Maximum energies of particles in the space radiation environment (Barth et al., 2002).
\r\n\tStatistical machine learning specifically poses some of the most challenging theoretical problems in modern statistics, the crucial among them being the general problem of understanding the link between inference and computation. This book intends to provide the reader with a comprehensive overview of linear method for regression, non linear method for regression, deep learning, unsupervised learning, artificial neural network, and support vector machine (SVM).
",isbn:null,printIsbn:null,pdfIsbn:null,doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"a3fb79b0a4a302d6318df11534e1ec85",bookSignature:"Dr. Andino Maseleno",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/8661.jpg",keywords:"Linear Method for Regression, Non Linear Method for Regression, Deep Learning, Unsupervised Learning, K-Means Clustering, Hierarchichal Clustering, Principal Component Analysis, Artificial Neural Network, Learning in Neural Network, Convolutional Neural Network, Support Vector Clustering, Multiclass SVM",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"July 3rd 2018",dateEndSecondStepPublish:"July 24th 2018",dateEndThirdStepPublish:"September 22nd 2018",dateEndFourthStepPublish:"December 11th 2018",dateEndFifthStepPublish:"February 9th 2019",remainingDaysToSecondStep:"3 years",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:null,coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"219663",title:"Dr.",name:"Andino",middleName:null,surname:"Maseleno",slug:"andino-maseleno",fullName:"Andino Maseleno",profilePictureURL:"https://mts.intechopen.com/storage/users/219663/images/system/219663.jpg",biography:"Dr. Andino Maseleno is a research fellow at the Institute of Informatics and Computing Energy, Universiti Tenaga Nasional, Malaysia. He was a visiting fellow in Centre for lifelong learning, Universiti Brunei Darussalam, Brunei Darussalam, in July 2016 till March 2017. He received the B.S. in Informatics Engineering from UPN 'Veteran” Yogyakarta, Indonesia in 2005, M.Eng. in Electrical Engineering from Gadjah Mada University, Indonesia in 2009, and Ph.D. in Computer Science from Universiti Brunei Darussalam, Brunei Darussalam in 2015.",institutionString:"Universiti Tenaga Nasional",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"1",institution:null}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"606",title:"Machine Learning and Data Mining",slug:"numerical-analysis-and-scientific-computing-machine-learning-and-data-mining"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"177731",firstName:"Dajana",lastName:"Pemac",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/177731/images/4726_n.jpg",email:"dajana@intechopen.com",biography:"As a Commissioning Editor at IntechOpen, I work closely with our collaborators in the selection of book topics for the yearly publishing plan and in preparing new book catalogues for each season. This requires extensive analysis of developing trends in scientific research in order to offer our readers relevant content. Creating the book catalogue is also based on keeping track of the most read, downloaded and highly cited chapters and books and relaunching similar topics. I am also responsible for consulting with our Scientific Advisors on which book topics to add to our catalogue and sending possible book proposal topics to them for evaluation. Once the catalogue is complete, I contact leading researchers in their respective fields and ask them to become possible Academic Editors for each book project. Once an editor is appointed, I prepare all necessary information required for them to begin their work, as well as guide them through the editorship process. I also assist editors in inviting suitable authors to contribute to a specific book project and each year, I identify and invite exceptional editors to join IntechOpen as Scientific Advisors. 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Therefore, a type of non-volatile memory using nanoparticles (NP) as floating gates has attracted much research attention because of its excellent memory performance and high scalability (Tiwari et al., 1996; Park et al., 2002). By utilizing discrete NP as the charge storage element, NP memory is more immune to local oxide defects than flash memory, thus exhibiting longer retention time and allowing more aggressive tunnel oxide scaling than conventional flash memory (Blauwe, 2002; Hanafi et al., 1996). In NP memory, the device performance and reliability depend on many factors, such as the ability to control NP size, size distribution, crystallinity, area density, oxide passivation quality, and the isolation that prevents lateral charge conduction in the NP layer (Ostraat et al., 2001). Thus, NP memory has driven extensive efforts to form NP acting as charging and discharging islands by various methods. Up to now, several techniques have been developed to form uniform NP in gate oxides. For example, Kim (Kim et al., 1999) employed low pressure chemical vapour deposition (LPCVD) to fabricate Si NP with a 4.5 nm average size and 5×1011cm-2 average density. King (King et al., 1998) fabricated Ge NPs by oxidation of a SiGe layer formed by ion implantation, and demonstrated quasi-nonvolatile memory operation with a 0.4 V threshold-voltage shift. Takata( Takata et al., 2003) applied a sputtering method with a special target to fabricate metal nano dots embedded in SiO. Various NP memory devices have been made to realize the fast and low-power operation of such devices, mostly using Si NP devices surrounded by SiO (Gonzalez-Varona et al., 2003). The programming efficiency has been improved with program voltages reduced far below 10 V, owing to the scaling of tunneling SiO2. Among the advantages related with the NP approach to FLASH technologies, worth to emphasize that owing to the discrete nature of the storage nodes, NP memories are expected to behave much better than standard FG devices in radiation environments.
This chapter focuses on this particular issue of the radiation hardness of FLASH, and in particular, NP memory technologies. After a review of the main sources of radiation in space and on earth, we will present a detailed review of the effects of radiation on CMOS electronic devices and discuss the state of the art of radiation effects on standard FG FLASH memories and NP FLASH memories. In the second part of the chapter, we will present and discuss an extensive study conducted on prototype Si nanocrystal (NC) FLASH memories irradiated with protons.
Radiation environments are encountered in military applications, nuclear power stations, nuclear waste disposal sites, high-altitude avionics, medical and space applications. Radiation type, energy, dose[1] - rate and total dose may be very different in each of these application areas and require in many cases radiation-tolerant electronic systems.
The space radiation environment poses a certain radiation risk to all electronic components on the earth-orbiting satellites and planetary mission spacecrafts. The irradiating particles in this environment consist primarily of high-energy electrons, protons, alpha particles, and cosmic rays. The weapon environment such as a nuclear explosion (often referred to as the "gamma dot") is characterized by X-rays, gamma, neutrons, and other reaction debris constituents occurring within a short time span. This can cause latchup and transient upsets in integrated circuits such as memories. Although the natural space environment does not contain the high dose rate pulse characteristics of a nuclear weapon, the electronics systems exposed can accumulate a significant total dose from the electron and protons over a period of several years. The radiation effects of charged particles in the space environment are dominated by ionization, which refers to any type of high energy particle that creates electron-hole (e-h) pairs when passing through a material. It can be either particulate in nature or electromagnetic. In addition to creating e-h pairs, the radiation can cause displacement damage in the crystal lattice by breaking the atomic bonds and creating trapping recombination centers. Both of these damage mechanisms can lead to degradation of the electronic performance. The ionizing electromagnetic radiations of importance are the X-rays and gamma rays. Ionizing particulate radiation can be light uncharged particles such as neutrons, light charged particles such as electrons, protons, alpha, and beta particles, and heavy charged particles (heavy ions) such as iron, bromine, krypton, xenon, etc., which are present in the cosmic ray fluences. Gamma rays (or X-rays) basically produce a similar kind of damage as light charged particles since the dominant mechanism is charge interaction with the material. Neutrons have no charge, and react primarily with the nucleus, causing lattice damage. In Fig. 1 is shown a summary of the possible radiation sources and their effects on electronic, optical and mechanical components.
Our planet is surrounded by a radiation rich environment, consisting of mainly energetic charged particles (electrons, protons, heavy ions, see Table 1). They can either be trapped particles, bound to trajectories dictated by the earth’s magnetic field, or free, transiting particles originating from the sun or from galactic sources and can be classified in three main categories: the Van Allen belts, the solar cosmic rays (solar flares), the cosmic rays (galactic and not).
Radiation sources and their effects on electronic, optical and mechanical components.
Particle type | Maximum Energy |
Trapped electrons | 10s of MeV |
Trapped Protons and Heavy Ions | 100s of MeV |
Solar Protons | GeV |
Solar Heavy Ions | GeV |
Galactic cosmic rays | TeV |
Maximum energies of particles in the space radiation environment (Barth et al., 2002).
This section discusses natural space environments in which most of the satellites operate, in orbits ranging in altitudes from low earth orbits (150-600 km) to geosynchronous orbits (roughly 35,880 km). Most of the particles in interplanetary space come from the sun in the form of a hot ionized gas called the solar wind; it flows radially from the sun with a speed that in proximity of the Earth varies from about 300 to 1000 km/s, and represents a solar mass loss of about 1014 kilograms per day.
The radiation environment of greatest interest is the near earth region, about 1-12 earth radii Re (where Re = 6380 km), which is mainly dominated by electrically charged particles trapped in the earth\'s magnetosphere, and to a lesser extent by the heavy ions from cosmic rays (solar and galactic). As the earth sweeps through the solar wind, a geomagnetic cavity is formed by the earth\'s magnetic field (Fig. 2).
The motion of the trapped charge particles is complex, as they gyrate and bounce along the magnetic field lines, and are reflected back and forth between the pairs of conjugate mirror points (regions of maximum magnetic field strength along their trajectories) in the opposite hemispheres. Also, because of the charge, the electrons drift in an easterly direction around earth, whereas protons and heavy ions drift westward. Interplanetary space probes such as the Voyager (and Galileo to Jupiter) encounter ionizing particles trapped in the magnetosphere of other planets, as well as the solar flares and heavy ions from cosmic rays.
Interactions between Earth magnetosphere and the solar windhttp://helios.gsfc.nasa.gov/magnet.html\n\t\t\t\t\t\t\t\t\t
Electrons in the earth\'s magnetosphere have energies ranging from low kilo electronvolts to about 7 MeV, and are trapped in the roughly toroidal region which is centered on the geomagnetic equator and extends to about 1-12 earth radii. These trapped electrons are differentiated by "inner zone" (<5 MeV) and "outer zone" (~7 MeV) electron populations. The trapped protons originating mostly from the solar and galactic cosmic rays have energies ranging from a few MeV to about 800 MeV. They occupy generally the same region as the electrons, although the region of highest proton flux for energies Ep > 30 MeV is concentrated in a relatively small area at roughly 1.5 Re. The actual electron and proton flux encountered by a satellite is strongly dependent upon the orbital parameters, mission launch time, and duration. Electrons and protons from the trapped radiation belts on interacting with spacecraft materials produce secondary radiation (e.g., "bremsstrahlung" or braking radiation from the deceleration of electrons). This secondary radiation can extend the penetration range of primary radiation and lead to an increase in dose deposition. Incident electron and proton fluxes are typically calculated from the trapped radiation environmental models developed by the U.S. National Space Sciences Data Center (NSSDC). The trapped particle fluxes responding to changes in the geomagnetic field induced by the solar activity exhibit dynamic behavior.
In addition to the trapped geomagnetic radiation, another contribution to incident particle flux for an orbiting satellite is the transiting radiation from the solar flares. These solar energy particle events (SPE), usually occurring in association with the solar flares, consist mainly of protons (90%), some alpha particles (5-10%), heavy ions, and electrons. This solar flare phenomenon is categorized as an ordinary (OR) event or an anomalously large (AL) event. Particle fluxes from the solar flares can last from a few hours to several days and peak flux during an SPE may be two to five orders of magnitude greater than background, within hours of the event onset. Periods of enhanced flux may last for days, with successive peaks due to multiple events and enhancements during shock passage. AL events (Fig. 3), although occurring rarely, can cause serious damage to ICs. For ordinary solar events, the relative abundance of helium ions can be between 5-10%, whereas ions heavier than He (e.g., carbon, oxygen, iron, etc.), referred to as the "heavy ions," are very small. However, the solar flare protons which contribute to the total ionizing dose radiation are not that significant a factor compared to the trapped radiation environment.
Distribution in energy of proton fluxes for major past SPEs (free space)
The particles from energetic solar flares (OR events) are heavily attenuated by the geomagnetic field at low altitude and low inclination orbits, such as U.S. Space Shuttle orbits (28.5° inclination). In a 500 km, 57° inclination orbit, some particle fluxes do penetrate. A characteristic of the geomagnetic field which is particularly significant is the South Atlantic Anomaly (SAA), referring to an apparent depression of the magnetic field over the coast of Brazil where the Van Allen radiation belts dip low into the earth\'s atmosphere. This SAA is responsible for most of the trapped radiation in low earth orbits (LEOs). On the opposite side of the globe, the Southeast-Asian anomaly displays strong particle fluxes at higher altitudes. A polar orbit at any altitude experiences a high degree of exposure, and at geosynchronous orbit, geomagnetic shielding is rather ineffective.
Another significant contribution to the transiting radiation is from cosmic rays originating from outside the solar system and consisting of 85% protons, 14% alpha particles, and 1% heavier ions. These galactic cosmic rays (GCR) range in energy from a few MeV to over GeV or TeV per nucleon. The total flux of cosmic ray particles (primarily composed of protons) seen outside the magnetosphere at a distance of earth from the sun (1 AU) is approximately 4 particles/cm2s.
Heavy energetic nuclei, HZE, represent ~1% of the GCR and as shown in Fig. 4, where is presented the distribution in energy of several important HZE nuclei, these particles have very high energies, sufficient to penetrate many centimetres of tissue or other materials. In addition, the HZE nuclei are highly charged and, therefore, very densely ionizing. As a consequence, even though the number of HZE particles is relatively small, they have a significant biological impact that is comparable to that of protons.
Abundances (a) and energy spectra (b) of GCR.
Silicon MOS (metal-oxide-semiconductor) devices are by many decades the mainstay of the semiconductor industry. When these devices are exposed to ionizing radiation, significant changes can occur in their characteristics. Ionizing radiation creates mobile electrons and holes in both the insulator and silicon substrate in MOS devices that may lead to a damage of the device. It is interesting to note that these properties have allowed the use of ionizing radiation damage as a tool for scientific study in a number of areas. Indeed, in the past, the basic mechanisms of carrier transport in insulators have been very effectively explored by using various types of ionizing radiation to create mobile carriers and then monitoring their motion by electrical means. These studies have furthered our understanding of polarons, excitons and trap-hopping processes. The generation of interface traps and oxide trapped charge in large numbers by ionizing radiation has allowed the identification of the atomic structures associated with these defects. By providing a means of altering the trapped charge at the SiO2/Si interface in a given device, the interaction of mobile charge carriers in the channel of an MOS device with that trapped charge can be explored. By creating trapped charge distributions in the oxide layer which provide traps for carriers, tunneling and carrier capture phenomena can be effectively studied. As the semiconductor industry progresses deep into the ULSI era, the technological impact of ionizing radiation effects becomes more and more important. In order to produce the extremely fine geometries required at high levels of integration, the processes used in the manufacture of the integrated circuits themselves may produce ionizing radiation. At the small geometries of current and future integrated circuits, latchup initiated by normal operating conditions has become a major concern. This trend toward small devices has made normal commercial ICs susceptible to single event upsets caused by ionizing particles created by the decay of residual radioactive material in IC packaging material. Thus many of the concerns for radiation hardened circuits have become a concern for standard commercial products. In addition, in order to make circuits for specialized applications requiring operation in an ionizing radiation environment, significant modifications to the technology employed must be made. There are a large number of specialized applications requiring ICs that have a known, predictable response to ionizing radiation. Satellite systems need electronic components that can operate in the harsh radiation environment around the earth and in space. Without such components satellites would have extremely limited capabilities. Many weapon systems require hardened components to perform their tasks properly trough an operational scenario. Nuclear power plants need instrumentation which can withstand the environment near the reactor and continue to provide reliable data. In the nuclear medicine field, is straightforward the importance of having electronic components with higher performances in radiation environments.
The way ionizing radiation affects MOS devices is mainly related to build up of oxide trapped charge, increased amount of density of interface states at the oxide boundaries and to the possibility to have single-event-upsets, SEU (Ma & Dressendorfer, 1989). When ionizing radiation passes through the oxide, the energy deposited creates electron/hole pairs with a generation energy of 18 eV/pair. The radiation generated electrons are much more mobile that holes and are swept quickly out of the oxide. Some of them undergo recombination with holes, depending on many different experimental factors. A final positive charge is then observed into the oxide, resulting from the unrecombined holes generated by radiation that remain trapped in the strained areas of the oxide close to the interfaces with Si or the gate material (Fig. 5). The trap sites responsible for this positive charge build up have been identified as E’centers, deep traps in the bulk of SiO2 originated by a silicon dangling bond in the oxide matrix. Furthermore, an increased amount of interface states is also observed after irradiation at Si/oxide interface. Pb centers have been found to be responsible of the observed interface states, microscopically related to non bridging silicon atoms between the crystalline silicon substrate and the silicon oxide matrix. This interface bond breaking during irradiation seems to be driven by the excess positive charge and strain present at interface. Finally, in the case of heavy ion irradiation when the incident particle has high enough Linear-Energy-Transfer(LET) transient effects become also important. Indeed the ion along its path inside the device create a dense cloud of electrons-hole pairs generating very intense transient currents that in many cases may result in different kinds of failures of the device itself, even rupture.
Detailed representation of the ionizing radiation damage mechanisms into SiO2.
Thus, when we are interested into the transient response of an MOS component to single events we perform heavy ion irradiations. When on the other hand we are interested into the effect on devices performance of accumulated damage during long time irradiation exposure we perform total ionizing dose (TID) irradiations, using gamma rays or in special cases electrons or protons.
In MOS microelectronic memory devices, information is stored as quantities of charge. Pulses of ionizing radiation are known to be effective in corrupting the information integrated circuits store. Errors induced by ionizing radiation can be classified in three main classes: soft errors, hard errors and failures. Soft errors are correctable simply by re-entering correct information into the affected elements and can be generated by single ionizing particle or by pulses of ionizing radiation. Hard errors are not recoverable, i.e. are not altered by attempts to rewrite correct information and are caused by single particles like neutrons and heavy ions. Finally, failure events prevent normal device operation and generally are connected to the high transient currents initiated by pulsed ionizing radiation or single events. While RAM can be made insensible to soft errors in many different ways ( by design (Liaw, 2003) or by software (Klein, 2005 ; Huang, 2010) ), NVMs are susceptible to all three categories of errors above. The lack of any refresh cycle of the stored information make flash memories vulnerable to data loss at each exposure to ionizing radiation. Considering that Flash memories standards impose a retention time for the data stored of 10 years at least and a minimum 106 write/erase operations before performance degradation starts, is clear that non-volatile memory cells are in a passive state for most of their lifetime.
Until recently, the effects of radiation in Flash memories have mainly been a concern for the space or aircraft applications. The heavy ions and other high energy particles which are abundantly present at altitudes far above the sea-level cause a variety of problems including the soft errors (mainly SEU, Single-Event-Functional-Interrupts (SEFI)), latchup (If the induced parasitic current levels are sufficiently high, they can cause permanent device failures such as a junction burnout) and hard errors pertaining to oxide degradation due to total dose (irreversible bit-flips due for example to high leakage current in the gate oxide). Recent experiments on current generation Flash memories have however shown that significant amount of radiation effects can be observed at the sea level or terrestrial environments. Previously, the most sensitive component of Flash memory used to be the control circuitry for sense amplifiers and charge pumps. The FG cell array on the other hand was considered to be relatively insensitive to radiation strikes at least at terrestrial levels. This is however changing rapidly because with only ~1000 or fewer electrons stored in the FG, the cells have now become sensitive to charge deposited by the terrestrial cosmic ray neutrons and alpha particles. But most important, because of the conductive nature of the floating gate, in presence of a weak spot in the tunnel oxide, possibly radiation induced, the whole charge stored could be lost with total loss of information. Even in the case that the damage does not generate device failure, data retention and device performance would be dramatically affected by this defect in the tunnel oxide (Oldham et al., 2006).
In the last decade different teams already investigated the effect of ionizing radiation on FG Flash memories and a summary on the results can be found in the works of Cellere (Cellere et al., 2004a, 2004b, 2004c, 2005) and Oldham (Oldham et al., 2006, 2007).
Cellere investigate the radiation hardness of standard FG memories, under 60Co, X-ray and 100 MeV protons. The result that worth to mention here is that independently (almost) from the radiation used, information loss starts at doses as low as 100 krad(Si).
Oldham investigates TID and SEE effects on commercial 2Gbit and 4Gbit NAND FG memories. TID effects, in reasonable agreement with Cellere, show that static errors rise abruptly above 75 krad(SiO2) while dynamic errors rise quickly at even lower doses. The errors were found to arise from zeroes that could not be erased into ones due to the failure of the erase function. The SEE were monitored in static and various dynamic modes for LET in the range 0-80 MeV cm2 mg-1. Error Cross sections seem to saturate to a value of ~10-12 cm2/bit.
NCMs are expected to have better resistance to ionizing radiation: being able to retain information with only a residual fraction of nanocrystals charged, these devices should be quite immune to radiation-induced leakage current, RILC (Larcher et al., 1999; Scarpa et al., 1997; Ceschia et al., 2000 ; Oldham et al., 2005), and they may in principle exhibit high resistance to both single event (SEE) and total ionizing dose (TID) effects. While some works already investigated the effect of ionizing radiation on FG Flash memories, until now, few works have investigated this issue in NC NVMs and will be briefly reviewed in the next.
Petkov (Petkov et al., 2004) report the first results pertinent to the high total dose (TID) tolerance of Si nanocrystal NVM cells studying prototype NC–Si field effect transistors made by ion implantation. Si ions were implanted at 5 keV to a fluence of 1.3 1016cm-2 into a bare 15 nm-thick SiO2 layer, grown on top of p-type doped Si wafer. The ion implantation profile shows a peak depth of 10 nm and a stoichiometry at the peak of 1.75:2. The wafers were annealed at 1050°C for 5 min in dry oxygen, during which time the nanocrystals were formed and the majority of the implantation-induced defects were annealed out. An optically transparent 50 nm poly-Si gate was deposited on top of the wafers. Reference samples without Si NCs were also used. Unfortunately Petkov et al. don\'t give further details about the final geometry of the device. Radiation experiments were carried out using 60Co and two different conditions were used: (1) VS = 0 V; VDS=1.5V; VG=±6V (write/erase square wave potential), and (2) all contacts grounded. They yielded indistinguishable results for the duration of the experiments, in which the maximum achieved dose was 15 Mrad(Si). The typical hysteresis of a device prior to and after irradiation were recorded on 15 NC–Si FETs with write/erase square wave potential applied to the gate. The electrical characteristics of all transistors were virtually unchanged and it is clear that negligible is the effect of ionizing radiation on position and height of the memory hysteresis. In their work, Petkov et al. consider also another set of 6 NC–Si FETs and three conventional FETs, exposed to ionizing radiation environment with all contacts grounded. The control n-channel FET yielded decreasing gate threshold with dose, notably below 1 Mrad(Si) and according to Petkov, this is considered to be consistent with the accepted models for degradation of metal-oxide-silicon structures under irradiation. The lack of change at 2 Mrad(Si) doses is attributed to saturation of interface defect generation and hole trapping. Both of the NC–Si FET show no significant changes in the entire test range of up to 15 Mrad(Si). This is ascribed to the ion-implantation-induced damage and the subsequent reconstruction of the oxide. Petkov et. al. justify this fact with the argument that oxide properties, especially these related to defect density, charge trapping and mobility, can differ greatly prior to implantation and after reconstruction. They conclude their work suggesting that for NC–Si technologies that do not utilize implantation, we can expect to observe a shift of the erased state upon radiation exposure, as in conventional FETs.
Oldham (Oldham et al., 2005) reported on the exposition to heavy ion bombardment and total ionizing dose of advanced nanocrystal nonvolatile memories. The test chips were experimental 4Mb Flash EEPROM memories fabricated using 0.13 μm design rules, with NAND architecture (Freescale). Channel hot electron (CHE) injection is used to write (that is, to add electrons to the nanocrystal array), and Fowler-Nordheim tunneling to erase (that is, to remove electrons from the array). The nanocrystals are deposited by a CVD process, where the density and diameter of the particles can be controlled by adjusting the deposition conditions. The tunneling oxide and control gate oxide are SiO2 with thicknesses of 4.3 nm and 5.6 nm respectively while the Si NCs have diameter of 4 nm. The heavy ion testing was done using a Single Event Effects Test Facility, which was tuned to 15 MeV/nucleon, using Ar, Kr, Xe and Au ions. Each exposure was to a total fluence of 107 particles/cm2. Total dose testing was done using a 60Co source with dose rate of 10 rad/s. Oldham et al. performed their tests in three modes: static mode, in dynamic read mode, and dynamic program and erase modes. In the static testing, a pattern was written, and errors counted after the exposure. In dynamic read testing, a stored pattern was read continuously during the exposure, and the errors counted. The write or program mode was tested by continuously doing a write/read cycle. The erase mode was tested by cycling continuously through erase/write/read steps, and counting errors when the pattern read differed from the pattern expected. Patterns that could be written were all zeroes, all ones, checkerboard, and inverse checkerboard. In heavy ion testing, the errors appear to be all static bit flips, zeroes (electrons storage) turned into ones(holes storage). Oldham estimates that about one ion out of 6 that hits the active gate area changes the state of the cell, even at the highest LET tested so far and the observed cross section is about one sixth times the geometric gate cross-section.
Cester (Cester et al., 2006) performed heavy ion irradiation tests on experimental nanocrystal memory cell arrays provided by ST microelectronics based on CAST architecture. Each nanocrystal MOSFET features W/L 0.2μm/0.3μm, with a tunnel oxide 5-nm thick and thermally grown on Si. The external control oxide consists of an oxide-nitride-oxide (ONO) stack with an equivalent oxide thickness (EOT) of 12 nm. Silicon nano-islands were realized by low pressure CVD (LPCVD) process in the Si nucleation regime using SiH as a precursor, followed by a post-deposition crystallization annealing of the islands. A nanocrystal density of 5 1011 cm-2 was determined by TEM measurements, with an average nanocrystal diameter of 6 nm. On average each cell contains 300 nanocrystals. Irradiations were performed using a tandem van der graaf accelerator. I (301 MeV, LET=64 MeV cm2mg-1) and Ni (182 MeV, LET=31,3 MeV cm2 mg-1) ions were considered at three different fluencies: 0.83 108 cm-2, 1.7 108 cm-2, 3.3 108 cm-2. The devices were unbiased during irradiations. Irradiations induce negligible changes in the drain current without affecting the subthreshold slope (swing). On the other hand Cester et al. observe that as the fluence of ions increases, the gate leakage current also increases being higher for ions with higher LET.
Wrachien (Wrachien et al., 2008) investigated the performance of nanocrystal memories, similar to those of Cester, and floating gate memories when irradiated with protons of 5 MeV and x-rays of 10 keV. The terminals were kept floating during irradiations and some of the devices were in write or erase state. Wrachien observe that X-rays are much more effective than protons in charge removal from charged devices. What arises in the work of Wrachien et al. is that the nanocrystal memories seem to behave better than the floating gate memories in these environments since higher doses are needed in the former case respect to the latter to observe a certain charge loss. Also the swing is found to behave better for NCM than FG and the charge retention measurements confirm these results indicating much higher retention for NC memories than FG and thus justifies the interest of the radiation effects community on NC NVMs.
The optimized Si NC NVM structures were in the form of capacitors and transistors with Si NCs fabricated according to the ultra-low-energy ion-beam-synthesis (ULE-IBS) technique (Normand et al., 2004). A schematic cross section of the gate area of the devices is shown in Fig. 6. The capacitors had a control-oxide (CO) thickness around 15.5 nm, a tunnelling-oxide (TO) of ~8 nm while the transistors had a CO thickness of 5 nm and TO thickness of 6.5 nm. For both capacitor and transistor structures, the NC layer consisted of Si NCs with mean size of 2-3 nm and density of 5 1011 cm-2. Reference devices with no Si NCs have been fabricated as well.
Schematic of the gate area of the Si NC NVM devices considered in our work.
The capacitor structures comprise 3 kind of square gates: 400x400 μm2, 200x200 μm2 and 100x100 μm2. The process flow considered in order to fabricate these devices is the following:
p-Si substrate with 9 nm thermally grown SiO2\n\t\t\t\t\t\t
Si+ implantation 1 keV, 2 1016 cm-2\n\t\t\t\t\t\t
annealing at 950°C/30 min in N2 (1.5% O2)
deposition 10 nm TEOS oxide
annealing at 900°C/15 min in N2\n\t\t\t\t\t\t
Al evaporation
Annealing 320°C/30min in N2
The TEOS oxide has been added in order to increase the CO thickness and thus improve the retention properties of the devices. The total gate oxide thickness of the implanted samples was ~25.5nm while reference samples (steps 2 and 3 skipped) had a thickness of ~19nm. The electrical properties of the above devices will be briefly presented in the next paragraphs.
The electrical properties of reference (no Si NCs) capacitors are shown in Fig. 7 where the high and low frequency C-V characteristics are presented together with the density of interface states (Dit) distribution along the Si band-gap. The oxide thickness extracted from Cox values is ~18.7 nm. The density of interface states throughout the band-gap is extremely low, 2 1010 eV-1 cm-2, thanks to the very good quality of the SiO2 oxide thermally grown on Si substrate.
C-V characteristics and Dit for a reference MOS capacitor with p-Si substrate (1015 cm-3), 18.7 nm SiO2 and Al gate of 400μm side: a) HF - LF characteristics, b) density of states calculated using the high-low frequency method (the HF and LF C-Vs are also shown)
In Fig. 8 is shown the J-V characteristic of the reference MOS capacitor. It is demonstrated there that the conduction mechanism through the oxide is based on Fowler-Nordheim (F-N) tunneling
a) Experimental J-V characteristic for a reference MOS capacitor with p-Si substrate (1015 cm-3), 18.7 nm SiO2 and Al gate of 400μm. Probe light was kept on during the measurement in order to ensure a reasonable amount of minority carriers in inversion(green curve), b) F-N plot of the J-V data in which is clear that for E-1 below 0.2 (MV/cm)-1, i.e. E above 5-6 MV/cm, F-N conduction starts.
and the B parameters extracted from the F-N plot are 194 MV/cm in accumulation (Al-side injection) and 287 MV/cm in inversion (Si-side injection). It should be reminded that the B parameter is related to the effective mass of the tunneling charge carrier and the barrier height. Assuming an electron effective mass in SiO2 of 0.42m0, the extracted barrier heights are 2.7eV and 3.4eV respectively.
C-V characteristics and Dit for a Si NC MOS capacitor with p-Si substrate (1015 cm-3), 8 nm SiO2 TO, 2-3 nm NCs, 15.5 nm CO and Al gate of 400 μm side: a) HF - LF characteristics, b) density of states calculated using the high-low frequency method (the HF and LF C-Vs are also shown).
The Si NC MOS capacitors present similar electrical properties with the reference capacitors. In Fig. 9, the high and low frequency C-V characteristics are shown together with the Dit distribution along the Si band-gap. The oxide thickness extracted from Cox values is ~24.5 nm. the density of interface states throughout the band-gap is extremely low, 2 1010 eV-1 cm-2, thanks to the very good quality of the SiO2 oxide thermally grown on Si substrate.
In Fig. 10 is shown the J-V characteristic of the reference MOS capacitor. It is demonstrated there that the conduction mechanism through the oxide is again based on F-N tunneling at least in accumulation (Al-side injection) with a B parameter extracted from the F-N plot of 186 MV/cm reasonably comparable with the one of the reference devices. In inversion (Si-side injection) on the other hand the B parameter extracted is very low in comparison with that of the reference capacitor: 100 MV/cm. Fig. 10c can help us in the explanation of this difference since as it is shown there, comparing the leakage current through the reference and the Si NC MOS becomes clear that for the latter conduction starts at much smaller fields in inversion, around 3.5MV/cm. Such a field cannot ignite F-N conduction so the above argument demonstrate that there is another conduction mechanism in competition with (maybe dominates) the F-N tunneling from substrate in the Si-NC memory devices in inversion. Of course the fact that F-N plot shows the characteristic linear behavior of every F-N mechanism is telling us that the mechanism dominating over the F-N injection from the Si substrate should be also an F-N mechanism. This last observation drives to the conclusion that the 100 MV/cm B value should arise from the F-N taking place from the electrons trapped in the NC layer that tunnel toward the gate and ignited by the augmented electric field present in the CO when electrons are present into the NCs while, at the same time, the electric field in the TO is reduced. It can be shown that when the overall, through the dielectric structure, electric field is 4 MV/cm and there is a detectable (in terms of flat-band voltage shifts) negative charge into the NCs, the electric field into the CO is around 5 MV/cm and thus able to ignite F-N. Thus the 100 MV/cm of the B value extracted for the Si-side injection case is related not to the barrier SiO2/Si-conduction band but SiO2/NC-Si-conduction band (Fig. 10d). The barrier extracted from the 100 MV/cm value is around 1.8 eV.
a) Experimental J-V characteristic for a Si NC MOS capacitor with p-Si substrate (1015 cm-3), 8nm SiO2 TO, 2-3nm NCs, 15.5nm CO and Al gate of 400 μm side. Probe light was kept on during the measurement in order to ensure a reasonable amount of minority carriers in inversion(green curve), b) F-N plot of the J-V data in which is clear that in accumulation F-N conduction starts at -6MV/cm while in inversion it seem to start at 3-4 MV/cm, c) comparison between the J-E characteristic of reference and Si NC MOS capacitors, d) Band diagram of the Si NC capacitor under VG=10 V without charges into the NC layer.
The memory properties of the devices with Si NCs have been recorded with two equivalent ways: gate sweeps and gate pulses. The latter of course is the one in which we are most interested since the memory in its final application is written/erased by voltage pulses.
Gate sweep bias measurements are performed sweeping the the gate voltage circularly i.e. inversion - accumulation - inversion with increasing amplitude of the applied maximum bias. In Fig. 11a are shown the C-V curves obtained with such a measurement; large hysteresis were found for amplitudes above 10V. It should be noted that the hysteresis are counter clock wise, indicating that charging is taking place from the substrate. Upon extraction of the flat-band voltages from the above C-Vs, it is possible to present the data as in Fig. 11b where the memory behaviour of the devices becomes clearer. Electron injection (backward sweeps) seem to start at around 10V, slightly earlier than holes injection (forward sweeps) which start at around 12V while saturation starts at 16V and 18V respectively.
a) C-V characteristics under gate bias sweeps of several amplitudes; Large hysteresis for amplitudes above 10V are shown, b) memory characteristic as extracted from Fig. 11a.
a) memory characteristic extracted from gate pulse measurements (the upper branch refers to positive pulses), b) Memory behavior under repeated positive and negative pulses. The black curve is obtained keeping the constant the erase (negative) pulse and varying the height of the write (positive) pulse, and the opposite is done for the red one.
Gate pulse measurements are performed applying in sequence pulses of increasing height to the gate and measuring at every pulse a C-V characteristic to monitor the flat-band voltage position. In such a way, with pulses of 1s duration, the results shown in Fig. 12a were obtained (where the upper branch refers to positive pulses and the lower branch to negative pulses). There are similarities between the memory behavior under gate bias sweeps and gate pulses like the maximum width and the saturation behavior at high fields, but, also one difference that is the decreasing (increasing) flat-band voltage in order to approach saturation for positive (negative) pulses. The reason of this phenomenon is that when the fields become high enough charges are not only injected into the NCs but also extracted. Actually there is a dynamic equilibrium between this two components at steady regime that drives to the smooth behavior observed with gate sweep measurements, on the contrary, this equilibrium is perturbed in presence of pulses favoring charge extraction at high fields and this explains the peculiar shape found for the memory characteristic in Fig. 12a.
In its final operation, the memory always switches from write state to erase state and vice versa. Thus, the gate pulse measurement, although gives important informations about the pulsed operation of the memory device, isn’t the best one to decide the program and erase condition to be used during its final operation. What should be done is to establish the strength of each positive (negative) pulse starting always from the same erased (programmed) state. This has been done for the Si NC capacitor memories and is shown in Fig. 12b. The most effective programming pulses are +14V and -18V. From now on we will consider as write state or erase state the condition into which is brought the device when programmed with a write pulse +14V,1s or erased with an erase pulse of -18V,1s respectively. The memory window of the device arises then as the difference between the flat-band voltages of the write and erase states. For the Si NC MOS capacitors presented here, the memory window is around 3V.
Charge retention measurements are performed charging a device into one of the two states write or erase and then the evolution with time of the flat-band voltage is recorded for 12 h at least. This is done 1) measuring at regular interval of times the C-V of the device (that was written or erased) in order to obtain a result similar to the example shown in Fig. 13a, and then 2) extracting from the C-Vs the flat-band voltage which is graphed as function of time.
a) Evolution with time of the C-V characteristic measured at regular interval of times for a Si NC MOS capacitor in the write state. The arrow show increasing time direction. Measurement at room temperature. b) Charge retention measurement in the write and the erase state of the Si NC MOS memory. Measurement performed at room temperature. The electrons loss rate is -4 mV/dec and the holes loss rate is 103 mV/dec.
The above procedure applied to our capacitors drives to the results shown in Fig. 13b where are summarized the measurements for both the write and the erase state. Since the retention curves present in log(t) a linear behavior it is usual to speak in terms of mV/dec loss rate. So, fitting the two curves shown, and assuming that the loss rate will be constant, it is possible to extrapolate the retention measurements to 10 years. For the erase state the charge loss rate is around 103 mV/dec while for the write state is much smaller, around -4 mV/dec. The charge loss extrapolated at the 10 years retention limit is 20%, thus within the FLASH design standards.
The higher loss rate in erase state (holes retention) than in the write state (electrons retention) has to do with the fact that holes may tunnel back to the substrate by means of imperfections in the TO remained after the implantation and annealing of the Si ions. Electrons on the other hand are not affected by such imperfections and thus the large TO thickness ensures a reliable quantum mechanical barrier against electron loss.
Si NC MOSFETs were provided in structures of two types: depletion (D) and enrichment (E). Furthermore, both types are provided in various W/L configurations: a) constant W=100μm and L=12,10,8,6,4,2 μm, b) L=100 μm/W=100 μm and constant L=40μm and W=40,20,15,10,8 μm.
Si-NC nMOS transistors were fabricated using a 7 nm thick SiO2 layer that was Si implanted and annealed under the same conditions as for NC MOS capacitors. No additional TEOS control oxide was deposited. The final gate dielectric stack includes 6.5 nm thick injection oxide, 2.5 nm thick Si NC layer and 5 nm thick control oxide.
The memory behavior of the Si NC MOSFETs has been recorded with the gate pulse method mentioned previously. Positive or negative Gate pulses of increasing height are applied in sequence on Fresh devices and after each pulse the Id-VG characteristic is recorded in order to monitor the transistor threshold voltage position. The outcome of such a measurement on
a) Id-VG characteristics after the application, in sequence, of positive or negative pulses of increasing height (in the legend); the fresh curve refer to the device at the beginning of the measurement i.e. uncharged; on the right of the fresh curve are the characteristics related to positive pulses while on the left are the ones related to negative pulses. b) threshold voltage extracted from a) as function of the gate pulse height; the upper branch is related to positive pulses while the lower branch arises from negative pulses. The pulse duration was constant: 30ms.
our devices, for pulses of 30 ms, is shown in Fig. 14a, while in Fig. 14b the threshold voltages extracted from the Id-VG characteristics are graphed as function of the gate pulse height. Thus, the write or erase states are defined here as the conditions determined by the application of the write pulse +9 V, 30 ms or the erase pulse -9 V, 30 ms respectively.
Should be mentioned that the swing of the Id-VG characteristics of such devices is around 127 mV/dec.
Charge retention measurements are performed in a similar manner with the measurement on capacitors except the fact that now Id-Vg characteristics will be monitored instead of C-Vs. The results are presented in Fig. 15. The overall behavior is very similar to that of NC MOS capacitors but the charge loss rates are much higher because of the thinner TO and CO of the transistor with respect to the capacitor structure. Values of -54mV/dec and 150mV/dec have been extracted for electrons and holes loss rates respectively. The overall charge loss extrapolated to 10 years retention is estimated to be ~57%.
Charge retention measurement in the write and the erase state of the Si NC MOSFET memory. Measurement performed at room temperature. The electrons loss rate is -54 mV/dec and the holes loss rate is 150 mV/dec.
In order to perform the measurement within few hours, smaller pulse durations have been considered here. The write and erase pulse are always +9 V and -9 V respectively but the duration is now 15 ms so the memory window will be smaller than ~2 V found with 30 ms. The endurance in these transistor memories is outstanding. Results are presented in Fig. 16a where endurance up to 106 W/E cycles demonstrate the robustness of these devices against stress induced leakage currents (SILC). The endurance measurement is a quite stressful operation for the memory device and for this reason is quite common provide, according to FLASH standards, the retention behavior of a transistor memory cell before and after endurance. In our case the comparison is shown in Fig. 16b. After endurance, the charge loss rates are both increased: electrons loss rate before endurance was -54mV/dec while after was -60mV/dec, holes loss rate before endurance was 150mV/dec while after was 172mV/dec. The extrapolated charge loss after 10 year retention is after endurance ~70% i.e. 13% charge lost because of the stress to which the memory underwent.
a) Endurance to w/e cycles performed on Si NC MOSFETs. A reduced pulse duration of 15ms has been considered with write pulses of +9V and erase pulses of -9V. b) charge retention measurement before and after endurance.
The Si NC memory devices, in capacitor and transistor form, presented in section 6, have been irradiated with protons at the Tandem accelerator of the Institute of Nuclear Physics, N.C.S.R. “Demokritos”. The energies used ensure that the kind of damage produced is related to TID effects. The ways TID effects alter the operation of NVM cells are essentially two: 1) loss of stored information in the form of bit-flips, and 2) charge retention issues after irradiations (failure to retain the information for 10 years). According to the existing literature on TID effects on standard FG NVMs, briefly reviewed in the previous sections, it is concluded that in FG cells, bit-flips are observed above 100 krad(SiO2) while retention issues are observed above ~5 Mrad(SiO2). In the next it will be demonstrated that NC NVM cells present a much higher hardness to TID effects than FG cells (Verrelli et al., 2006, 2007).
The protons considered in our irradiation tests had energies of 1.5MeV and 6.5 MeV. The proton fluences (particles/cm2) and the doses (rad(SiO2) ) considered are shown in Table 2. One important parameter that was constantly monitored during the irradiation was the flux (particles/cm2s) of the particles that was kept at ~5 109 protons/cm2s and this was done keeping constant both the proton current driven by the Tandem (200pA) and the beam spot size. It is very important that the flux remain constant during irradiation cause it is known to be related to changes in the effects produced by radiation (Ma & Dressendorfer, 1989) and thus may complicate the interpretation of the results. The samples irradiated have physical dimension of 1.5x1.5 cm2 while the proton beam spot has been tuned to be the largest possible i.e. 0.5x0.5 cm2. One sample at a time has been irradiated and upon irradiation of all the samples, their electrical characteristics have been studied in our laboratory. The irradiation and all the electrical measurements took place at room temperature and the characterization of the radiation effects ended within one month period time from irradiation. Actually the fastest the samples are characterized after irradiation the better it is, because the irradiation effects have the property to anneal out with time also at room temperatures (Ma & Dressendorfer, 1989). All the samples have been irradiated with floating terminals except some NC MOS capacitors and transistor which were programmed to “1” or “0”.
Irradiation at 1,5 MeV | Irradiation at 6,5 MeV | ||
CAPACITORS | |||
FLUENCE (cm-2) | DOSE (Mrad(SiO2) | FLUENCE (cm-2) | DOSE (Mrad(SiO2) |
5*1013 | 123 | 5*1013 | 119 |
1*1013 | 24.6 | 1*1013 | 23.7 |
5*1012 | 12.3 | 5*1012 | 11.9 |
1*1012 | 2.46 | 1*1012 | 2.37 |
5*1011 | 1.23 | 5*1011 | 1.19 |
TRANSISTORS | |||
3*1011 | 0.74 | ||
3*1012 | 7.42 | ||
1*1013 | 24.6 | ||
3*1013 | 74.2 |
Fluencies and doses for the samples involved in this experiment. The capacitors were both NC MOS devices and reference devices i.e. MOS capacitors with no NCs. The transistors were NC MOSFET devices only.
At first, we should remark that the capacitor and the transistor samples have a main difference: the former work “vertically” while the latter work “horizontally”. Indeed, in capacitors, the substrate-gate electric field rules everything while in transistors, Id passes from the source to the drain through the channel formed by the inversion layer in the Si substrate and the whole process is confined into few μm from Si-SiO2 interface.
SRIM simulations on our structures show that 1.5 MeV and 6.5 MeV protons end their trajectories into the Si substrate at depths from the Si-SiO2 interface of 80 and 400μm respectively (for this reason irradiation took place with the devices face to the beam i.e. protons always enter the devices from their gates). This represent an important limitation for capacitor structures which work vertically. The reason is that when a particle like a proton with the energies above mentioned penetrate matter, at the beginning of its track it loses energy in small steps slowing down almost entirely through Coulomb interactions with the atomic electrons of the target material. Because of the large number of these interactions, the slowing down procedure is nearly continuous and along a straight-line path. As the particle slows down, it captures electron(s) to form a neutral atom and thus has an increased probability to have nuclear collisions that may induce displacements and vacancies in the target material lattice. The result is that at the end of range of their tracks, protons destroy the Si crystalline structure transforming it into a porous-like material. Of course the above mentioned effect depends from the fluence of protons. It was found experimentally that for fluencies above 1014 protons/cm2 the MOS behavior is completely lost due to the isolation achieved between the Si back contact and the gate of the capacitor. The presence of the damage and its amount can be monitored through the value of the series resistance in C-V measurements which increases as the fluence is increased. As it is demonstrated in Fig. 17, this dependence has been found to be approximately linear with the fluence in both the NC MOS capacitors and the reference (no NCs) MOS capacitors.
Dependence upon the fluence of the series resistance measured during C-V measurements on irradiated NC MOS capacitors and reference (no NCs) MOS capacitors.
As mentioned in 3.1, one of the parameter of MOS devices more affected by ionizing radiation is the density of interface states. After irradiation the C-V and G-f characteristics of reference (no NCs) MOS and NC MOS capacitors have been measured in order to estimate the Dit. Both methods, high-low frequency and conductance, give similar estimations. An example of the effects on the MOS characteristics is shown in Fig. 18a-18c where the C-V frequency dispersion is shown for some of the irradiated NC MOS capacitors.
The exctracted values of Dit at mid-gap have been graphed in function of the dose and are shown in Fig. 18d.
For both reference and NC MOS devices, Dit increases sub-linearly with dose. Within the measurement errors, our data are in good agreement with the empirical relationship (Ma & Dressendorfer, 1989) that asserts Dit to be proportional to Dose2/3. Dit distributions were found to be U shaped for the various MOS capacitor samples, with a clear peak in the upper half of the band gap, at around 0.2eV above mid-gap, giving evidence of a sharply distributed electron state in agreement with other observations (Ma & Dressendorfer, 1989).
One important question to answer was to which extent the radiation effects described above affect the MOS characteristics. In order to determine whether the F-N injection mechanism was altered by the ionizing radiation damage to the SiO2, the B parameter has been monitored on all the irradiated samples and the result is shown in Fig. 19. This parameter, within experimental errors, does not seem to be affected by the irradiation dose.
C-V frequency dispersion for irradiated NC MOS capacitors at different proton fluences: a) 5 1013 p/cm2, b) 5 1012 p/cm2, 5 1011 p/cm2. d) Dit versus dose for Reference (without NCs) MOS and NC MOS capacitors irradiated with protons 1.5 MeV and 6.5 MeV. Dit reference value for non irradiated devices is also shown. The lines correspond to linear fits of the NC MOS capacitors experimental data to the relationship Dit ~ Doseb.
MOS capacitors irradiated with floating terminals exhibit C-V characteristics shifted to lower voltages compared to the characteristics of non-irradiated samples, in agreement to the well-known observation (Ma & Dressendorfer, 1989) that irradiation creates a net trapped positive charge (Qot) into the SiO2 layer.
After irradiation of fresh and programmed (+14V/1s write pulse) MOS capacitors, the net positive trapped charge was calculated according to the relation: Qot = -ΔVfb • Cox where ΔVfb is the flat-band voltage shift induced by irradiation. The Qot vs. radiation-dose data shown in Fig. 20 indicate the following:
Values of the B parameter related to F-N conduction in (a) reference MOS and (b) NC MOS capacitors after irradiation. The dashed lines correspond to the values observed before irradiation.
Values of the B parameter related to F-N conduction in reference MOS (a) and NC MOS capacitors (B) after irradiation. The dashed lines correspond to the values observed before irradiation.
In all cases, Qot is well below the number of the created electron-hole pairs, thus indicating that only a relatively small number of holes survive the initial fast recombination process i.e. the radiation yeld is far smaller than unity (Fig. 20b). The number of electron-hole pairs created by irradiation was evaluated as the ratio of the energy lost by the incident protons into the SiO2 layer (obtained through TRIM simulations) to the 17eV electron-hole pair generation energy (Ma & Dressendorfer, 1989) in silicon dioxide.
Programmed NC-MOS capacitors, exhibit increased (~ 2 times) Qot values compared to capacitors with uncharged NCs. This is attributed to the internal electric field generated by the charged NCs that reduces the hole recombination probability (Ma & Dressendorfer, 1989).
The amount of trapped charges in irradiated un-programmed NC MOS capacitors was found to be almost one order of magnitude higher than in the reference MOS samples. This can be related to the extra trapping sites located in the injection and control oxide in the form of excess silicon atoms left behind by the ULE-IBS technique.
In all cases Qot shows saturation for high irradiation doses (Fig. 20a).
All the programmed NC MOS capacitors undergo a bit flip 1→0 following irradiation, (Fig. 21b), in agreement with Petkov (Petkov et al., 2004) where bit flip were observed at 150krad.
Flat-band voltage after irradiation for a) fresh NC MOS capacitors and b) programmed “1” NC MOS capacitors.
Fig. 21a indicates that under irradiation the induced positive oxide trapped charge results in a shift of the C-V characteristics by 2V (the overall memory window is about 2.9V). If the oxide trapped charge is not removed from the oxide a permanent shift of the memory window would result, causing serious problems in reading the memory state. It was found that our devices could be restored to their initial memory window by tunnel annealing i.e. by electric field stressing (Ma & Dressendorfer, 1989). The memory behavior of 1.5MeV irradiated NC MOS capacitors was examined by symmetrical sweep C-V measurements of increasing width (2→-2→2, 8→-8→8,etc.) and under pulse operating conditions (see Fig. 22a). The initial, dose dependent, radiation induced shift disappears gradually by increasing the voltage sweep. Therefore, the memory window of irradiated devices approaches the memory window of the unirradiated devices, as also reported by Petkov (Petkov et al., 2004). In particular it was found that the radiation induced oxide charge can be removed with 1 write or erase pulse as shown in Fig. 22b.
For what concerns the NC MOSFETs similar results with the one presented above holds. As found for the NC MOS capacitors, the radiation induced oxide charge can be easily removed by electric field stressing (for example 1 write or erase pulse). No bit flip has been observed on charged (write state) devices as shown in Fig. 23. Comparing the VFB shifts observed for the programmed NC MOS capacitors with the Vth shifts for programmed NC nMOS transistors it can be concluded that for the latter devices the effect of radiation induced positive charge trapped into the gate oxide is reduced. It is believed that this effect can be ascribed to the smaller thickness of control and tunneling oxides in the transistor case i.e. to
a) Memory behavior after application of positive and negative pulses (heights from 2V to 20V, 1s duration) on irradiated NC MOS capacitors at 1.5MeV. The initial flat-band voltage differences disappear as higher gate pulses are applied, indicating the removal of the radiation induced positive oxide charge. b) Flat-band voltage evolution during 1s +14V/-16V write/erase cycles on irradiated NC MOS capacitors. The 0 cycle represent the after irradiation flat-band voltage. Differences between the flat-band voltage values of unirradiated and irradiated devices are not observed after the very first write or erase pulse, indicating the immediate removal of the radiation induced positive oxide charge.
Threshold voltage measured after irradiation for charged (write) transistors.
the fact that a larger percentage of oxide volume is at tunneling distance from the gate or substrate and thus a smaller volume is left for the radiation induced Qot (Ma & Dressendorfer, 1989).
The above result indicate that the read failure of irradiated NC transistor cells may appear only at doses above 1-10 Mrad(SiO2), thus more than 10 times higher than in FG cells.
The charge retention time of the NC non-volatile memory devices is a characteristic of critical importance. What is required is that the write and erase states remain clearly distinguished after a 10 yrs retention period. Charge retention was here measured through a waiting time of 12h after placing the devices in full write or erase state conditions. In Fig. 24a is presented the overall evolution of the memory window with time, while in Fig. 24b and\n\t\t\t\t\t\tFig. 24d are shown the extracted flat-band voltage decay rates, dVfb/dLog(t).
Charge loss rate for the write state is strongly dependent on the irradiation dose while for the erase state no such dependence is observed. It was found that the write state flat-band voltage decay rate depends on irradiation dose as Dose2/3, (see Fig. 24b); the same dose
a) Memory window evolution with time for 1.5MeV protons irradiated NC MOS capacitors. Memory window for unirradiated devices is also indicated. The dashed line is the Vfb of fresh unirradiated devices. These results applies also for 6.5MeV irradiations. b) Flat-band voltage decay rates for write state(1s, +14V) vs dose for irradiated NC MOS capacitors with 1.5MeV and 6.5MeV proton energies. The electron loss rate follows the relationship Dose2/3, the same valid for Dit. c) Flat-band voltage decay rates for write state (1s, +14V) are plotted vs Dit and comparison with the relationship dVfb/dLog(t)=const*Dit is also shown to demonstrate the linear correlation found between electron loss rate and Dit. d) Flat-band voltage decay rates for erase state (1s, -16V) vs dose for 1.5MeV and 6.5MeV proton energies. A small increase in the loss rate is observed but not clear is the dependence with dose.
dependence that applies for Dit. This strongly suggests that the loss rate of stored electrons is directly related to the damage induced by irradiation at the Si-substrate/SiO2 interface (Fig. 24c) as it was initially postulated by Shi (Shi et al., 1998). Previous measurements of electron loss at high temperatures revealed that the long-term retention of the present devices is due to the electron storage in NC traps (Dimitrakis & Normand, 2005).
Regarding the erase state (hole storage), the measured flat-band voltage decay rates show a small increase with respect to those of non-irradiated samples and unlike electrons they do not exhibit any clear dependence on dose. These results indicate that the discharging of “0” programmed NC MOS devices is indeed through defects located in the Si-rich injection oxide.
Compared to unirradiated NC devices, the reduction in the extrapolated memory window at 10-yrs of irradiated NC devices does not exceed ~20% (worst case of samples irradiated with 120Mrad(SiO2)) being ~15% the charge lost by unirradiated devices while for irradiated ones it raises to ~35%.
Concerning the transistors, once again similar results with those presented for the capacitors have been found. Memory window as a function of the waiting time is shown in Fig. 25. It is clear that even in the worst case of NC MOS transistors irradiated with 75Mrad(SiO2), long time charge storage behavior is still observed. The 10-yrs extrapolated values show that the charge lost is ~74% after irradiation at 75Mrad(SiO2) with ~17% more charge lost respect to the unirradiated devices.
It should be remarked that both capacitors and transistor structures irradiated with doses up to ~100 Mrad(SiO2) do not show failure of the retention characteristic. This means that retention failure in NC NVM cells may appear only at doses higher than 100 Mrad(SiO2), thus more than 10 times higher than in FG cells.
Memory window evolution for unirradiated and irradiated at the highest dose NC MOS transistors. Extrapolations at 10 years shows that irradiated devices lost 40% of reference window.
Another important specification for non-volatile memories relate to the ability to endure repeated write/erase cycles. Endurance measurements, shown in Fig. 26, were carried out through a 15ms +9V/-9V write/erase pulse regime on all irradiated transistors. Neither degradation, nor drift in the memory window has been observed for all irradiated devices.
Memory window evolution for unirradiated and irradiated at the highest dose NC MOS transistors. Extrapolations at 10 years shows that irradiated devices lost 40% of reference window.
In this chapter Si nanocrystal non-volatile memory devices were presented and characterized electrically. Memory windows as large as 3-4V have been shown with excellent retention and endurance characteristics. The above devices, in capacitor and transistor configuration, have been used in irradiation experiments with high energy protons and high fluencies showing superior radiation hardness, more than 10 times, respect to standard floating gate memories. It was found that transistor memory cells lose their information only above 108 rad(SiO2) which is outstanding. Furthermore, electron retention is affected by radiation and in particular has been identified a clear relationship between electron loss rate and density of interface states, driving to the conclusion that the Si NC NVMs considered in this work loose stored electrons by tunneling through the interface states. Hole’s loss rate doesn\'t seem to be affected by the radiation. Endurance to w/e cycles remains unaltered after irradiation.
The authors would like to acknowledge the European Space Agency for financial support. We would like also to thank the collaborators who contributed to this research: Dr. P. Normand, Dr. P. Dimitrakis, Prof. M. Kokkoris and Mr. I. Anastasiadis.
Acute ischemic stroke (AIS) remains the second cause of death worldwide [1], despite showing a mortality rate reduction of 1.19% [2]; only in 2017, there were 6 million 167, 291 deaths; 1, 291,000 more with respect to 1997. During the same period, the survival rate increased by 0.02%; this caused an increment in the disability-adjusted life years percentage (DALYs), which went from 4.17 to 5.29% [2].
\nData from the World Health Organization (WHO) indicate that stroke represents the third cause of permanent adult disability worldwide [3], and is present in 90% of survivors. Motor deficits after stroke account for the high rates of long-lasting disability. The most common impairments are related to speech, or language and communication disorders (aphasia and dysphasia), apraxia [4], swallowing, depression, cognitive impairment, and hemiparesis of the contralateral limb [5] characterized by muscle weakness or spasticity in distal rather than proximal muscles [6]. These deficits ultimately cause chronic disability, affecting the ability to work and the patient’s independence and autonomy for performing daily life activities such as dressing or eating, ensuring they will require long-lasting care, which also deteriorates their quality of life and that of the patients’ caregivers.
\nStroke complications represent a considerable economic burden both individually and as a society; such complications are associated with a substantial increase in household expenses related to a higher requirement of medical attention, medication, lost workdays, and payment to external or additional caregivers, and in several cases, physical rehabilitation. It is estimated that the United States alone had an annual expenditure of 45.5 billion dollars during the 2014–2015 period, which is only expected to increase through 2035, according to estimations of RTI international [7].
\nIt is therefore fundamental to revisit the procedures regarding basic and clinical research points of view, as well as the most recent recommendations issued by the American Heart Association/American Stroke Association (AHA/ASA), which endorse multiple-component quality improvement initiatives including emergency department education and multidisciplinary teams with neurological management experience, thus increasing the application of fibrinolytic treatment IV.
\nThe strategies that are currently being studied in search of treatments for cerebral ischemia can be categorized into four areas: clinical care, neuroprotection, neurorestoration strategies, and rehabilitation therapy.
\nThe term neuroprotection is defined as the intentional intervention, either inhibition or modulation, that takes place at a certain point during the ischemic cascade, to intervene in a specific mechanism of damage to prevent tissue injury from increasing during the acute phase of ischemia [8]. The neurorestoration is developed through the stimulation of neurogenesis and neuroplasticity to restore the tissue and functional integrity of the neural tissue.
\nIn the clinical setting, several recanalization strategies have been explored to restore blood flow to the injured area of tissue as soon as possible, to assure the lesser damage and decrease secondary sequelae to the original lesion. Finally, physical therapy has become a rehabilitation tactic that has positively impacted the recovery of patients’ independence, autonomy, and quality of life, which is worth reviewing.
\nCerebral ischemia is caused by an abrupt and sustained occlusion of blood flow to a large artery that unties a series of biochemical alterations that are known as the ischemic cascade, Figure 1 [9]; during the development of such changes, a set of mechanisms that lead to cell death occurs: ionic imbalance and excitotoxicity, oxidative stress, and inflammation [10].
\nKey points to the pathophysiology of stroke.
The reduction of blood flow leads to a depletion in levels of glucose and O2, which alters aerobic metabolism, increasing lactic acid accumulation. Simultaneously, astrocytes use stored glycogen to provide energy to the neurons in the form of lactate [11]; but, because aerobic metabolism is interrupted at this time, lactic acid continues to accumulate, causing lactic acidosis, which causes ionic dysfunction [12]. Ionic alterations, together with Na+/K+ pump inactivity, give rise to neuronal depolarization, which leads to the opening of the Ca2+ channels and the subsequent release of excitatory neurotransmitters such as glutamate, causing increased activation of ionotropic receptors, especially NMDA, increasing the Ca2+ flux into the cell [13].
\nCa2+ is an essential protagonist within the ischemic cascade since it is capable of activating a significant amount of proteins that lead to cell death, and overproduction of free radicals; such proteins are calpains [14], endonucleases [15], calmodulin [16], and A2 phospholipase (Figure 1) [17]. Activation of these proteins leads to a further increase in free radical production and other oxidant species that directly damage structural molecules and activate inflammatory processes [18].
\nThe mitochondria are where the highest production of free radicals takes place; under normal conditions, superoxide anion (O2\n−) and hydrogen peroxide (H2O2) are produced continuously and eliminated by antioxidant enzymes such as superoxide dismutase (SOD), catalase, and glutathione peroxidase [19]. Alternatively, under ischemic conditions, reperfusion provides sufficient substrate for different enzymatic oxidation reactions to take place, causing an overproduction of free oxygen radicals (ROS) and the inactivation of antioxidant enzymes [20]. Concurrently, nitric oxide (NO) increases due to the activation of endothelial and neuronal nitric oxide synthases as a result of increased Ca2+ concentration, NO reacts with ROS and forms a highly toxic peroxynitric acid (ONOOH) [21].
\nFree radicals promote mitochondrial membrane permeability and allow for cytochrome c to be released into the cytosol, where the intrinsic pathway of apoptosis becomes activated, the concentration of free radicals also increases lipid peroxidation and protein denaturalization [22], DNA fragmentation, and activate several signaling pathways that lead to neural death, such as PI3K/AKT [23], Bcl2, p53 [24] and others. From the moment of the occlusion, endothelial cells express damage-associated molecular patterns (DAMPs), produce ROS and adhesion molecules that allow for their activation and that of surrounding mast cells and macrophages, which, as a consequence, release histamine, proteases, TNF-a, and chemokines [25]. The production and release of these molecules promote the blood-brain barrier (BBB) rupturing, thus causing peripheral leukocyte invasion into the injured brain parenchyma [26].
\nMicroglial cells are then activated in the non-perfused region of the brain parenchyma [27], microglial cells acquire phagocytic characteristics and a predominantly pro-inflammatory phenotype (M1), which in turn increases the release of interleukin-6 (IL-6), interleukin 1β (IL-1β), tumor necrosis factor-alpha (TNF-α), NO molecules, and prostanoids [28]. Peripheral immune cells such as neutrophils, B lymphocytes, T lymphocytes, and NK are recruited into the injured tissue, this event is thought to contribute both beneficially by inducing the release of anti-inflammatory cytokines and growth factors, and negatively by increasing the lesion through a sustained release of proinflammatory cytokines and free radicals [29].
\nWithin the process of the ischemic cascade, three points are identified that could classify as strategic to restore neuroprotection (ionic imbalance, excitotoxicity, and inflammation); nonetheless, most neuroprotective drugs act in many of the phases of the ischemic cascade, which is why they cannot be classified into a single step of neuroprotection.
\nEarly diagnosis of stroke is a predictor for better clinical outcomes [30]; therefore, its confirmation is a pressing matter for the treatment to begin as soon as possible from the recognition of symptoms onset [31]. Currently, different strategies for acute ischemic stroke are being used in the clinical setting and are part of the AHA/ASA clinical practice guidelines [32].
\nThe differential diagnosis for stroke includes transient ischemic attacks, seizure, syncope, migraine, and brain tumors [33]. To establish a correct and timely diagnosis and to determine the best course of action, the clinician must rely on laboratory testing [34] (blood glucose is usually high, total cholesterol, LDL, HDL, AST, CPK-MB), and although the gold standard for diagnosis is a cerebral angiography, clinicians try to avoid it by choosing different methods such as imaging testing, including the first-line non-contrast CT scans, CT angiography, MRI, and MRI angiography [32, 35, 36]. In the earliest stages of acute stroke, CT scans are less useful for ischemic stroke diagnosis but can rule out hemorrhagic stroke [36]. Other clinical tests such as EKG, EEG, and the National Institutes of Health Stroke Scale (NIHSS) help establish differential diagnosis and treatment plan [35].
\nSpecific and timely reperfusion treatment is essential to determine the course of the clinical outcome and to improve survival. Once the ischemic etiology has been established, and the patient is stable, treatment should start promptly. Currently, two major therapeutic strategies are being used to treat cerebral ischemia to allow for recanalization and reperfusion. The treatment of choice will depend on time to treatment and etiology of the injury; these therapies are thrombolysis using pharmacological agents and mechanical thrombectomy [35, 37, 38, 39].
\nAt present and still after decades, the FDA only approves the use of recombinant tissue plasminogen activator (rTPA), also known as alteplase, as the sole pharmacological option for recanalization [35, 39]. Alteplase initiates local fibrinolysis when administered intravenously by hydrolyzing the peptide bond in plasminogen to form plasmin [40]. The standard IV dosage is 0.9 mg/kg for 60 min, with a 10% bolus over 1 min within 4.5 h of AIS onset [31].
\nAlthough alteplase is the only drug available for thrombolysis, most stroke sufferers do not receive this drug as treatment. There usually is a delay in recognition of the symptoms and the time window in which rTPA must be administered is from 3 to 4.5 h from onset of symptoms, and benefits diminish over time [39, 41], which is why the new AHA/ASA guidelines recommend not waiting for clinical improvement before administration [32]. Also, not all patients are eligible, since candidates must be ≤80 years of age, without diabetes or stroke history, with an NIHSS score ≤ 25, not currently taking oral anticoagulation, and without radiologic evidence of ischemic injury involving more than one-third of the MCA territory [42].
\nComplications that are associated with its use are limited: BBB integrity alterations, and hemorrhagic transformation, granting that other studies have shown it to be well tolerated by patients using warfarin or other anticoagulants [38], in controversy with the new AHA/ASA guidelines that suggest it should not be administered if the patient received heparin 24 h before [32, 35, 43]. Other drugs are also available, such as aspirin, which must be delivered within 24–48 h after stroke onset. Although the guidelines emphasize that it should not be used to replace mechanical thrombectomy or IV alteplase, aspirin continues to be the choice for secondary prophylaxis [32, 44], even when the 2018 guidelines find no benefit from its use for the treatment of an ongoing AIS [32].
\nFurthermore, the FDA approves of endovascular treatments, which are reported to have a time window of up to 8 hours from the onset of symptoms [38].
\nFor patients with large vessel occlusion, less responsive to rTPA, intra-arterial therapy is recommended, since it leads to higher recanalization rates by being able to infuse the drug directly into the occluded area or the clot itself [35, 45]. About 10% of patients with AIS fall into this category, but only a few centers can perform endovascular procedures in proper conditions [46].
\nAlso, endovascular mechanical thrombectomy using contact aspiration (CA) [47], which has been described before [48], and stent retrievers (SR), especially those of new generations [49], for clot rupturing and aspiration has shown significant benefits in large vessel occlusion [50] regarding clinical outcomes and lower complication rates [49]. Notwithstanding, CA alone, without the use of a SR, is associated with a greater need for rescue treatment, and thus, worse outcomes [51]; the SR might also increase the risk for hemorrhagic transformation and neurological deficit [52].
\nIncreased costs of endovascular treatments, as well as their complexity and need for trained personnel, cause patients to have less access to them. Therefore, exploring new pharmacological therapies should be continued.
\nIn the search to find new alternatives of neuroprotective agents, a great variety of molecules have been explored that affect one or several strategic points of the pathophysiology, and that promise good results; some are mentioned below.
\nDuring the onset of AIS, glucose and oxygen concentrations decrease, and this promotes the activation of adenosine monophosphate-activated protein kinase (AMPK). This process upregulates cellular pathways that control energy metabolism through catabolic pathways such as glycolysis and lipid oxidation to increase adenosine triphosphate (ATP) production and decrease its consumption through the inhibition of gluconeogenesis. Observations have been made regarding the fact that the activation of this enzyme for short periods increases neural survival, but its activation for extended periods will lead to cell death through apoptosis, necrosis, and autophagy [53], which is why several drugs that modulate AMPK activation have been tested recently in search for beneficial effects.
\nTo mention some, metformin has been widely studied for cerebral ischemia since it possesses pleiotropic activity and modulates AMPK activation [54]. In 2016, Zhang et al. administered 7 mg/kg of metformin intraperitoneally to C57BL/6 mice for 7 days, before middle cerebral artery occlusion (MCAO). After MCAO, the authors observed that it induced neuroprotection by reducing infarct size, through lower AMPK, results that were not observed if administered for short periods of 1–3 days before MCAO, or after the occlusion; also, these benefits were not found in the case of reperfusion [55]. Also, the neuroprotective effect of metformin was observed in a global ischemia model in rats; after administration, apoptosis decreased, and mitochondrial biogenesis was induced [56]. Other experiments have demonstrated that metformin has the potential to improve memory and learning through the increase in brain-derived neurotrophic factor (BDNF) and p7056k protein [57]. On the other hand, it has also been implicated in the reduction of IL-6, IL-1β, TNF-α, and adhesion molecule levels, as well as a decrease in neutrophil infiltration [58]. Considering these results, it is crucial to clarify how this modulation is carried out since there is some controversy about the mechanism (Table 1).
\nMain neuroprotective agents in ischemia.
\n
Atorvastatin is a statin that has pleiotropic effects, since it allows angiogenesis and synaptogenesis, increases blood flow, blunts atherosclerotic plaque formation, and provides neuroprotection in cerebral ischemia model [59] by reducing aquaporin 4 expression (AQP4) [60], thus, preventing cerebral edema and the increase of infarct size. This statin has also been reported to attenuate cognitive deficit [61] through caspase 3 inhibition and avoiding neural death in the CA1 region of the hippocampus.
\nThere is also a great variety of neuroprotective drugs or molecules that act closer by modulating inflammation, through the promotion of an anti-inflammatory microglial phenotype activation; only the most representative will be mentioned below.
\nDRα1 recombinant protein linked to the MOG peptide has demonstrated the ability to decrease macrophage migration and monocyte activation through its binding to CD74, which translates to a reduction in infarct size [62]. It has also been shown that it reduces proinflammatory cytokine expression, such as IL-1β, I-17, TNF-α, and INF-ϒ, as well as lowers T lymphocyte infiltration and promotes a polarization toward an M2 phenotype macrophage activation [63].
\nCop-1 or glatiramer acetate is a copolymer formed by four amino acids (L-alanine, L-lysine, L-glutamic, and L-tyrosine) that has shown to exert neuroprotective effects by being able to reduce infarct size and improve neurological deficit [64]. Cop-1 increases the expression of IL-10, BDNF, Insulin-like growth factor-1 (IGF-1), and neurotrophin (NT-3) in the choroid plexus [65], and the cortex, which stimulates greater neurogenesis [66]. Mangin et al. and their study group obtained similar results; they reported that Cop-1 is capable of reducing COX-2, CD32, TNF-α, and IL-1β, as well as inducing greater neurogenesis and thus, reducing memory loss in mice with cerebral ischemia [67].
\nOn the other hand, food strategies have also been proposed; for example, diet-induced ketosis has demonstrated its neuroprotective effects. Xu et al. observed, in 2017, that the ketogenic diet induced a reduction in infarct size through the overexpression of transcription factors HIF-1α, pAKT, and AMPK [68]; in 2018 Stefanovic, beneficial effects of administering exogenous β-hydroxybutyrate intraperitoneally were also observed in a model of cerebral ischemia induced by endothelin-1 in rats. He reported that the ischemic penumbra cells had a diminished glucose uptake, which translated into less ROS production, astrogliosis, and neuronal death [69]. Ketone bodies or ketosis is worth further exploration since clinical trials in Alzheimer’s patients with mild cognitive decline have shown improvements in verbal memory after being treated with a ketogenic diet [73].
\nDietary administration with docosahexaenoic acid (DHA) has also proven to have anti-inflammatory and neuroprotective effects in cerebral ischemia through the reduction of proinflammatory cytokine expression, such as TNF-α, IL-1β and IL-6; even, a decrease in macrophage and microglial activation and a decrease in leukocyte infiltration to the lesion site [70]. Similar observations were made by Cai et al. who noted that macrophage, neutrophil, and T and B lymphocyte infiltration was significantly decreased, besides stimulating an anti-inflammatory macrophage (M2) activation [71]; DHA is also capable of inducing neurogenesis and angiogenesis [72], which makes it a promising molecule for future experimental research.
\nMany of the cytokines and growth factors that result from immunomodulation processes are directly involved in neurorestoration processes, the latter understood as the set of strategies that seek to reconstruct the affected neural circuits through neuroplasticity or neurogenesis [74].
\nNeurotrophins are a group of proteins that are involved in the maintenance and survival of the central nervous system [75]; this includes BDNF, NT-3, NT-4, NT-5, nerve growth factor (NGF), and IGF-1. Neurotrophins interact with two types of receptors, Trk (tyrosine kinase receptors) and the p75 receptor that belongs to the TNFR receptor family, implicated in apoptosis processes.
\nAmong the most studied neurotrophins are BDNF and NT-3; BDNF is produced by almost all brain cells and is known to participate in processes of proliferation, survival, and neuronal differentiation. Its receptors are widely distributed [76] and activate critical signaling pathways such as PLCγ, PI3K, and ERK, which ultimately lead to phosphorylation and activation of the transcription factor CREB that mediates the expression of genes that are essential for the survival and differentiation of neurons [77]. NT-3 has also been involved in the processes of cell proliferation and differentiation through the notch pathway [78], as well as participating in processes of memory and learning [76].
\nExperiments have shown that the increase of neurotrophic factors in the ischemia model is commonly related to a better functional or memory recovery and that it is usually associated with neurogenesis or neuroplasticity—as in the case of metformin, which showed an increase in BDNF expression and that induced a more significant recovery of memory and learning [57]. Also, Cop-1 was able to induce the increase of BDNF, IGF-1, and NT-3; which correlated with the increase in neurogenesis [65]; and the experiments of Luan et al. showed that patients with cerebral ischemia who presented higher levels of NGF obtained a better functional recovery at 3 months after the ischemia [79].
\nStem cell transplantation has also been linked to better neurological recovery; although clinical trials have not reported the expected results [80], basic research using stem cells has shown an increase in neurological rehabilitation and suggested mechanisms include the overexpression of BDNF and IGF-1 [81, 82], as well as immunomodulatory cytokines like IL-10, which together induce a polarization toward an anti-inflammatory M2 microglial phenotype [83].
\nIn recent years, there has been an increase in the interest of studying how the external environment has a direct effect on the structure and neuronal function, that is, on neuroplasticity [84], and that is why researchers keep studying what kind of external characteristics (specifically physical and social activity) can increase these factors and thereby obtain more significant benefits.
\nIn 2017, Chen et al. explored whether a specific type of environment stimulated the production of BDNF in rats with cerebral ischemia, and what they observed was that physical stimulation increases the expression of neurotrophic factors more than social stimulation and obtains a higher neurological recovery [85]. Mang, on the other hand, observed that the increase in BDNF after an ischemic event is determined by the type of aerobic exercise and the val66met variant of the BDNF gene [86].
\nThe effects on NT-3 have also been evaluated, and the results have been very similar; there is an increase in its levels with physical stimulation after the ischemic event and a more significant functional recovery [87]. Other proteins have also been associated with neuronal plasticity through axonal growth, such as the growth-associated protein 43 (GAP-43), which has been observed to increase when rats with cerebral ischemia undergo fastigial electrostimulation [88].
\nElectrical stimulation directly into the fastigial nucleus (FNS) has proven to be beneficial in a model of MCAO [89]. The mechanism through which FNS has shown to improve walking balance and neurological scores is due to the activation of the PKA/cAMP pathway, suppressing the expression of Rho-Kinase, and through the overexpression of GAP-43 protein [89].
\nIn this sense, experiments continue to be designed to establish the efficacy of training types and times to modulate inflammation, the production of neurotrophins, and the impact on patient mobility, as in the proposal developed by Scalzo et al. [89] that gives rise to the continued development of a well-founded physical therapy for patients with cerebral ischemia.
\nPost-stroke physical rehabilitation (PR) is of utmost importance as a non-pharmacological strategy for neuroprotection and neurorestoration but, most significantly, should be aimed at restoring and regaining motor impairment during the chronic period [90], and to promote the functional autonomy of the patient [4]. Recovery of body function assessment depends on whether the patients can perform everyday activities on their own and is measurable by several different scales such as UE-FM score for the upper extremity, and the Barthel Index for Activities for Daily Living scale [4].
\nFunctional and cognitive deficit severity is related to tissue integrity [91], and it is not clear whether recovery results from biological processes or physical rehabilitation [91, 92]. Some clinical parameters that can be observed at the bedside, such as early finger extension and shoulder abduction, can act as predictors of long-term (over 6 months) recovery after stroke [93]. Spontaneous recovery of upper and lower limbs occurs depending on the type, location, and severity of the lesion, in approximately 60–70% of cases [93] during the first 2–6 months [4, 94], period after which most people believe they have achieved maximal recovery and stop with either physical or pharmacological therapy [4, 95]. Interventions should be designed according to the stage of neurological recovery the patient is in, with the consideration that early chronicity is not a contraindication for continuing rehabilitation [4].
\nPhysical rehabilitation must start early, if possible, during the first week post-stroke [96], because there is an intensification in neuroplasticity during the early stages [91], employing different mechanisms such as the axon regeneration [88], and the higher expression of growth-promoting genes, such as GAP-43. This lesion-induced plasticity that happens during the first days post-stroke [90, 97, 98] reportedly lasts around 6 months after stroke [4, 91, 95, 97]. Also, therapy must continue after such a period, to take advantage of behavior-induced plasticity [95], which is still possible after 1 year of having had the stroke [4].
\nPR has also been proven to elicit neuroprotection and neurorestoration in other neurological disease models, such as Parkinson’s, through the upregulation of BDNF and GDNF and prevention of inflammatory response [99]. The following therapies are currently under study for neurorestorative purposes during the post-stroke chronic period:
\nEnvironmental enrichment focuses on inducing adaptation to different environments, including toys and complex tasks, to improve functional outcomes [97]. Also, this type of therapy has shown to enhance angiogenesis by increasing CD31 and VEGF [97]. Furthermore, environmental enrichment upregulates BDNF secretion, and other neurotrophic factors [85, 90].
\nWang et al. found improvements in spatial learning and memory, number of synapses, and an increase in the expression of synaptogenesis markers. GAP-43, a protein involved in neural plasticity through axonal growth, is upregulated during the first 28 days after stroke in mice exposed to environmental enrichment. Likewise, other markers involved in synaptogenesis like SYN and PSD-95 achieve better concentrations in the brains of mice treated with environmental enrichment [97].
\nFunctional electrical therapy has been used alongside other types of electrical stimulation to induce repetitive muscular contraction to mobilize certain joints [6]. Somatosensory stimulation might enhance neurorehabilitation after stroke through the stimulation of corticomotoneuronal excitability [6]. It has been proposed that this type of therapy increases muscle strength, reduces spasticity, and facilitates voluntary movements, among other motor benefits [6].
\nGuided self-rehabilitation (GSR) is a method in which the intensity of training can be increased inside the home environment. While combined with conventional rehabilitation, it has proven to be efficacious in engaging the patients in their recovery through a contract between the patient and the therapist, allowing for an increased sense of responsibility and motivation for the patients, who are required to register their progress in a diary [100]. Although not many physical therapists accept such an approach [100], positive changes have been observed after 1 year of GSR and conventional rehabilitation in ultrasound measuring of the soleus’ and medial gastrocnemius’ thickness and fascicle length, as well as clinical improvement, observed in soleus extensibility and ambulation speed [101] in chronic stroke patients.
\nConstraint-induced therapy requires constraining the non-affected limb for 90% of the waking hours, forcing the patient to use the paretic limb, inducing the increase of use-dependent plasticity, although this therapy is not practical for most of the population [6].
\nVideogame- or virtual reality-based (VRb) therapies have been under study for upper extremity functional recovery in acute and subacute or chronic patients [91, 96, 99, 102]; the rationale for such approaches is that they promote motor learning and repetitive, intense movements, and in the specific case of virtual reality, the patient is exposed to interactive visual, auditive, and proprioceptive feedback [91, 102]. Different videogame and VRb therapies have reported improvements in fine dexterity, grip strength [96], and grasp force [99] in upper extremities, and, activities of daily living [91] and cognition [102] in young and elderly patients after several weeks of rehabilitation. Better results have been observed when combined with conventional therapy, although it is still not known whether it enhances or speeds up recovery [91].
\nIn addition to continuing the search for pharmacological agents that allow the neuroprotection and neurorestoration of tissue affected by cerebral ischemia, the development of physical therapy and diet modification offers new horizons that have shown satisfactory results in the clinical setting in short times. However, it has not yet been possible to establish a protocolized treatment that can be added to the health care guidelines; so it is important to continue exploring all possible strategies to improve the quality of life of people who have suffered a cerebral infarction and that of their caregivers.
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