toxin offers the advantage that it lacks the systemic side effects of oral drugs such as excessive somnolence or generalized muscle weakness. It allows to offer a local treatment, specifically in the muscle disorder.
Botulinum toxin treatment of spasticity, especially in children, is very effective, always within a global vision. But we cannot forget that it is also a very effective treatment for focal dystonia.
In these cases, its use has been a very effective option, assuming a radical change in the prognosis and in the quality of life of the patients, its use being accepted as routine treatment.
The following table shows a summary of the percentages of efficacy, duration, and complications of the use of this toxin in the different types of focal dystonia:
Gets better | Beginning | Duration | Complications | |
---|---|---|---|---|
Laryngeal adductor | 96% | 1–2 days | 10–16 weeks | Voice dysphagia |
Blepharospasm | 90% | 1–3 days | 12–15 weeks | Ptosis |
Cervical | 70% | 3–7 days | 8–12 weeks | dysphagia |
Oromandibular | 70% | 2–7 days | 12–14 weeks | dysphagia |
Abductive laryngeal | 70% | 1–2 days | 10–16 weeks | voice dysphagia |
Hand in hand | 60–80% | 3–7 days | 12–14 weeks | hand weakness |
Nowadays it is also not only used for dystonia and spasticity but for upper obstetric brachial palsy (C5-C6), during the first months of life, where it avoids shoulder limitation, and congenital muscular torticollis (infiltrating the sternocleidomastoid and trapezius).
This toxin is used more and more to treat these pathologies improving the life quality of the patients reducing the adverse effects of alternative treatments used in the past.
IntechOpen’s Academic Editors and Authors have received funding for their work through many well-known funders, including: the European Commission, Bill and Melinda Gates Foundation, Wellcome Trust, Chinese Academy of Sciences, Natural Science Foundation of China (NSFC), CGIAR Consortium of International Agricultural Research Centers, National Institute of Health (NIH), National Science Foundation (NSF), National Aeronautics and Space Administration (NASA), National Institute of Standards and Technology (NIST), German Research Foundation (DFG), Research Councils United Kingdom (RCUK), Oswaldo Cruz Foundation, Austrian Science Fund (FWF), Foundation for Science and Technology (FCT), Australian Research Council (ARC).
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