Displacement of GPS double frequency signals caused by first to fourth order ionospheric delay
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\\n\\nLaunching 2021
\\n\\nArtificial Intelligence, ISSN 2633-1403
\\n\\nVeterinary Medicine and Science, ISSN 2632-0517
\\n\\nBiochemistry, ISSN 2632-0983
\\n\\nBiomedical Engineering, ISSN 2631-5343
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\\n\\nPhysiology (Coming Soon)
\\n\\nDentistry (Coming Soon)
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\\n\\nNote: Edited in October 2021
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\n\nDesigned to cover fast-moving research fields in rapidly expanding areas, our Book Series feature a Topic structure allowing us to present the most relevant sub-disciplines. Book Series are headed by Series Editors, and a team of Topic Editors supported by international Editorial Board members. Topics are always open for submissions, with an Annual Volume published each calendar year.
\n\nAfter a robust peer-review process, accepted works are published quickly, thanks to Online First, ensuring research is made available to the scientific community without delay.
\n\nOur innovative Book Series format brings you:
\n\nIntechOpen Book Series will also publish a program of research-driven Thematic Edited Volumes that focus on specific areas and allow for a more in-depth overview of a particular subject.
\n\nIntechOpen Book Series will be launching regularly to offer our authors and editors exciting opportunities to publish their research Open Access. We will begin by relaunching some of our existing Book Series in this innovative book format, and will expand in 2022 into rapidly growing research fields that are driving and advancing society.
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\n\nVeterinary Medicine and Science, ISSN 2632-0517
\n\nBiochemistry, ISSN 2632-0983
\n\nBiomedical Engineering, ISSN 2631-5343
\n\nInfectious Diseases, ISSN 2631-6188
\n\nPhysiology (Coming Soon)
\n\nDentistry (Coming Soon)
\n\nWe invite you to explore our IntechOpen Book Series, find the right publishing program for you and reach your desired audience in record time.
\n\nNote: Edited in October 2021
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These one-dimensional (1D) graphene sheets rolled into a tubular form have been the target of many researchers around the world. This book concentrates on the semiconductor physics of carbon nanotubes, it brings unique insight into the phenomena encountered in the electronic structure when operating with carbon nanotubes. This book also presents to reader useful information on the fabrication and applications of these outstanding materials. The main objective of this book is to give in-depth understanding of the physics and electronic structure of carbon nanotubes. \nReaders of this book should have a strong background on physical electronics and semiconductor device physics. This book first discusses fabrication techniques followed by an analysis on the physical properties of carbon nanotubes, including density of states and electronic structures. Ultimately, the book pursues a significant amount of work in the industry applications of carbon nanotubes.",isbn:null,printIsbn:"978-953-307-499-3",pdfIsbn:"978-953-51-4483-0",doi:"10.5772/980",price:159,priceEur:175,priceUsd:205,slug:"electronic-properties-of-carbon-nanotubes",numberOfPages:698,isOpenForSubmission:!1,isInWos:1,isInBkci:!0,hash:null,bookSignature:"Jose Mauricio Marulanda",publishedDate:"July 27th 2011",coverURL:"https://cdn.intechopen.com/books/images_new/468.jpg",numberOfDownloads:117214,numberOfWosCitations:134,numberOfCrossrefCitations:46,numberOfCrossrefCitationsByBook:6,numberOfDimensionsCitations:110,numberOfDimensionsCitationsByBook:9,hasAltmetrics:1,numberOfTotalCitations:290,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"October 12th 2010",dateEndSecondStepPublish:"November 9th 2010",dateEndThirdStepPublish:"March 16th 2011",dateEndFourthStepPublish:"April 15th 2011",dateEndFifthStepPublish:"June 14th 2011",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6,7,8",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"9142",title:"Prof.",name:"Jose Mauricio",middleName:null,surname:"Marulanda",slug:"jose-mauricio-marulanda",fullName:"Jose Mauricio Marulanda",profilePictureURL:"https://mts.intechopen.com/storage/users/9142/images/1746_n.jpg",biography:"Jose Mauricio Marulanda has a Doctor of Philosophy in Electrical Engineering from Louisiana State University. 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Overall, the residual power declines with increasing frequency, and is consistent with a flicker noise distribution plus white noise at high frequencies. An in-depth understanding of the related mechanisms that cause seasonal variations is expected to separate signal from noise better in the GPS positions. Possible errors include both geophysical effects (e.g., mis-modelled tides and unmodelled non-tidal loading displacements) and technique-specific errors (e.g., long-term orbit mis-modelling and long-wavelength multipath effect). Previous researches find that geophysical models could only interpret ~40% of the seasonal power. Much of the residual seasonal power is most likely caused by unidentified GPS technique and/or analysis errors [6, 12].
Ionospheric delay is one of the main error sources in GPS positioning. At present, most GPS precise data processing only consider the first order ionospheric delay correction, which consists of more than 99.9% of the ionosphere effects and is usually removed by forming an “ionosphere-free” linear combination (LC). The remaining terms, that are the higher-order terms, however, do not cancel in the LC combination. The second order term is affected by both the ionospheric electron content and the geomagnetic field [31, 32], whereas the third order term is mainly affected by the ionospheric electron content and is much smaller in magnitude. At GPS frequencies, the fourth order and subsequent terms are negligible [32]. In recent years, higher-order ionospheric (HOI) effects, as one type of GPS technique-specific errors, have been studied on the GPS coordinates by many authors [3, 7,8,11,13,18,26]. Munekane analysed the influence of the second order ionospheric delay model [26]. Applied to regional and global networks, the model helped to furnish a quantitative explanation of the characteristics of the change of scale in the time series observed in the Japanese GPS Earth Observation Network (GEONET). Other authors have addressed the global GPS networks both with and without considerations of HOI effects. Comparisons of these solutions revealed systematic shifts in the site positions, reference frame origins, together with orbits and scale factors. They confirmed that ignoring HOI delay could lead to magnitude of centimeter-level or even larger error in positioning. It could also generate spurious diurnal, semi-annual and annual signals in the GPS coordinate time series, which might be wrongly interpreted as tidal effects or crustal movement.
To investigate the contribution of HOI terms, including the second and third order delay, to the GPS coordinate time series would do benefit to establish a more precise terrestrial reference frame and make a more reasonable interpretation of the motion characteristics of the tracking stations in the crustal monitoring network. Because of these reasons, the first and second GPS reprocessing campaign implemented by IGS analysis centre have already incorporated the second order ionospheric delay correction into the latest data processing strategy http://acc.igs.org/reprocess2.html
In this chapter, we focus on the effects of the second- and third-order ionospheric terms on the characteristics of GPS coordinate time series in terms of seasonal variations (the word “seasonal” mainly is used to represent both annual and semi-annual periods) and noise amplitudes, following the approach of previous authors concerned with coordinate-level effects [7, 8]. Although the effects of differential bending of the GPS signals due to the ionosphere propagation have been noted at the signal level, they are beyond the scope of this chapter. The ionospheric maximum years from 1999 to 2003 are selected for investigation. These years mark the peak of the previous solar cycle [16,25,28]. It permits a more complete understanding of the effects on coordinate time series and facilitates the analysis of recent GPS coordinate time series.
Firstly the modelling method of HOI correction in GPS precise data processing is investigated, and then the impact of ionopsheric delay with different orders on the GPS dual-frequency carrier signals is quantified. Based on this, the GPS data of 104 evenly distributed IGS sites are reprocessed using GAMIT. Analysis is begun by comparing the differences caused by HOI effects in terms of differences in site coordinates and velocities. Then the periodic characteristics and noise amplitudes of coordinate time series with and without HOI corrections are assessed. The evaluation of the solutions is based on the comparison of the coordinate time series characteristics of each coordinate component.
The ionospheric delay on the carrier phase that extended to the fourth order can be written as [30]:
where
where
Table 1 shows the displacement of GPS double frequency signals caused by ionospheric delay with different orders. From Table 1, we observe that the second and third order ionospheric delay must be taken into consideration in the GPS data processing so as to acquire high quality and consistency results in mm level, especially for those GPS observations during the peak of the solar cycle. The impact of the fourth order ionospheric delay is less than 0.1% of that of the third order, thus can be ignored in the GPS data processing.
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\n\t\t | \n\n\t | \n\n\t | \n
1228 | \n\tGPS(L2) | \n\t | \n | \n | \n | \n
1575 | \n\tGPS(L1) | \n\t | \n | \n | \n | \n
Displacement of GPS double frequency signals caused by first to fourth order ionospheric delay
The IERS convention 2010 recommends that the impact of HOI delay must be taken into consideration when establishing future terrestrial reference frame [30]. In order to determine the impact of HOI delay on the coordinate time series of IGS sites, a contrast experiment is set up based on the latest model recommended by IERS convention 2010 and recent published results to reprocess the GPS data of 104 evenly distributed IGS sites. In experiment A, only the first order ionospheric delay is calculated, while in experiment B, the impacts of the second and third order ionospheric delay are considered. Except for the different way in dealing with the ionospheric delay, all the other strategies are exactly the same in both runs. Figure 1 shows the spatial distribution of the IGS stations. Stations are selected from part of the ITRF sites with high geodetic quality, which satisfy the following criteria: (a) evenly distributed worldwide; (b) continuously observed for at least 3 years; (c) locations far from plate boundaries and deforming zones; (d) velocity accuracy better than 3 mm/yr. During the calculation, we use the GAMIT/GLOBK (V10.4) as our platform [9, 10].
Distribution of the selected 104 global IGS reference stations during GPS data processing. Red stars represent sites used in the noise analysis and seasonal analysis.
Users could realize HOI delay correction in GAMIT 10.4 by setting the parameters Ion model as GMAP and the Mag field as IGRF11 or DIPOLE in the control file called sestbl. At the same time, a new folder called ionex should be created under the project directory to save daily ionosphere file. After that, we have to switch on the -ion command when using sh_gamit to process the data, since the default setting is only calculate the first order ionospheric delay.
The global Vertical Total Electron Content (VTEC) data read by GAMIT are provided by the Center for Orbit Determination in Europe (CODE) ftp://cddis.gsfc.nasa.gov/pub/gps/products/ionex/yyyy/ddd/codgddd0.yyi.Z
In our data processing, several parameters are resolved simultaneously, including site coordinates, earth orientation parameters, satellite orbits, tropospheric delay and the horizontal gradient parameters [17]. The stations are given loose constraints, among which the constraints of 5cm are set to IGS core stations, and 1dm to the non-core stations [22]. Ten degree is chosen for the satellite cut-off elevation angle, and the observations are weighted with site-specific, elevation-dependent weighting based on an assessment of the post phase residuals [15, 22, 38]. Corrections have been implemented for solid earth tide, ocean tide and pole tide, among which the FES2004 model is used to calculate site displacement due to ocean tidal loading [23]. Absolute antenna phase center offsets and variations are used [35]. Vienna Mapping Function 1 (VMF1) troposphere mapping functions are used to calculate the tropospheric delay [5]. Atmospheric tidal correction and non-tidal loading corrections are not applied [22, 30]. Pressure and temperature for the a priori zenith hydrostatic delay are provided with receiver-independent exchange (RINEX) meteorological files (.m) and values from VMF1 [37]. After obtaining the weekly baseline resolutions, datum transformation is performed with GLOBK to obtain sites’ coordinate time series and velocities under the ITRF [36].
Spectral analysis can be used to investigate the frequency characteristics of coordinate time series, including the main cycle components and the periodic variations. The Lomb-Scargle periodogram method is used in this chapter. This method overcomes the shortcomings of the classical periodogram, which can only be applied to equidistant data and to search for cycles in equidistant data, and is widely used in computing the noise spectrum of GPS coordinate time series [24, 41, 44]. The basic idea of this method is to obtain an improved periodogram through the redefinition of every angular frequency by introducing a time lag
Let
where
The definition of
The GPS site velocity error tends to be overestimated approximately 4 times or even by an order of magnitude if the effect of coloured noise is ignored, thus producing incorrect geophysical interpretations [24,39,19-21]. To incorporate the effect of coloured noise, the best approach is to apply MLE to estimate the modelling parameters and the noise components simultaneously.
Considering the influence of the colored noise, daily solution observation sequence of each coordinate component can be modeled as follows [27]:
where
The coefficients
Using the MLE algorithm, the unknown amplitude
where
where
In this section, the impact of HOI delay on the variations of stations’ coordinates, velocities, and the variations of the GPS coordinate time series are investigated.
To investigate HOI effects on site coordinates, the solutions from experiment A and experiment B are compared. Considering the reliability of the limitation of the observation processing span, only sites with continuous time series having a length of more than 2.5 years are included. For sites interrupted by antenna change or earthquakes or other causes, the data span having the longest time interval for the same station is used. Figure 2 shows the global site coordinate differences resulting from the modelling of the HOI corrections. The values shown in this figure are the differences in the final coordinates that are estimated from the weekly baseline solutions using the Kalman filtering method applied in GLOBK software. A pattern of high-latitude sites shifted northwards and equatorial sites shifted southwards is observed in the horizontal components, and the former sites have smaller offsets than the latter sites, as also found by reference [31] and reference [8].
Differences in coordinates produced by HOI corrections (Top: horizontal components, bottom: Up component).
Figure 3 shows the spatial distribution of stations’ velocity and its uncertainty difference in the North, East and Up component between experiment A and B. From Figure 3, we observe that HOI delay has some impact on the long term velocity of IGS sites, but has almost no impact on its velocity uncertainty. The mid-to-low latitude stations are most affected, while those in the high-latitude region suffered small effects (except for OHIG). With respect to the Up component, the maximum velocity difference reaches up to 1mm/year for stations near the equator, e.g. GUAM in the West Pacific and KOKB in Hawaii. Compared with the Up component, the horizontal components are relatively less affected with maximum velocity difference of no more than 0.5mm/year, and can be neglected. Another interesting phenomenon is that ignoring HOI delay may lead to over-estimation of the Up component for stations in the southern hemisphere and at the same time under-estimation of stations’ vertical velocity in the northern hemisphere. Therefore, HOI delay must be considered in the high precision data processing for equatorial stations, so as to acquire more reliable vertical velocity in the application of meteorology and geodynamic studies, such as postal glacial rebound, sea level change, etc.
Velocity (left) and uncertainty (right) variation of global IGS stations caused by HOI delay correction (top: Up component, middle: East component, bottom: North component)
To investigate the impact of HOI delay on the scatter of stations’ displacement time series, the WRMS of coordinate time series of IGS sites both before and after HOI delay corrections are separately calculated. Let
where
where
From Figure 4 we can see that, most stations’ vertical WRMS decrease after HOI delay correction, accounting for 66% of the total stations. The biggest improvement gathers near the equator, for example, the HOI delay could explain 4% of the vertical WRMS at station IISC (13°N). The WRMS variation in the North component shows remarkable regional characteristics. 47% of the stations’ WRMS decreased, and most of them gathered in South Asia, with WRMS reduction between 4% to 10%, including 5 stations in China, among which the WRMS reduced by 10% for station LHAS.. Different from the Up and North components, the East component does not yield big improvement after higher order ionospheric delay correction, among which only 33% of the stations’ WRMS reduced, and most of them located in the Oceania, America and coastal areas around Asia. Besides, we also notice that the WRMS in the North component of most stations in Europe are increased by 5% to 10% after HOI delay correction. Further work is still required to determine the reason.
HOI delay induced WRMS variation (left) and variation rate (right) of global IGS stations (top: Up component, middle: East component, bottom: North component)
To study the periodic variations caused by HOI corrections, detailed study of the periodic characteristics and differences between solutions is restricted to only those sites with more than 4 years of data (not necessarily consecutive), without known offsets caused by hardware changes and without known coseismic and/or postseismic deformation signals or identifiable effects of snow covering the antenna. The selected sites are shown as red stars in Figure 1. The Lomb-Scargle periodogram method is applied to calculate the power spectral density (PSD) of the coordinate time series using CATS [42]. After obtaining the spectra files, the periodic spectra diagrams are plotted for the N, E and U components.
PSD Variations of the IISC coordinate time series
Figure 5 shows the spectra diagrams for the IISC site. Red lines represent the post-correction (IG) results and blue lines represent the pre-correction (NO) results. In this figure, periodic signals over 3.5 years are truncated to show the short-period signals clearly. For both two runs (IG and NO), there are periodic characteristics shown in the GPS coordinate time series. However, the corresponding main power spectra values are changed with different directions. The U component show a more obvious periodic characteristic than the N and E components, as its power value is approximately 5-10 times greater than those of the other two components. Additionally, signals with small periodicity (less than 0.5 year) are found in all components. In general, the main contributors to seasonal variations include gravitational excitation, thermal origin and hydrological dynamics [6, 33]. Ocean tides, solid Earth tides and atmospheric tides, which are associated with gravitational excitation, have been modified in the GPS carrier phase data processing using relatively precise theoretical models. Thus, effects of the thermal origin and hydrological dynamics may produce variations in our GPS coordinate time series. Additionally, the thermal noise of the antenna, local multipath effects and model errors such as satellite orbital models, tropospheric delay models and other technique-specific system errors can induce seasonal deformation at the sites [2,12,22,35,42].
To display the overall variations caused by HOI corrections clearly, we stack all the spectra of the selected sites for two runs by component and smoothed with a Gaussian smoother. Figure 6 shows the analysis results. Vertical dashed lines are plotted in Figure 6 to indicate harmonics of 1.0 cycle per year (cpy). We can see that no matter with or without HOI corrections, all the three components exhibit very similar behaviour, except that the E component without HOI corrections shows a different pattern. Peaks are evident at harmonics of approximately 1 cpy up to at least 6 cpy. Although the two lower frequencies appear to match the annual and semi-annual periods, it becomes progressively more apparent at the higher frequencies that harmonics of 1.0 cpy do not fit the observed peaks well. It is also evident that the power remains on the high-frequency sides of 1.0 and 2.0 cpy. Vertical dashed lines are also drawn for the harmonics of 1.04 cpy, and they fit the observed sub-seasonal spectral peaks well, especially for the relatively narrow 3rd, 4th, 5th and 6th peaks of all three components. This is a strong indication that the observed seasonal bands actually consist of 1.0 cpy, 2.0 cpy together with 1.04 cpy, which is called the GPS “draconitic” year [34]. In addition to the 1.0 cpy and 2.0 cpy harmonics (annual and semi-annual harmonics), the indications of 1.04 cpy harmonics also persist largely unchanged after HOI corrections, especially for the U component. Moreover, they are even more remarkable after corrections, especially for the 4th, 5th and 6th peaks in the N and E components. Therefore, HOI corrections may not be the main contributions to our inferred harmonic generating tone at 1.04 cpy. Ignoring these corrections can even submerge this type of harmonic.
Stacked periodograms in the N, E, and U components of coordinate time series for the selected sites. a) north, b) east, and c) up; each has been smoothed using a Gaussian smoother. Vertical dashed lines indicate harmonics of 1.0 cpy (blue) and 1.04 cpy (green).
Before corrections, the stacked results for the E component do not show a regular pattern (obvious peaks for the annual and semi-annual signals), which is unlike the other two components. After corrections, more consistent and normal variations are shown in the E component, which is also true for the high-frequency harmonics of N component. If we ignore these corrections, the result can be a spurious signal, and cause an unreasonable seasonal pattern for the E component. After HOI corrections, there are overall decreases for all seasonal amplitudes (such as annual, semi-annual, 1.04 cpy), especially for the N and E components, indicating that these corrections can weaken the noise existing in the global coordinate time series. We will examine this question more closely in the next section.
The Cartesian coordinates are also analyzed. Figure 7 show the stacked results of the Z coordinate. It is quite similar to those in the Up component.
As for
In this section, the Maximum Likelihood Estimation method (MLE) is applied to analyse the noise characteristics of the coordinate time series. In the beginning, the optimal noise model is determined. Under the optimal noise model, the effects of HOI corrections on the site noise amplitudes and seasonal signals are assessed.
Pre-correction | \n\t\tPost-correction | \n\t\tPre-correction | \n\t\tPost-correction | \n\t\tPre-correction | \n\t\tPost-correction | \n\t|
IISC(77.6,13.0) | \n\t\t-0.26 | \n\t\t-0.29 | \n\t\t-0.35 | \n\t\t-0.21 | \n\t\t-0.79 | \n\t\t-0.67 | \n\t
BRAZ(312.1,-15.9) | \n\t\t-0.55 | \n\t\t-0.49 | \n\t\t-0.20 | \n\t\t-0.39 | \n\t\t-0.34 | \n\t\t-0.34 | \n\t
BJFS(115.9,39.6) | \n\t\t-0.35 | \n\t\t-0.38 | \n\t\t-0.16 | \n\t\t-0.18 | \n\t\t-0.50 | \n\t\t-0.42 | \n\t
AUCK(174.8,-36.6) | \n\t\t-0.33 | \n\t\t-0.29 | \n\t\t-0.24 | \n\t\t-0.29 | \n\t\t-0.46 | \n\t\t-0.49 | \n\t
ZIMM(7.5,46.9) | \n\t\t-0.31 | \n\t\t-0.26 | \n\t\t-0.28 | \n\t\t-0.20 | \n\t\t-0.26 | \n\t\t-0.24 | \n\t
KERG(70.3,-49.4) | \n\t\t-0.07 | \n\t\t-0.15 | \n\t\t-0.27 | \n\t\t-0.45 | \n\t\t-0.33 | \n\t\t-0.32 | \n\t
NYA1(11.86,78.92) | \n\t\t-0.43 | \n\t\t-0.40 | \n\t\t-0.37 | \n\t\t-0.40 | \n\t\t-0.45 | \n\t\t-0.45 | \n\t
CAS1(110.5,-66.3) | \n\t\t-0.66 | \n\t\t-0.70 | \n\t\t-0.25 | \n\t\t-0.22 | \n\t\t-0.45 | \n\t\t-0.43 | \n\t
Spectral index of GPS coordinate time series. Pn, Pe and Pu represent the spectral index of the coordinate time series in the N, E and U component, respectively. The terms “pre-correction” and “post-correction” refer to the index values computed from position time series without and with HOI corrections.
The spectral index of the coordinate time series is first calculated to help determine the potential noise type. Table 2 lists the spectral index of the selected sites located in different latitudes. Here sites are selected mainly considering that they are located in low-, mid- and high-latitude areas from two hemispheres. As shown in Table 2, the noise spectral index values for the three components at all tabulated sites are between -1 and 0 whether HOI effects are considered or not. The same result holds for the other sites except that the values for a few sites range between -1 and -2. The coloured noise still exists in the coordinate time series. Therefore, it can be inferred that coloured noise is present at all the selected sites, and that HOI corrections cannot remove this kind of coloured noise.
Based on the above results and previous studies involved in noise analysis, four types of noise model are selected here to determine the optimal noise model for the global sites. The selected noise models are white noise (WN), flicker noise (FN), random walk noise (RW) and power law noise (PL). In general, the larger the MLE value, the more effective the noise model is [24, 19-21]. According to the Langbein experiment, using a significance level of 95%, we can distinguish two different noise models if the difference between the MLE values of the two models is greater than 3.0. In this chapter, the white noise model (WN) is used as the null hypothesis. We compare the other three combined models (white noise plus flicker noise (WN+FN), white noise plus random walk noise (WN+RW), and white noise plus power law noise (WN+PL)) with this hypothesis model.
MLE differences between selected models and WN for U component. Star represents WN+FN models, Triangle represents WN+RW models, Circle represents WN+PL models. (Top: NO results, bottom: IG results).
The MLE differences for different models relative to WN are shown in Figure 8 for the selected sites. Y-axis represents the difference values. The site names are shown on the x-axis. Here only the U component results are shown (similar results can also be found for N and E components). The MLE differences can be found to distinguish between different noise models. Overall, compared with the WN model, both the MLE differences for WN+FN and WN+PL are greater than 3.0, and the differences can be distinguished easily. The RW+WN noise model is not as obviously different from the WN model, and the RW noise does not make a marked difference. After HOI corrections, the MLE differences for most sites remain unchanged. According to the noise model determination method defined above, HOI corrections have little influence on the determination of the optimal noise model for global sites. Therefore, the same optimal noise model can be selected for both runs. Given the small MLE differences between WN+FN and WN+PL and the uncertainty of the WN+PL model in determining the noise components and other parameters, the WN+FN model is selected as the optimal noise model. In the following analysis, all the results are obtained under this optimal noise model.
Noise amplitudes estimated in coordinate time series plotted as a function of latitude. a) white noise, b) flicker noise: red star, post-correction results; green star, pre-correction results.
We estimate the noise amplitudes for each coordinate component of the stations for both runs. Figure 9 shows the amplitudes of white noise and flicker noise. We split them in Figure 9 to denote the noise amplitudes variations of each noise type as a function of latitude. Zero value in Figure 9 means that the maximum likelihood estimation algorithm fails to distinguish the white or flicker noise coefficients. Table 3 lists the average noise amplitudes of sites located in different latitudes.
\n\t\t\t | \n\t\t\n\t\t\t | \n\t\t\n\t\t\t | \n\t||||||||||
\n\t\t\t | \n\t\t\n\t\t\t | \n\t\t\n\t\t\t | \n\t\t\n\t\t\t | \n\t\t\n\t\t\t | \n\t\t\n\t\t\t | \n\t|||||||
\n\t\t\t | \n\t\t\n\t\t\t | \n\t\t\n\t\t\t | \n\t\t\n\t\t\t | \n\t\t\n\t\t\t | \n\t\t\n\t\t\t | \n\t\t\n\t\t\t | \n\t\t\n\t\t\t | \n\t\t\n\t\t\t | \n\t\t\n\t\t\t | \n\t\t\n\t\t\t | \n\t\t\n\t\t\t | \n\t|
-90° ~ -60° | \n\t\t1.85 | \n\t\t1.78 | \n\t\t1.99 | \n\t\t1.77 | \n\t\t4.81 | \n\t\t4.52 | \n\t\t2.33 | \n\t\t2.38 | \n\t\t2.94 | \n\t\t2.60 | \n\t\t7.29 | \n\t\t6.30 | \n\t
-60° ~ -30° | \n\t\t1.80 | \n\t\t1.86 | \n\t\t2.36 | \n\t\t2.19 | \n\t\t5.34 | \n\t\t5.27 | \n\t\t2.54 | \n\t\t2.44 | \n\t\t2.47 | \n\t\t2.74 | \n\t\t11.36 | \n\t\t8.26 | \n\t
-30° ~ 0 | \n\t\t2.38 | \n\t\t2.13 | \n\t\t3.16 | \n\t\t2.50 | \n\t\t6.20 | \n\t\t5.86 | \n\t\t3.30 | \n\t\t3.13 | \n\t\t3.00 | \n\t\t5.23 | \n\t\t11.24 | \n\t\t11.11 | \n\t
0 ~ 30° | \n\t\t2.51 | \n\t\t2.22 | \n\t\t3.73 | \n\t\t2.98 | \n\t\t7.30 | \n\t\t6.42 | \n\t\t3.49 | \n\t\t3.31 | \n\t\t3.99 | \n\t\t4.30 | \n\t\t9.55 | \n\t\t9.89 | \n\t
30° ~ 60° | \n\t\t1.57 | \n\t\t1.53 | \n\t\t2.42 | \n\t\t1.87 | \n\t\t5.62 | \n\t\t5.07 | \n\t\t2.73 | \n\t\t2.36 | \n\t\t2.82 | \n\t\t2.85 | \n\t\t6.83 | \n\t\t6.22 | \n\t
60° ~ 90° | \n\t\t1.13 | \n\t\t1.48 | \n\t\t1.91 | \n\t\t1.39 | \n\t\t6.29 | \n\t\t5.34 | \n\t\t3.96 | \n\t\t3.66 | \n\t\t3.35 | \n\t\t3.41 | \n\t\t8.74 | \n\t\t8.62 | \n\t
Average noise amplitudes for sites in different latitude areas. The terms “noion” and “ion” refer to the noise amplitudes computed from position time series without and with HOI corrections.
Generally speaking, variations of the amplitudes of white noise and flicker noise are latitude dependent. The noise amplitudes decrease as the latitude increases. The WN variations are more obvious than FN. This relationship has also been found in reference [24] and [41]. After HOI corrections were applied, there is an overall decrease in noise amplitudes, whereas the dependence of the variation in noise amplitudes on latitude still remained. Although HOI corrections can produce regional shifts at given sites and larger coordinate differences on mid- and low-latitude areas (Figure 2), the principal source of latitude-related variations in noise amplitudes may not be related to these corrections. It is worth noting that the corrections as modelled are not perfect, so there could be errors in the model. For most sites, the flicker noise amplitude is greater than that of the white noise, especially in the U component. Different noise amplitudes are found in different components for the same site. For both white noise and flicker noise, the noise amplitudes of the N and E component are smaller, and the noise amplitudes of the U component are the greatest. This is consistent with the lower precision of the U component relative to the N and E components. From the above results, we conclude that HOI corrections may not improve the precision of the U component substantially.
Noise amplitudes estimated in the pre-corrected coordinate time series as a function of the noise amplitudes estimated in post-corrected time series. a) white noise, b) flicker noise.
Figure 10 further shows the variations in noise amplitudes after HOI corrections. We added “x=y” diagonal line in figure to see deviations more clearly. The farther the points locate to the diagonal line, the greater the amplitudes changes are. The percentage of stations whose noise amplitudes are reduced by the HOI corrections is labelled on the plot. A comparison of the solutions from IG and NO shows that amplitudes of both WN and FN generally decrease for most sites, and the WN amplitudes decrease more remarkably after HOI corrections. For flicker noise, the amplitudes of 67.5% of the selected sites exhibit a decrease in the N component and yield the most satisfactory results. Compared with flicker noise, white noise yields a more satisfactory result for the global sites in terms of the percentage of sites with decreasing amplitudes (61.4%, 71.6% and 81.8% for N, E and U, respectively). Based on our results, HOI effects can maximallyexplain 44.02% (NICO), 91.10% (NOT1) and 49.8% (NICO) of the WN amplitude in the N, E and U components, respectively. The NICO and NOT1 sites are both located in mid-latitude areas (35°~37°N). For FN, the noise amplitudes decreased most at the same site, ANKR (39.88°N), and the summed proportions were 67.63%, 53.59% and 71.30% for the N, E and U components, respectively. For the global sites, the total noise amplitudes decreased, and HOI corrections must be considered if GPS coordinate time series are used to interpret geophysical phenomena. Moreover, noise amplitude variations caused by HOI corrections differ for sites in different areas, and the amplitudes of the sites in mid- or low- latitude regions show greater variations than those in other areas. Therefore, separate analysis and comparisons for different areas are recommended to obtain more meaningful conclusions.
Section 5.4 shows that HOI corrections can weaken the overall amplitudes of seasonal signals qualitatively. Here, we quantify the effects of these corrections on seasonal signals. To have a clear understanding of seasonal signals variations at the global sites caused by HOI corrections, the annual and semi-annual amplitudes are estimated under the relatively optimal noise type (WN+FN) using MLE. The 1.04 cpy harmonics is not estimated considering that these anomalous seasonal signals lead to the errors of annual amplitudes’ great increase. Figure 11 shows the annual and semi-annual amplitudes estimated in the GPS coordinate time series both with and without HOI corrections. We also added “x=y” diagonal line in this figure as Figure 10. In general, the annual amplitudes decreased in height, but this trend cannot be generalised. For certain stations, the annual amplitudes even increased. HOI corrections are effective for approximately one-half of the GPS sites in the horizontal components. Also note that the semi-annual amplitudes of the sites are much more strongly affected by the corrections. It is probable that there is a good match between the seasonal amplitudes and the HOI corrections or that the observed variations are related to HOI effects. This finding is especially important to ensure a reliable interpretation of the non-linear variations in the station position time series. However, these results (Figure 11), as well as the noise amplitudes variations in Figure 9-10, show that HOI effects explain the data from the studied sites partially, especially in the height component, in terms of seasonal amplitudes’ variations for the global sites. The discrepancy could be due to loading model deficiencies or other systematic errors involving particular techniques, such as the thermal expansion and troposphere models.
Seasonal amplitudes estimated in the pre-corrected coordinate time series, plotted as a function of the seasonal amplitudes of the post-corrected time series. a) annual signal, b) semi-annual signal. The percentage of stations whose seasonal amplitudes was reduced by the HOI corrections is shown on the plot.
In this chapter, the modelling method of the HOI delay correction is analysed and the magnitude of ionospheric delay with different orders on the GPS dual frequency carrier phase signals is determined. By reprocessing GPS data of evenly distributed IGS sites, the contribution of HOI delay to the global GPS coordinate time series is investigated. Our results indicate an overall improvement based on an analysis of the global sites. The following conclusions have been drawn:
HOI corrections can lead to big velocity variations of global IGS stations, among which the vertical velocity reaches up to 1mm/year for stations near the equator. Ignoring HOI delay correction will lead to over-estimation in the Up component of sites in the southern hemisphere and under-estimation also in the Up component of sites in the northern hemisphere.
The WRMS of coordinate time series in the Up component of stations near the equator and in the North component of stations in South Asia can be remarkably reduced if HOI delay correction is considered. Station LHAS in China exhibits the biggest improvement, and the WRMS in the North component reduced by 10%.
Whether or not HOI corrections are considered, the noise spectral index always ranges between -1 and 0, and HOI corrections have a negligible influence on the determination of the optimal noise model for our selected four noise types. In terms of noise amplitudes, although HOI corrections can produce regional coordinate shifts at given sites, noise amplitude variations related to latitude are still present. The principal source of the latitude-related variations in noise amplitudes may not be related to these corrections, and that HOI corrections may not substantially improve the precision of the U component. At most sites, the amplitudes of both white noise and flicker noise decrease as a result of the corrections, while the white noise amplitude showing a more remarkable change. The U component of the white noise amplitude decrease at 81.8% of all the selected sites as a result of the corrections, and the N component of the flicker noise amplitude decrease at 67.5% of all the selected sites. To obtain more meaningful conclusions, a separate analysis and comparison for different areas is still recommended.
The results of an analysis of stacked periodograms show that a common fundamental of 1.04 cpy, together with the expected annual and semi-annual signals, satisfactorily explaines all the observed peaks. HOI corrections may not represent the primary contribution to our inferred harmonic generating tone at 1.04 cpy. Nonetheless, there is a good match between the seasonal amplitudes and the HOI corrections, and the observed variation in the coordinate time series is related to HOI effects. HOI delays partially explain the seasonal amplitudes in the coordinate time series, especially for the U component. The annual amplitudes for all components are decreased for over one-half of the selected IGS sites. Additionally, the semi-annual amplitudes for the sites are much more strongly affected by the corrections.
The effects of HOI corrections on GPS coordinate time series further show that the application of HOI corrections should become a standard part for precise GPS data analysis. It is worth noting that more accurate correction models still need to be investigated. When contemplating routine inclusion of the higher-order corrections, one should consider generalizing these corrections by using a more accurate model of the Earth’ magnetic field and by using a more representative ionosphere which takes into account the ray-bending errors and the actual vertical spread of ionospheric density with altitude.
We thank Petrie, E. J, R. W. King and J. Ray for their constructive advices in the analysis. We also thank IGS for providing the GPS data and MIT for providing the GAMIT/GLOBK software. This research is supported by the Changjiang Scholar Program, the National Natural Science Foundation of China (41374033 and 41304007) and the National 863 program of China (2012AA12A209).
This chapter explores, on a brain circuitry level, why patients receiving extended intranasal insulin therapy continue to be able to ambulate independently, pay attention, speak, and participate in jokes even throughout late-stage AD [1, 2, 3]. We find that extended intranasal insulin administration can preserve pragmatic functioning even when there are temporal lobe and frontal lobe volume losses consistent with Alzheimer’s brain (AD) volume loss. A series of CT scans of a patient receiving extended intranasal insulin from mild cognitive impairment (MCI) diagnosis and those from the same patient 5.5 years after AD diagnoses are examined. At baseline, this patient’s original MCI CT scans indicated no significant intracranial pathology and normal aging brain morphology. Over time, we show how this patient demonstrates slower atrophy rates in occipital and thalamic structures as compared with the structural imaging of patients with disease progression from MCI to AD not receiving intranasal insulin therapy. Enhancing neuronal activity in the areas of the brain associated with pragmatic competence reduces the likelihood of anomia typical of late-stage AD.
This chapter is structured as follows: Section 1 examines studies of the perfusion of intranasal insulin in older adults concerning neuropsychiatric tests of cognitive decline in MCI and AD. Section 2 discusses CT scans and the medical and social history of the patient case study used in this chapter. Section 3 examines CT scans at three distinctive points in the patient’s MCI to AD progression (at MCI diagnosis and 3.5 and 5.5 years receiving intranasal insulin therapy). Section 4 suggests that results demonstrating extended intranasal insulin treatment may slow disease progression by reducing some areas of neuronal atrophy in the (thalamus) cortico-pulvinar projection system associated with the anomia typical of late-stage AD.
In MCI and AD, the intranasal delivery of insulin has been found to enhance brain insulin activity either through improved glucose metabolism or reducing hypothalamic inflammation [4]. The route of intranasal insulin to the central nervous system (CNS) is via the olfactory and trigeminal neural pathways which innervate the nasal cavity and provide a direct connection to the CNS [5]. Given the short time frame (15–30 minutes) by which intranasal insulin reaches the brain, it is assumed that extracellular delivery from the nasal mucosa, instead of axonal transport, is the main transport mechanism. Glucose metabolism abnormality is thought to play a critical role in pathophysiological alterations by inducing multiple pathogenic factors such as oxidative stress, mitochondrial dysfunction, glycolysis, and Krebs citric acid cycle [6]. By pharmacologically restoring disrupted brain insulin signaling that ensues from glucose insufficiency [7], intranasal insulin is thought to promote neurol survival.1
Recent studies of the perfusion of intranasal insulin into the regional areas of the brain cortex demonstrate two main regional cortical areas of penetration. Akintola et al. [10] found that, in older adults, intranasal administration of insulin significantly increased perfusion through the occipital gray matter by 6.5% (P = 0.001) when compared to the administration of placebo as well as perfusion into the thalamus (P = 0.003). Perfusion through the parietal gray matter was also increased by 4.3% after administration (P = 0.034) in older adults.
According to the authors, increased perfusion strongly suggests that intranasal insulin therapy might restore energy demand and neuronal activity in these regions. They note:
We observed that intranasal insulin application increased perfusion of the thalamus. The thalamus receives information from almost all sensory systems and relays the information to associated cortical areas. From literature, increased cerebral blood flow has been linked to vasodilatation around the active area due to increased energy demand [11]. Also, insulin has been shown to be a vasoactive modulator that regulates peripheral and cerebral blood flow possibly via a direct vasodilatory effect [12]. Taken together, our finding of increased perfusion in some brain areas would support the hypothesis that intranasal insulin application might restore energy demand and neuronal activity in these regions [4, 10].
The thalamus is a central mechanism in understanding and formulating language [13]. It passes information from one cortical area involved in language generation to another, including semantic feature binding and the generation of lexical items [14]. Pragmatics, in particular, relies on both the left and the right hemispheres, and the thalamus mediates from the superior temporal cortex and posterior parietal cortex, or the “language eloquent cortex” in humans [15, 16].
The thalamus is also relevant to “cognition,” which includes the capacity to pay attention and to process multiple channels of information at once, i.e., to engage in “intentionally guided attention” or “engagement in action” [17]. An explicit mechanistic model has even been developed for thalamic stimulation effects on language and cognition that incorporate modern activation and connectivity data called the “specific alerting response” (SAR). The SAR effect involves secondary switching in the striatum caused by the activation of thalamostriatal projections, whereas the “anomia effect” implicates the disruption of the cortical synchronization action of the pulvinar via the cortico-pulvinar-cortical projection system [18].2 In this SAR model, the retained ability to speak (an “anti-anomic” effect) depends upon the preservation of nuclei within the thalamus to regulate the transmission of information to the cortex and between cortical areas [21]. As such, the thalamus acts as a “selective engagement mechanism” which suppresses right frontal cortical activity, preventing it from interfering with language [17]. As Crosson [22] notes:
In Alzheimer’s disease, it is well recognized that the thalamus is essential for generating attention [23], and its anterior and medial nuclei are involved in declarative memory functioning [24]. Anatomic evidence from AD patients shows that thalamic volume reduction in Alzheimer’s disease has been related not only to anomia but also to global cognitive decline in all of these areas: motor behavior, emotional, motivational, associative, and cognitive abilities [25]. Nevertheless, until de Jong et al. [26], the direct correlation between measurements of decreasing thalamic volume and cognitive functioning in Alzheimer’s disease had never been reported in the literature.
Intranasal administration of insulin also significantly increased perfusion through the occipital and parietal gray matter in older adults [10]. The occipital lobe is the visual processing center of the mammalian brain containing most of the anatomical region of the primary visual cortex. It also contains the ventral stream of vision that enables ability to focus on motor actions in response to outside stimuli. The parietal lobe is a source of speech and reading. Next to the occipital lobe, the parietal lobe integrates sensory information among various modalities, including proprioception, mechanoreception, and visuospatial processing. The posterior parietal cortex, also referred to as the dorsal stream of vision, receives somatosensory and/or visual input that can be transmitted to motor signals [27].
In MCI and AD, impairments in the dorsal stream of visual perception and processing have been found to be a predictor of AD [28]. Increasing impairment in visuospatial skills, visual object processing, and visual recognition of human emotion processing are common on test scores of AD patients as part of annual cognitive deterioration [29, 30, 31]. Previous studies of MCI and AD patients receiving extended intranasal insulin have demonstrated unusual patterns of relatively limited annual cognitive declines as measured by several years of neuropsychiatric batteries. This was the case in tests covering visuospatial skills and executive function and inference tests which required simultaneous attention and the processing of multiple sources of information in parallel such as the VOSP Number Location, Pentagons, Modified Rey, CATS-Fact, and Affect Matching tests [2]. Furthermore, the short-term administration of intranasal insulin (21 days) has been found to significantly improve response inhibition on discordant items of an executive function-attention test (the Stroop test) [32, 33]. In addition, visuospatial function was significantly improved in performance on the Benton Visual Retention Test (BVRT) after 40 IU of insulin detemir, regardless of apoe4 status [32, 34].
Observational data on one patient receiving extended intranasal insulin therapy showed that even 5.5 years after AD diagnosis, he was still able to walk independently, pay attention to his physical surroundings, process visual information, and make verbal inferences [2]. Another patient who began intranasal insulin at MCI/mild dementia diagnosis after having lost the ability to manage his finances, shop, or independently go to doctor’s visits returned to being able to do all of these tasks and even to going skiing after 3 years on treatment.
Computed tomography (CT) is a structural medical imaging method that employs computer-based tomographic reconstruction to delineate bodily structures based on their ability to block X-ray beams. CT images are used to identify structural abnormalities, such as space-occupying lesions or intracranial neoplasms, although CT images are less fine in detail than newer structural imaging technologies [35].
The key CT structural markers of disease development in the progression from MCI to AD include atrophy rate measurements in the hippocampus and medial temporal lobe (the inner part of the temporal lobe, near the divide between the left and right hemispheres) [36]. In addition, ventricular enlargement of portions of the lateral ventricles adjacent to the medial temporal lobe (MTL) is also a sensitive marker of the transition from MCI to AD [37, 38, 39]. Thus, in the disease progression from MCI to AD, hypometabolism in glucose uptake leads to increased atrophy rates of lateral ventricles adjacent to the MTL and to a reduction of hippocampal volume and then to the temporal neocortex. Finally, the disease progresses into adjoining association and primary sensory areas [40, 41].
The medial temporal lobe in particular is thought to be involved in declarative and episodic memory. Deep inside the medial temporal lobe is the region of the brain which includes the hippocampus, the amygdala, the cingulate gyrus, the thalamus, the hypothalamus, the epithalamus, the mammillary body, and other organs, many of which are of particular relevance to the processing of memory. Studies of single-dose intranasal insulin demonstrate that intranasal does reach the hypothalamus but these results did not reach statistically significant levels ([10]:793). Other single-dose studies of intranasal insulin to diabetics showed acutely increased resting-state functional connectivity between the hippocampal regions and multiple regions within the DMN, i.e., the medial frontal cortex; the medial, lateral, and inferior parietal cortex (IPC); and anterior (ACC) and posterior cingulate cortex (PCC). These are brain regions directly linked to interactive higher cognitive functions [42]3 including language. The uncus,4 an anterior extremity of the parahippocampal gyrus, a deep structure within the limbic system of the MTL, is of central importance in protecting/rescuing hippocampal neurons from amyloid-induced neurotoxicity [43, 45, 46].
Conversely, patients on extended intranasal insulin should demonstrate slower rates of atrophy as the insulin restores energy demand and neuronal activity in occipital and parietal gray matter regions and the thalamus [10]. CT scans over the AD disease course of a patient receiving extended intranasal insulin can be hypothesized to illustrate patterns closer to “normal aging” of MCI even 5–6 years after AD diagnosis (see also Additional materials). Thus, it can be hypothesized that AD patients receiving extended intranasal insulin therapy may demonstrate slower atrophy rates in occipital and thalamic structures than MCI to AD patients not receiving this therapy.
A series of three CT scans were conducted on patient “AR” between May 2012 and April 2018. AR was between the ages of 82 and 88 during this time and was being treated by a Kaiser Permanente Neurologist who diagnosed him with Alzheimer’s disease in December 2012 after a May 2012 diagnosis of mild cognitive impairment. The patient was moved out of state in September 2017 when his 82-year-old girlfriend developed Parkinson’s disease. He subsequently lived near his daughter in an Alzheimer facility and was seen by a qualified university neurologist until his death in December 2018.
The patient initially became involved in the compassionate use of twice-daily intranasal insulin for the purposes of reducing cognitive decline in June 2013. This treatment was administered by nurses who also gave him his daily medications and reminded the patient to conduct daily or weekly hygiene (bathing, tooth brushing, correct dressing). The patient ate independently or with minor assistance throughout the course until the final months of his life when he needed assistance with cutting up his food (8/18–12/18). During the years of 2012–2017, AR was still able to live in his home with his 80-year-old girlfriend who cooked, shopped, and drove him to their social activities, and his financial and medical management was done by his daughter [2]. While residing in his Alzheimer residence facility (11/17–12/18), AR was still ambulatory, fed himself, ate with the early AD patients at the dining room, and was highly conversational even at this stage of disease progression [3].
AR’s medical history at MCI diagnosis was (5/12) OSA, diverticulosis, tinnitus, lumbar stenosis, and BPH. His medications were memantine, donepezil, tamsulosin, multivitamin, and intranasal insulin (at 6/13). At 10/16, the same medications, all blood work normal.5 At 4/18, the same medications, all blood work normal. At 4/18, 5.5 years after his original AD diagnosis and at age 88, his doctor stated to AR’s daughter that the patient was still “very functional with good language skills” and, to the doctor’s surprise, still possessed “the body of a 70-year-old” [3].
AR was diagnosed with MCI in May 2012 based on a Slums test score (24/30) and a mild cognitive impairment AD8 score = 0/8. His neurologists stated: “The patient came in because he had begun to not remember essential tasks, lost his keys and had begun to become disoriented at times. For example, he could not remember the proper freeway exit for the airport or where he was on the freeway despite having driven to that airport on that same route for over 40 years. Patient himself feels memory not so good. He was also beginning to forget the names of plants at the botanical gardens which he once knew he could. His girlfriend thinks his memory issue may be out of the ordinary in forgetting day to day conversations [47].”
CT scans were ordered due to this “altered level of consciousness.” The initial CT findings of AR’s neurologist at this time stated there was “no significant intracranial pathology” with “normal aging brain morphology.” All other CT findings were also “normal,” i.e., “intact (calvarium, central skull base, temporal mastoids: adequate; cellular, non-sclerotic, paranasal sinuses: well aerated; brain showed no acute intracranial bleed, large vessel territory infarct, or mass effect) (CT Results 5/12).”6 B-12 and TSH levels were also in normal limits (5/12). Indeed, the overall assessment of AR’s 5/12 CT scan was summarized succinctly as “changes of aging brain.”
In terms of his memory loss, however, the neurologist’s findings were more uncertain. He noted: “Robust looking man. Gait brisk, very cordial and engaging and gives detailed history but when asked his profession, he seemed to have to think awhile before he recalled he was a science teacher.” Clearly AR’s neurologist detected something was amiss when he stated: “While patient score is in the mild cognitive impairment range, and while he is very intellectually active: plays bridge, studies German, goes folk dancing still I think he should be scoring higher than he does. While I cannot make a diagnosis of Alzheimer’s now, I think we need to follow up in 6 months and see how it goes [47].”
Nevertheless, CT at 5/12
In AR’s case such ventricle enlargement was, in fact, a sensitive measure of disease progression. Six months later in his follow-up visit (12/18), AR’s Slums score had dropped by 4 points to 20/30, and his AD8 score increased by 1 point to 1/8. Even more disease progression was evident in cognitive measures of his short-term memory: AR scored 4/8 in story recall and had a 0/5 recall of objects 5 minutes later [47]. At this point in time, December 2012, AR’s neurologist diagnosed him with early AD. He noted: “Impression and plan: It is now clear that this is early Alzheimer’s. Will begin Aricept. Gave information on Alzheimer’s disease and referral number of our incredibly skilled and compassionate memory clinical social worker. Follow up on 3–4 months [47].”
AR, in conjunction with his family, made the decision to begin intranasal insulin therapy in June 2013, 6 months after his 12/12 AD diagnosis. At this point, his MMSE score was 24 (3/13), and his word recall after 10 minutes was 0/9 (3/13) [2]. The patient’s functional abilities had also markedly deteriorated from a year previous at his 5/12 MCI diagnosis. AR could no longer manage his finances or his medical treatments and could no longer drive. His family also noticed the development of significant social and linguistic withdrawal, irritability, and flattened affect ([1]:331–333). For example, AR expressed very little positive emotion upon seeing his daughter and granddaughter at the airport after a 6-month separation. Furthermore, he was unable to participate in conversations or even access anything about himself such as how he was feeling, often remaining silent for extended periods of time, and withdrawing from social engagement ([1]:331–333).
The patient’s family began compassionate use of intranasal therapy (6/13) at twice daily for AR (20 IU per dose). Over the subsequent 6–8 months of treatment, they noticed a marked return of pragmatic functioning, an increase in social and linguistic participation (even returning to telling and understanding jokes), self-awareness, and decreased irritability ([1]:333–35). AR himself reported just 2 days after beginning therapy that his head hurt less, spontaneously holding his head with his hand and stating to his daughter: “Oh, it is like I have had a terrible headache for a long time.”
A return of meaningful linguistic interaction after intranasal insulin therapy and a stabilization of the further deterioration were also noted by other patient’s family members after several months. This stabilization was reflected in his 2014 and 2015 neuropsychological battery of tests. These cognitive tests revealed a marked slowing of annual percent decline in executive function and visuospatial scores compared with average annual declines [2, 31]. AR also was able to use and respond affectively to humor in conversations, related areas of the brain typically associated with significant deterioration in AD progression [52].
A CT scan was taken on AR in October 2016, just over 3 years after the patient began receiving intranasal therapy (Figure 1a and b). Again, the overall neurologist’s impression was “age-related volume loss.” The record reads:
(a) and (b): CT scans of patient AR, 10/16.
Comparison: “Comparison is made with 05/17/2012. There is no evidence of intracranial hemorrhage, mass, mass effect, large infarct or midline shift. Prominence of the ventricles and sulci are noted, likely age-related volume loss. Scattered periventricular white matter hypodensities are noted, most commonly seen with small vessel ischemic changes. Vascular calcifications are noted. Partial opacification of the ethmoid and sphenoid sinuses noted. Bones are unremarkable. Impression: No evidence of acute intracranial process.
This diagnosis of “age-related volume loss” after 3 years receiving intranasal insulin suggests some positive effects of extended therapy. AR’s neurologist noted in his 10/16 comments that the patient was: “alert and oriented” with “5/5 strength in all 4 extensions with full distal sensation; no saddle anesthesia; 2+ symmetric reflexes throughout and ambulates without difficulty [47].”
Figure 1a and b shows evidence of AD disease stage progress. For example, in his 10/16 notes, AR’s neurologist comments on the “prominence of the ventricles and sulci” which are more enlarged (the ventricles) and deeper (the sulci in the frontal lobe) (Figure 1a) than AR’s 5/12 MCI diagnosis CT scan (Figure 2). Furthermore, AR’s memory was very uneven; he stated that he quit smoking when he was 30 years old but did not remember his daughter who lived out of state.
CT scan of patient AR, 5/12.
Further clarification of the positive effects of intranasal insulin therapy at 3 ½ years after his AD diagnosis can be observed comparatively. Figure 3 shows a structural MRI of the typical progressive atrophy (of medial temporal lobes and hippocampus) in an older cognitively normal (CN) subject, an amnestic mild cognitive impairment (aMCI) subject, and an Alzheimer’s disease (AD) subject. In this disease progression from MCI to mild AD, the hippocampus of the subject in Figure 3 shows marked atrophy as indicated by the white arrows. Hippocampal atrophy, especially left volumes, and its contribution to memory decline in the process of Alzheimer’s disease have been often described and are widely accepted [53, 54].
Structural MRI of the typical progressive atrophy (of medial temporal lobes and hippocampus) in an older cognitively normal (CN) subject, an amnestic mild cognitive impairment (aMCI) subject, and an Alzheimer’s disease (AD) subject.
In contrast, AR’s CT scan (Figure 1a) shows a hippocampus size that is still relatively robust. As indicated by the white arrow in Figure 1a, AR’s left hippocampus is similar to that of the patient in Figure 3 at MCI disease stage. Figure 1a and b also shows significantly less overall frontal cortex atrophy, medial temporal lobe atrophy, and occipital lobe atrophy as compared with disease progression of the MCI to AD patient (Figure 3). These are significant positive effects of extended intranasal insulin as illustrated in AR’s 10/16 CT scan.
A return of meaningful linguistic interaction after intranasal insulin therapy and a stabilization of AR’s executive functioning test scores also reflect his neurologist’s overall interpretation of “age-related” (vs AD disease progression related) volume loss in his 10/16 CT scan. AR’s executive functioning capacities at year 4 after AD diagnosis include still being able to actively watch a TV series in several 45-minute episodes. In addition, on one occasion, when a scratched DVD disk caused the episode to pause, AR was able to immediately alert his daughter of the need to fix the problem. This demonstrates that AR was actively paying attention [2]. Prolonged attention span was found across patients with Phelan-McDermid syndrome after 1 year receiving intranasal insulin [55].
Another patient diagnosed with mild AD improved his executive functioning area scores (immediate recall, delayed free recall, and animal recall scores) after 8 months receiving intranasal insulin [2]. As Sperling et al. [56] note, AD causes considerable damage to the neurobiological substrate of episodic memory, the hippocampal-entorhinal complex (located in the medial temporal lobes) early in the course of the disease. After several years receiving intranasal insulin therapy, the patient continued to demonstrate capabilities in visual processing skills (occipital and parietal lobe functioning) as well as improvements in executive functioning under targeted therapy. At 3 years, he had returned to being able to ski (2019) after having lost the ability to manage his finances, shop, or independently go to doctor’s visits [2].
At year 5 ½ after AD diagnosis and at 5 years receiving intranasal insulin therapy (12/17–12/18), AR was still able to inferentially reason. He was also fully ambulatory, eating with the mild AD patients at his nursing home, and looked at books and TV while paying attention to both. His visual skills were also still intact. For example, one day AR was walking independently back to his room with his daughter and headed toward a large automatic opening and closing door to the Alzheimer wing which was being held open by a staff member. AR immediately turned to his daughter and asked: “Can we go through?” His daughter responded: “Yes.” Then AR was able to remember, proceeded to analyze contextual information and to simultaneously warn her of possible impending danger, telling her: “Hurry up. It closes fast” [3].
Figure 4 is AR’s CT scan at 5 years receiving intranasal insulin therapy (5 ½ years after AD diagnosis) (4/18). Figure 5a and b presents subcortical segmentation of MRI scans after boundary correction of a subject classified as MCI (4a) and of a subject diagnosed with probable Alzheimer’s disease (4b) [26].
CT scan of patient AR, 4/18.
(a) and (b): subcortical segmentation of MRI scans, after boundary correction, of a subject classified as MCI (a) and of a subject diagnosed with probable Alzheimer’s disease (b) (sagittal view) [
Consistent with our hypothesis that extended therapeutic usage should slow AD disease progression, AR’s 4/18 CT scans demonstrate that his occipital lobe does not show a significant shrinkage of gray matter volume (indicated by black arrow, Figure 4). Similarly, AR’s thalamus, indicated by the yellow arrow (Figure 4), is also not as atrophied in terms of volume loss as the AD patient (Figure 5b) despite his significant frontal volume loss and lateral ventricle enlargement consistent with late-stage AD [50].
AR’s retained volume in the occipital and thalamic subcortical structures supports previous findings that intranasal insulin directly reaches the occipital cortical brain regions and the thalamus in older adults [10]. These results suggest such enhanced insulin action in these brain areas can, in fact, slow AD disease progression.
Figure 6a and b demonstrates how AR clearly shows signs of advanced AD by 4/18. AR’s neurologist noted of his 4/18 CT scan:
(a) and (b): CT scans of patient AR, 4/18.
Yet, as (again) compared with probable AD (Figure 7b), AR demonstrates less overall volume loss even with respect to the medial temporal lobe. Furthermore, in AR’s case, left hippocampus atrophy is less pronounced than right (Figure 6a and b). This is also a significant finding because, as de Jong et al. [26] found in their Alzheimer’s disease group, volume reduction of the
(a) and (b): subcortical segmentation of MRI scans, after boundary correction, of a subject classified as MCI (a) and of a subject diagnosed with probable Alzheimer’s disease (b) (axial view) [
The potential of intranasal insulin to curb the development and progression of AD [57] is by avoiding decreases in cerebral glucose metabolic rate within a complex neuronal network which comprises the hypothalamus, hippocampus, thalamus, and cortical brain structures. A series of CT scan results of a patient receiving extended administered intranasal insulin usage shows delayed atrophy of key areas of the brain associated with cognitive, visual, executive, and pragmatic functioning as compared to disease progression in MCI to AD patients not receiving therapy. These findings, particularly those that demonstrate slowed atrophy of the thalamus and occipital lobe, strongly suggest that extended intranasal insulin treatment might slow disease progression by reducing some areas of neuronal atrophy in the (thalamus) cortico-pulvinar projection system [18] associated with the anomia typical of late-stage AD [58, 59]. They also highlight the importance of thalamic stimulation on language and cognition and the ability of the preservation of nuclei within the thalamus to regulate the transmission of information to the cortex and between cortical areas [21]. The reduced atrophy of the occipital lobes in this patient on extended intranasal insulin therapy is also significant because lesion studies have shown that the pulvinar is critically involved in visual perception, attention, and visually guided behavior [21], which can include directing visual attention to a cued location.
The slowing of atrophy of the thalamus is also consistent with the hypothesized medial pathway of insulin [2, 3, 60] in which the thalamus is reached via the olfactory tubercle. Future research is required to refine precisely how intranasal insulin promotes glucose utilization in these neuronal networks, i.e., through changes in hippocampal synaptic plasticity and/or by increasing synapse density and dendritic plasticity in structures that process visual input ([61]:216).
Future follow-up studies are needed to explore how intranasal insulin’s potential effectivity for reducing transition rates from amnestic MCI to AD is related to preserving those neurological structures associated with pragmatic tasking. Specifically, additional studies are required consisting of mapping out the bulk flow of intranasal insulin along the olfactory and trigeminal pathways between the nasal passages and the CNS into deeper structures within the medial temporal lobe (MTL) ([45, 62]:491). The region of the MTL showing the greatest atrophy in mild cognitive impairment is the entorhinal cortex, which is precisely part of the parahippocampal gyrus and is the same region that has been postulated by Braak and Braak [40] to be the site where AD pathology is first expressed.
Additional practical studies are necessary to understand the relationship between the olfactory system and the delivery route of intranasal insulin on such hippocampal structures within the MTL to further elucidate the potential of intranasal insulin therapy. AR’s continuing pragmatic abilities including sarcastic utterances, utilizing empathic tone and pragmatic discourse markers [3] 6 years after AD diagnosis and 5 ½ years on intranasal insulin, point toward the partial effect of intranasal insulin on deeper hippocampal brain structures. The right parahippocampal gyrus, for example, has functions beyond the contextualizing of visual background stimuli and identifying social context such as the inclusion of paralinguistic elements of verbal communication resulting in the ability to employ sarcasm [63]. As Smith [43] notes:
Many years (up to 50) before the symptoms (of AD) occur, neurofibrillary tangles start to form in neurons in the parahippocampal gyrus. At some stage, this process is exacerbated, and many projection neurons in the MTL then start to die, leading to atrophy of the lobe and to early signs of memory deficits. Once denuded of their input from the MTL, neurons in the target areas of neocortex show reduced activity, leading to slower metabolism and a fall in local blood flow. They will no longer function properly in the neural networks underlying higher cognition [64].
The findings in this chapter also illustrate, on a brain circuitry level, AR’s other continued pragmatic capacities even with late-stage AD [2, 3]. Several weeks before his death from a post-hip surgery-related heart attack, AR was still able to employ a bodily related metaphor: “I am tired. It seems like that is all I say. What a pain in the ass that is.” This statement involves the capacity to abstract and inhibit literal interpretation, both of which are associated with executive functioning tasks. Other linguistic evidence of AR’s preserved pragmatic competence even 5.5 years after his AD diagnosis include telling jokes and using humor to assert autonomy [1, 2, 3]. The capacity to detect, understand, and respond to humor deteriorates significantly in the progression of AD [65]. Scholarship on the neural basis of humor processing precisely suggests that humor engages a core network of cortical and subcortical structures, including temporo-occipito-parietal areas involved in detecting and resolving incongruity [66]. The temporo-parietal junction incorporates information from the thalamus, among other systems.
Treatment-induced improvements in neuronal activity in the thalamus and occipital and parietal lobes can bring moderate to significant improvements in communication exchanges with caregivers, thereby reducing the AD patient’s social and communicative isolation, lessen caregiver stress, and improve executive functioning. Furthermore, AR’s annual, standard blood tests did not reveal abnormalities or indicators of chronic intranasal insulin therapy leading to (further) desensitization of his brain insulin signaling [67] a concern expressed in the literature [57].7
The results contained in this paper are the first published CT scans of a patient receiving extended intranasal insulin use. Begun at early MCI diagnosis, the extended use of intranasal insulin could substantially impact sites along the olfactory pathway (hypothesized to be affected early on in AD).8 This could potentially arrest the further spread of the disease process in the involvement of the hippocampus, areas of the neocortex in the parietotemporal and frontal lobes, as well as hypothalamic inflammation linked to age and disease-related declines in insulin sensitivity [4, 46]. One patient after 8 months of intranasal insulin was administered a series of pre- and post-therapy neuropsychological tests, including visuospatial skills, visual spatial ability, visual working memory, and executive functioning after beginning intranasal insulin [2]. Eight months later, his neurologist concluded that: “There was about a two-year reversal of cognitive impairment while receiving intranasal insulin, going from mild dementia to mild cognitive impairment [3].” A return to MCI from early AD is a significant therapeutic achievement that deserves further application and investigation.
Several previous studies on 153 MCI and AD patients involved in the short- (4 months) and medium-term (12 months) administration of intranasal insulin using the ViaNase device to deliver the drug confirm the findings of the preservation of
The finding in this chapter of the reduction of caregiver stress after the longer-term administration (3 plus years) of intranasal insulin is also evident from qualitative findings from an open-label study of 22 MCI and AD patients on the compassionate use of intranasal insulin.10 These patients displayed, before ViaNase delivered treatment, significant symptoms of social and linguistic withdrawal, flattening of affect, and irritability, as well as moderate to high levels of family-reported caregiver stress [1, 2, 3, 60]. Several publications also extensively document treatment-mediated improvements in language, visuospatial, and, in particular, executive functioning test scores of patients at moderate AD and an early MCI patient (5) and a return of pragmatic competence in the areas of jokes, self-expression, and empathy in early and moderate AD and MCI patients [1, 60]. Over 90% of caregivers of the 22 compassionate use patients also reported moderate to very strong reductions in caregiver stress after 1 year of intranasal insulin administration to their family members [1, 60, 73, 74].
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Since 1983, he has been a faculty member of the RO Perelman Department of Dermatology, NYU School of Medicine, where he is codirector of a training grant in cutaneous biology. Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. 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She has more than fifteen years of teaching and research experience. She has published more than 550 scientific publications/communications, including 15 books, 50 book chapters, 100 original research papers, 380 research communications in national and international conferences, and 12 patents. She is a member of the editorial board of five journals and acts as a reviewer for several national and international journals. 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