*3.2. Thrust Fault Activation during Stimulation—China*

This example shows that faults can have both permeable zones and zones that do not transmit pressure or fluids. A horizontal well drilled along a reservoir layer in a thrust zone is shown in Figure 24. This well was parallel to and 300 m shallower than the thrust fault mapped on reflection seismic. Given this vertical separation, it was thought that hydraulic stimulation of the well would not affect this structure. In order to evaluate the stimulated resource volume of this treatment, fracture seismic data were recorded using 1600 receivers in a surface grid.

The recording for each stage shows that there is a zone in the nearby tear fault that is permeable for only part of the length of the well. The permeable zone is active for only four of the stages during the treatment. For stimulation stages near the toe and near the heel of the well, the trust fault was seismically inactive. During the tear-fault-related four stages, the stimulation pressure was transmitted down to the thrust fault and caused many larger microearthquakes. None of the other treatment stages cause microearthquakes in the thrust. Evidently, the fracture seismic imaged permeable zone transmitted the pressure from the pumping to the thrust and a large number of MEQ are stimulated during the four stages.

**Figure 24.** MEQ in the trust fault that is 300 m below the well were activated during only four middle stages of the well treatment. The pressure from the stimulation propagated along the tear fault down to the thrust and caused activation in the thrust zone. The pressure from the stimulation activated resonances in the tear fault so that it was mapped in the fracture seismic intensity volume. The side view of the fracture image volume (**left** panel) shows the tear fault, the well, and the MEQ in the trust fault. The oblique view (**right** panel) show that the tear fault is very close to the well (50 m).

The side view in Figure 24 shows the width and height of the tear fault and that is permeable. The tear fault is approximately 50 m from the well path. The fracture image volume in Figure 24 shows the tear fault width and height. The width mapped is the same width and location as the location of the four stages. The height of the tear fault goes vertically above the well and below the trust fault depth.

### *3.3. Large Single Grid in Thrust Zone, No Stimulation—Colombia*

This example shows how fracture imaging using fracture seismic is integrated with 3D reflection seismic in a new area to select drilling location (Sicking et.al., 2017) [25]. This large area in Colombia had not been actively explored for over 60 years. The reservoir in this area is the Rosa Blanca formation that produces gas in areas where it is naturally fractured. During the decade of the 1950s, this area had been drilled with little success. There were many dry holes but one well struck a highly fractured zone and blew out. Subsequently, the area was abandoned.

In 2012, before initiation of new drilling, a modern 3D reflection seismic survey was collected and, as an independent acquisition, a 4650-channel fracture seismic dataset was recorded that covered 50 square km. The fracture seismic area was in the middle of the area covered by the reflection seismic survey. Before any wells were drilled, the reflection seismic data was processed and migrated using pre-stack depth migration and a complex detailed 3D interval velocity model was computed (Figure 14).

The fracture seismic was processed using the fracture seismic method and a fracture seismic intensity volume was computed that included data from 15 h of recordings. The depth tie between the active and fracture seismic data was ensured by the use of the same interval velocity model for both depth migrations. The intensity volume was integrated with the reflection seismic depth migration volume in order to find the structural positions of the most active fractures in the Rosa Blanca.

The fracture seismic traces were analyzed for resonance using spectrograms (Figure 1). The high fracture seismic intensity and resonance observed at this site is likely due to the high stress state caused by the compressional forces in this region of the northern Andes. The spectrograms help to identify time periods for computing the fracture seismic volumes. While the behavior of the resonances is not yet well understood, experience dictates that very active resonance time periods are the best times to use in fracture seismic depth migration to compute the intensity volume.

Figure 25a shows a map view of the horizon slice extracted along the target horizon from the fracture seismic intensity volume. It is overlaid with the structural contours interpreted from the reflection seismic volume for the same horizon. The horizon map shows that the highest intensities are in the hanging wall of the thrust fault. The black symbols are the locations of dry wells drilled in the 1950s. They are all in the low fracture seismic areas of the Rosa Blanca. The small red circle shows the location of the well that blew out in the 1950s. This well is at the top of the structure and in a higher fracture seismic area, which indicates fracturing on the Rosa Blanca. A new well shown by the large black circle was drilled into the hanging wall of the thrust fault and in an area of high fracture seismic.

**Figure 25.** Identifying zones of fracturing in reservoir before drilling. Panel (**a**) shows the fracture seismic intensity extracted from the volume along the reservoir horizon with the overlay of the structural contours interpreted from the 3D reflection seismic. The traces of the thrust faults are shown. The highest fracture seismic are parallel to and out in front of the thrust fault. Panel (**b**) shows a vertical cross section through well X with the fracture seismic overlaid on the reflection seismic. The yellow line shows the horizon that was extracted to get the slice shown in (**a**). The fracture seismic intensity is higher down dip from where well X was drilled. Dry holes (small black circles) drilled before this analysis are in zones of low fracture seismic intensity. An old well that blew out (shown by the small red circle) and Well X are in zones of high fracture seismic.

Figure 25b shows the vertical cross section of the reflection seismic and the fracture seismic intensity volume through the new well. The reflection seismic data are in black and the overlay of the intensity in color. The intensities show that the hanging wall of the thrust is the most active and that the structure in the fracture seismic volume follows the structure in the 3D reflection data.

Integration of fracture seismic, together with interpretation of reflection seismic, can be used to indicate potential areas for drilling. Based on these data, a test well was drilled, and a heavily fractured reservoir was found in the zone of high intensity. From when the well was put on production and until April of 2019, this well has produced 1.7 BCF gas. Based on the results of Well X, we conclude that the high fracture seismic intensity along the flank of the thrusts does indicate areas of active fractures. By active, we mean seismically active with the implication, based on experience, that the fractures are also permeable.

### *3.4. Roll Along Fracture Seismic during 3D Reflection Seismic Acquisition—Texas*

This example shows how fracture seismic can aide in selecting drilling locations. A 3D reflection seismic survey was collected in the Permian basin of west Texas using a nodal recording system. There were approximately 6500 simultaneously active nodes in the receiver array.

The fracture seismic data were collected concurrently with the reflection seismic by programming the nodes to record at night for 2 h when the crew was not shooting. This recording schedule meant that a very large area was covered by the fracture seismic for each day of recording. Each day of the fracture seismic recordings were processed as an independent data set. Multiple days of recording were selected such that there was substantial overlap in the independent intensity volumes. Nine

hours of recordings over the area of the proposed horizontal well were selected for fracture seismic intensity computation.

Map and cross section slices of the fracture seismic intensity volume are shown in Figure 26. The well shown in Figure 26 was not drilled until two years after the seismic acquisition. The depth slice shows that the volume has areas of high intensity and areas of low activity. The proposed well path is predominantly in a zone of low activity with some higher activity at its toe and heel.

**Figure 26.** Slices of the fracture seismic intensity volume that was computed from data recorded during a 3D reflections seismic acquisition before the well was drilled. The depth slice (**a**) of the fracture seismic intensity volume is shown at the depth of the proposed well. The vertical slice (**b**) is along the path of the proposed well. The logs of the acid uptake show that the uptake was highest in the zones of highest fracture seismic intensity and lowest in the zones of low fracture seismic intensity. This result supports the interpretation that the fracture seismic intensity shows the zones of natural fractures.

Shown in both the depth slice and the vertical slice along the well path is the log for the volume of acid uptake during the stimulation. This log shows that the acid uptake is highest in the zones that had higher fracture seismic intensity and was lowest in the zones of low fracture seismic intensity. They are consistent with the interpretation that the zones of higher fracture seismic intensity have higher fracture density and connectivity. This well was not economic. If the fracture seismic intensity volume had been used to plan the well, it could have been relocated to a zone of high-density natural fractures.

### *3.5. Roll along Fracture Seismic during 3D Reflection Shoot—Wyoming*

This example shows how fracture seismic is used for areal evaluation before development. A 3D reflection seismic survey was recorded in Wyoming that covered a very large area. A smaller area was selected for the fracture seismic recording. The entire receiver array of 6000 geophones was used for recording several hours on seven different days during the active seismic acquisition. The fracture seismic was recorded such that there was a 50% overlap in the fracture seismic intensity volume between recordings. Each recording time was processed as an independent project and the seven fracture seismic intensity volumes were merged later.

The depth slice at the reservoir depth from the fracture seismic intensity volumes for all seven recordings is shown in Figure 27. The slice shows a fault zone across the Northern part of the volume that is also mapped in the 3D reflection seismic. There are two large areas of high fracture seismic intensity in the SW and NE corners of the survey area. These areas are separated by a NW to SE trend of lower fracture seismic activity.

The seams in the final merged volume are readily apparent in the depth slice shown in Figure 27. The fracture seismic intensity volumes are from data that were recorded a few days apart. The fracture seismic intensity during one day of recording is not the same for the other days. Differences in the fracture resonances can account for much of the differences. Processing may also account for small differences in the amplitude from one day to the next. It should be noted that there was a 50% overlap in the intensity volumes from one day of recording to the next such that every voxel in the volume has contributions from two days. Even with the presence of the seams, the fracture seismic intensity volume reveals important information on the natural fracture zones of this prospect and the optimal locations for drilling and stimulation.

### *3.6. Roll Fractures and Well Treatments—Illinois*

This example shows how pre-existing fracture systems impact stimulation. Pre-stimulation fracture seismic was recorded over a well site in the New Albany shale after the well was drilled, but a few weeks before the well was stimulated. These data were used in the planning for the stimulation. Fracture seismic was also recorded during the stimulation. This allowed for the comparison of the fracture seismic intensity volume before, and after stimulation.

Spectrograms were computed from the fracture seismic data recorded pre-stimulation and from the fracture seismic data recorded during stimulation. Samples for both are shown in Figure 28. The top panel shows the spectrogram for a time window pre-stimulation and reveals a narrow band resonance in the 50 Hz to 60 Hz range, along with a broad distribution of signals at lower frequencies. For comparison, the spectrogram for a time window during the stimulation is shown in the lower panel of Figure 28. The resonances are mostly in the lower frequency bands but have substantial changes in amplitude, character, and frequency band. These changes correlate with the stimulation pressure and fluid rate pump curves (Figure 16).

**Figure 28.** Spectrograms computed from pre-stimulation fracture seismic data (**top**) and data recorded during stimulation (**bottom**).

The fracture seismic intensity volume computed for this pre-stimulation time period shows that the fracture seismic activity is very high at the toe of the well and has significant zones of low activity in the middle of the well path (Figure 29, left panel). The fracture seismic volume from the pre-stimulation time period was used to plan the stimulation. During the first three stages of the stimulation, problems were encountered in getting the fluid to flow into the formation. The pre-treatment data were used to analyze the stress field to determine that the pressure used in the pumping should be reduced to solve this problem.

**Figure 29.** The fracture seismic intensity volume computed from fracture seismic data recorded before stimulation show that the stimulation activated the same fractures that were mapped before the stimulation activity. The left panel shows a depth slice of the intensity volume from the pre-stimulation data. The middle panel shows the depth slice of the pre-stimulation intensity with the overlay of the fractures active during stimulation. The right panel shows the connectivity pathways computed from the 16 intensity volumes computed for each stage.

Comparing the pre-stimulation fracture seismic (left) to the fracture volume (middle) that was computed during the stimulation shows that the fractures that are computed from the data recorded during the stimulation follow the intensity patterns in the fracture seismic volume computed pre-stimulation. The overlay of the fractures computed during stimulation on the fracture seismic intensity computed pre-stimulation show that the pre-existing fracture system impacts the performance of the stimulation with the highest intensity zone during the pre-frack time having the highest density of activated fractures during the stimulation.

Using the fracture seismic intensity volume computed from the pre-stimulation and the volume computed during stimulation we forecast the connectivity pathways (Figure 29, right panel) in the reservoir that will produce the most fluid flow during production. These were computed by first thresholding the amplitude in each of the intensity volumes for each stage of the stimulation. In each voxel for each stage, the amplitudes that were below this threshold were reset to zero. For each voxel, the number of volumes that were above the threshold for that voxel were counted and the count for that voxel was stored in the repeated activity volume.

For example, with 16 stages, each voxel has the possibility of containing a number between 0 and 16. The connectivity pathways are then seen as the highest number of threshold crossings. This attribute volume is used to model the pressure and fluid transmission through the reservoir. The connectivity pathways for this example show that zones of best connectivity in the reservoir are the most active in the pre-stimulation fracture seismic volume.

### *3.7. Pump Startup Time Fracture System—Texas*

This example shows how the pressure from the stimulation produces fracture seismic intensity in the fracture system before formation breakdown. Formation breakdown is when the fractures near the well open and allow the initiation of fluid flow into the reservoir. The fracture seismic data recorded before formation breakdown can provide very useful details about the reservoir.

Figure 30 shows a spectrogram for 30 min of data recorded in the Eagle Ford shale during pressure buildup for the first stage of a hydraulic stimulation. During startup, the increasing pressure moves into the rocks causing resonances in the permeable fractures that are connected to the well at Stage 1. The observed resonances grow in amplitude and complexity with increasing pressure. The resonances transition from low-amplitude dispersive to high-amplitude turbulent after formation breakdown. These resonances are very di fferent from those observed during the pre-stimulation in the New Albany shown in Figure 28.

**Figure 30.** Spectrogram during Stage 1 startup shows the resonances transition from low amplitude to high amplitude as the pressure is increased with pumping time. Formation breakdown causes a substantial change in the resonance as the fluid begins to flow into the formation. The lavender bars mark the 5 min of data that are used to compute the fracture images.

The 5 min of trace data marked by the lavender lines in Figure 30 were selected for computation of the pre-breakdown fracture seismic volume. These minutes were selected because of the high fracture seismic signals in the spectrogram and because it is before formation breakdown. Previously, it was not expected that the fractures would emit such high-intensity fracture seismic resonances before formation breakdown.

The depth slice at the well depth of the fracture seismic intensity volume computed from these 5 min is shown in Figure 31. The feature trending from SW to NE and terminating at the well is a fault that was previously observed in the 3D reflection seismic data. The depth slice shows the fracture seismic intensity stimulated by the startup of pumping with the overlay in black lines of the fractures. The fractures map the connectivity to the perforation location for Stage 1.

**Figure 31.** Depth slice of fracture intensity volume computed for 5 min fracture seismic data and the overlay of the computed fractures. The fractures show the connectivity pathways that connect to the well at the Stage 1 perforations.

This section of the Eagle Ford has a large number of fractures, as can be seen in the 3D reflection section shown in Figure 23. The interpretation is that only a few of these fractures were activated during Stage 1 startup. Most of the fractures in the volume are not activated with the increase in pressure. Only the most permeable fractures are activated during the startup time before the first stage formation breakdown. The fracture lines form a pattern that might have been in related to a previous stress direction that is different from the one in place today.


Preface

Neuroprotection is a key approach to maintaining brain health to prevent the retraction of synapses, accumulation of neurodegenerative proteins (tau, β-amyloid peptide, α-synuclein, huntingtin, or any misfolded proteins), activation of neuroinflammation, or even the breakdown of the blood-brain barrier. Neuroprotection can be applied to chronic neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, Lewy's body diseases, Huntington's disease, amyotrophic lateral sclerosis, or even brain tumors), acute neurological disorders (brain trauma, stroke, transient ischemia, epilepsy, or cerebral hemorrhage), or even mental disorders (psychosis, depression, or schizophrenia). The traditional view of neuroprotection is often restricted to the use of agonists or antagonists of neurotransmitter receptors. While this is still a great approach to safeguard neurons, neuroprotection strategy is not limited to modulating neurotransmitter receptors. Neuroprotection can be accomplished by (1) natural products, (2) herbal medicine, (3) different forms of exercise, (4) learning new skills or languages, or (5) even good sleeping patterns. From all these new perspectives, the concept of neuroprotection is limited not only to the protection of neurons in the pathogenesis of diseases but also to the prevention of any detrimental factors leading to neuronal cell loss.

The major aim of this book is to focus on different approaches to achieve neuroprotection. In this book, most of our authors review the advantages of neurotransmitter receptors. Mititelu-Tartau and Bogdan's group reviews the imidazoline ligands and opioid ligands in Alzheimer's disease. They review the neuroprotective effects of agmatine on memory. In addition, they also summarize the findings of using different opioid receptor ligands to elicit neuroprotection. Similarly, Yanuar's group reviews the beneficial effects of the adenosine A2A receptor antagonist. It has been reported that the adenosine receptor antagonist elicits neuroprotective effects, partially because of its signaling pathways to activate the cytosolic fraction of cAMP. Yanuar's group reviews how A2A antagonists provide neuroprotection.

Apart from modulating neurotransmitter receptors, Flood's group reviews another very important pathological factor leading to neurodegeneration: neuroinflammation. Microglial cells are the major line of cells to be activated to produce cytokines and free radicals to damage neurons. Interestingly, Flood's group reviews how different adrenergic receptor agonists and antagonists modulate microglial responses. This independent review suggests that modulation of neuroinflammation can also be achieved by intervening neurotransmitter receptors and their associated signaling events.

Neuroprotection can be disease specific but use different approaches. Nian and Lo review the neuroprotection of aging eyes, in which aging-associated macular degeneration often occurs in the elderly. With the progression of the disease and identification of biological targets at different states of the disease, the strategy of neuroprotection can be changed.

Taken together, neuroprotection receives increasing attention from different approaches in different states of neurodegenerative diseases, acute neurological disorders, and even mental disorders. Even in disease progression, neuroprotection can prevent the spread of neuronal damage or neuronal loss from one region to other regions. This book will give insights to scientists in the field to stimulate their research, medical professionals to review their clinical practices, and others who would like to learn more about different neuroprotective approaches.

#### **Raymond Chuen-Chung Chang, PhD**

Laboratory of Neurodegenerative Diseases, School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong

#### **Yuen-Shan Ho, PhD**

**1**

Section 1

Neurotransmitter

Receptor as Target for

Neuroprotection

School of Nursing, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University, Kowloon, Hong Kong Section 1

Neurotransmitter Receptor as Target for Neuroprotection

**3**

**Chapter 1**

Perspective

even stop progressive neurodegeneration.

**1. Introduction**

neuroprotection.

genetic approaches (**Figure 1**).

Introductory Chapter: Concept

Neuroprotection is an approach to preserve neurons so that neurons cannot be hurt by different pathological factors in neurodegenerative diseases. It can be an approach before the onset of the disease so that neurons cannot be affected by any risk factors. It can also be an approach during the progression of the disease to prevent spreading of injury from one neuron to neighboring neurons. Therefore, neuroprotection can also be one approach as "disease-modifying agent" to delay and

The concept of neuroprotection has long been confined to intervene neurotransmitter receptors via agonists and antagonists. A very well-known example is the neuroprotective effect of caffeine via adenosine receptor, because caffeine is an A2 receptor antagonist. Caffeine can exert neuroprotection via adenosine A2 receptor to protect dopaminergic neurons in an experimental model of Parkinson's disease (PD) by using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) as a toxin agent [1]. Therefore, drinking coffee has been considered to be neuroprotection. Apart from adenosine receptor on neurons, it is now known that microglial cells also express A2 receptor, and A2 receptor antagonist or caffeine can reduce activation of microglial cells [2]. Since caffeine or A2 receptor antagonists can protect neurons and minimize activation of microglial cells, research is still very active in this direction. Indeed, investigation of other neurotransmitter receptor antagonists, agonists, blockers, or even partial blockers is still a very active research area in

While it is exciting to reveal differential neuroprotective effects via modulating receptors for different neurotransmitters, we should not restrict ourselves to this perspective only. In fact, a wider scope of neuroprotection has been evolved. The concept of neuroprotection can now be categorized into three groups: (A) pharmacological intervention, (B) non-pharmacological intervention, and (C) cellular and

In group A neuroprotective approaches, pharmacological intervention includes modulation of neurotransmitter receptors (as introduced above), anti-oxidative stress, and anti-inflammatory responses [3]. These are classical pharmacological approaches. These methods have been explored for decades and can be used for both neuroprotection and as disease-modifying agents. Their effects can be target-specific for one single protein (e.g., receptor for neurotransmitter or one type of cytokines) or pathway-specific (anti-oxidative responses using nuclear factor erythroid 2-related factor 2, Nrf2). Since single biological target may limit the beneficial effects and may not be able to intervene the complexity of the disease

of Neuroprotection - A New

*Raymond Chuen-Chung Chang and Yuen-Shan Ho*

#### **Chapter 1**

## Introductory Chapter: Concept of Neuroprotection - A New Perspective

*Raymond Chuen-Chung Chang and Yuen-Shan Ho*

#### **1. Introduction**

Neuroprotection is an approach to preserve neurons so that neurons cannot be hurt by different pathological factors in neurodegenerative diseases. It can be an approach before the onset of the disease so that neurons cannot be affected by any risk factors. It can also be an approach during the progression of the disease to prevent spreading of injury from one neuron to neighboring neurons. Therefore, neuroprotection can also be one approach as "disease-modifying agent" to delay and even stop progressive neurodegeneration.

The concept of neuroprotection has long been confined to intervene neurotransmitter receptors via agonists and antagonists. A very well-known example is the neuroprotective effect of caffeine via adenosine receptor, because caffeine is an A2 receptor antagonist. Caffeine can exert neuroprotection via adenosine A2 receptor to protect dopaminergic neurons in an experimental model of Parkinson's disease (PD) by using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) as a toxin agent [1]. Therefore, drinking coffee has been considered to be neuroprotection. Apart from adenosine receptor on neurons, it is now known that microglial cells also express A2 receptor, and A2 receptor antagonist or caffeine can reduce activation of microglial cells [2]. Since caffeine or A2 receptor antagonists can protect neurons and minimize activation of microglial cells, research is still very active in this direction. Indeed, investigation of other neurotransmitter receptor antagonists, agonists, blockers, or even partial blockers is still a very active research area in neuroprotection.

While it is exciting to reveal differential neuroprotective effects via modulating receptors for different neurotransmitters, we should not restrict ourselves to this perspective only. In fact, a wider scope of neuroprotection has been evolved. The concept of neuroprotection can now be categorized into three groups: (A) pharmacological intervention, (B) non-pharmacological intervention, and (C) cellular and genetic approaches (**Figure 1**).

In group A neuroprotective approaches, pharmacological intervention includes modulation of neurotransmitter receptors (as introduced above), anti-oxidative stress, and anti-inflammatory responses [3]. These are classical pharmacological approaches. These methods have been explored for decades and can be used for both neuroprotection and as disease-modifying agents. Their effects can be target-specific for one single protein (e.g., receptor for neurotransmitter or one type of cytokines) or pathway-specific (anti-oxidative responses using nuclear factor erythroid 2-related factor 2, Nrf2). Since single biological target may limit the beneficial effects and may not be able to intervene the complexity of the disease

#### **Figure 1.**

*A summary of different neuroprotective approaches.*

progression, neuroprotective effects from herbal medicine or natural products receive increasing attention in scientific research because of their multiple effects on different biological targets [4–6]. For example, it has been shown that triterpenoids extracted from *Prunella vulgaris* has anti-inflammatory effects [7]. We have proved that polysaccharide part of *Prunella vulgaris* can modulate the immune responses of microglia and macrophages [8, 9]. Therefore, *Prunella vulgaris* exerts neuroprotection toward neurodegenerative diseases against neuroinflammation.

In group B neuroprotective approaches, non-pharmacological approaches receive increasing attention. Since it is quite difficult to ask a healthy adult or even elderly to constantly take medicine even though it is herbal, non-pharmacological approaches to earn neuroprotection are most welcome. Among these different methods, exercise is the best to prevent nearly all kinds of diseases. Exercise can be further divided into aerobic and resistance exercises, in which aerobic exercise is suitable for motor-healthy adults or elderly. However, there is a large population of elderly who have difficulty in their motor functions. Resistance exercise becomes an excellent tool for them. Both aerobic and resistance exercises can affect the metabolisms of the body and induce trophic factors like myokines, released from muscles and liver [10, 11]. Since body metabolism is important, diet control is also important to reduce any risk factors leading to the development of neurodegenerative diseases, such as diabetes, hyperlipidemia, or hypercholesterolemia. All of these risk factors are related to vascular components, which may further add on vascular dementia [12–14]. Apart from exercise, it is well-known that, maintaining social activity is essential to keep our brain healthy [15]. In addition, sleeping can promote clearing of pathological factors, such as β-amyloid (Aβ) peptide and phosphorylated tau protein [16, 17]. Also, it has been recently shown that learning second language or bilingualism can be neuroprotective [18]. Furthermore, increasing lines of evidence have shown that acupuncture can help adjusting the body metabolism and immunity [18, 19]. Therefore, acupuncture can also be considered to be one method in non-pharmacological approaches. One key point should be noticed that all these neuroprotective approaches are multiple targets. This may be why they are so effective in minimizing neurodegeneration to preserve neurons.

Neuroprotective approaches in group C are the new extension of multiple effects from trophic factors secreted by genetically engineered cells or viral vector. Alternatively, stimulating the proliferation and differentiation of endogenous stem

**5**

*Introductory Chapter: Concept of Neuroprotection - A New Perspective*

cells, application of induced pluripotent stem cells (iPSC), or mesenchymal stem cells are popular trends in scientific research to prevent neurodegeneration and

**2. Neuroprotective effects of herbal medicine and natural products**

we have investigated polysaccharides extracted from different herbs [23].

more potent antioxidants are required to provide neuroprotection.

In experimental PD using 6-hydroxydopamine (6-OHDA) as toxin agent, we employed oxyresveratrol, which is a natural product but a structural analog of resveratrol, and found that it can attenuate neurodegeneration [35, 36]. For this kind of neurodegenerative disease requiring high levels and high capacity of antioxidant, another method is to employ pro-drug approach so that oxidant cleave the precursor and the product becomes potent antioxidant. Interestingly, polyphenol (-)-epigallocatechin-3-gallate (EGCG) from green tea falls in this category [37]. The advantages of using herbal medicine or natural products are to make use of their multiple effects. In neurodegenerative diseases, a wide array of stress responses is stimulated because of free radicals or accumulation of misfolded or

We have first found that polysaccharides from *Nerium indicum* exert neuroprotective effects against β-amyloid (Aβ) neurotoxicity cultured neurons [24, 25]. Then, we also found that neuroprotective effects of *Verbena officinalis* and *Ganoderma lucidum* [26, 27]. Having investigated different herbal medicine, we found that the polysaccharides from *Lycium barbarum* (Wolfberry) are potent [28, 29]. Polysaccharides can be extracted in hot water or from alkaline condition and elicit neuroprotection [30]. It should be noted that not all polysaccharides, but only some sub-fractions provide neuroprotective effects. Apart from neurons in the brain, polysaccharides from wolfberry can also protect the retina against experimental glaucoma and stroke [31–33]. As harvesting and planting processes have good agricultural practice and the extraction can be done under stringent control of good manufacturing practice, we choose wolfberry as our long-term study. Wolfberry is indeed an anti-aging Chinese herbal medicine. We would like to understand the concept of "anti-aging." Therefore, we have investigated its application in different aging-associated neurodegenerative diseases [34]. In fact, not all aging-associated neurodegenerative diseases can be attenuated by the polysaccharide fraction of Wolfberry. In Parkinson's disease (PD),

Since there are several chapters about the effects of neurotransmitter receptors, we will focus on some neuroprotective approaches only, as this is an introductory

This direction of neuroprotection is the most controversial approach among different pharmacological tools. This is because most of the herbal medicine or natural products have a wide array of effects. If we use traditional way of thinking to target a specific protein or signaling pathway, herbal medicine fails to do so. However, if we are aware of neurodegenerative diseases that are usually multifactorial, we can then accept that herbal medicine should be the direction to prevent neuronal loss and spreading of neurodegeneration. Our group has long been working on discovering herbal medicine as neuroprotective agents and investigating their underlying mechanisms. Since most of the herbal medicines are in decoction form, for oral consumption, the effective components in different herbs are not limited to one single chemical. The small molecules being extracted from one herb can also be found from other herbs. There are many laboratories investigating those small molecules and have Research and Development (R&D) to be commercial products. In contrast, big molecules such as polysaccharides have been an unexplored area. In fact, a large portion of components from herbs is polysaccharides. When we use hot water to prepare decoction, what we can easily absorb is polysaccharides. Therefore,

*DOI: http://dx.doi.org/10.5772/intechopen.85631*

neuronal loss [20–22].

chapter.

*Neuroprotection*

**Figure 1.**

*A summary of different neuroprotective approaches.*

progression, neuroprotective effects from herbal medicine or natural products receive increasing attention in scientific research because of their multiple effects on different biological targets [4–6]. For example, it has been shown that triterpenoids extracted from *Prunella vulgaris* has anti-inflammatory effects [7]. We have proved that polysaccharide part of *Prunella vulgaris* can modulate the immune responses of microglia and macrophages [8, 9]. Therefore, *Prunella vulgaris* exerts neuroprotection toward neurodegenerative diseases against neuroinflammation. In group B neuroprotective approaches, non-pharmacological approaches receive increasing attention. Since it is quite difficult to ask a healthy adult or even elderly to constantly take medicine even though it is herbal, non-pharmacological approaches to earn neuroprotection are most welcome. Among these different methods, exercise is the best to prevent nearly all kinds of diseases. Exercise can be further divided into aerobic and resistance exercises, in which aerobic exercise is suitable for motor-healthy adults or elderly. However, there is a large population of elderly who have difficulty in their motor functions. Resistance exercise becomes an excellent tool for them. Both aerobic and resistance exercises can affect the metabolisms of the body and induce trophic factors like myokines, released from muscles and liver [10, 11]. Since body metabolism is important, diet control is also important to reduce any risk factors leading to the development of neurodegenerative diseases, such as diabetes, hyperlipidemia, or hypercholesterolemia. All of these risk factors are related to vascular components, which may further add on vascular dementia [12–14]. Apart from exercise, it is well-known that, maintaining social activity is essential to keep our brain healthy [15]. In addition, sleeping can promote clearing of pathological factors, such as β-amyloid (Aβ) peptide and phosphorylated tau protein [16, 17]. Also, it has been recently shown that learning second language or bilingualism can be neuroprotective [18]. Furthermore, increasing lines of evidence have shown that acupuncture can help adjusting the body metabolism and immunity [18, 19]. Therefore, acupuncture can also be considered to be one method in non-pharmacological approaches. One key point should be noticed that all these neuroprotective approaches are multiple targets. This may be why they are

so effective in minimizing neurodegeneration to preserve neurons.

Neuroprotective approaches in group C are the new extension of multiple effects from trophic factors secreted by genetically engineered cells or viral vector. Alternatively, stimulating the proliferation and differentiation of endogenous stem

**4**

cells, application of induced pluripotent stem cells (iPSC), or mesenchymal stem cells are popular trends in scientific research to prevent neurodegeneration and neuronal loss [20–22].

Since there are several chapters about the effects of neurotransmitter receptors, we will focus on some neuroprotective approaches only, as this is an introductory chapter.

#### **2. Neuroprotective effects of herbal medicine and natural products**

This direction of neuroprotection is the most controversial approach among different pharmacological tools. This is because most of the herbal medicine or natural products have a wide array of effects. If we use traditional way of thinking to target a specific protein or signaling pathway, herbal medicine fails to do so. However, if we are aware of neurodegenerative diseases that are usually multifactorial, we can then accept that herbal medicine should be the direction to prevent neuronal loss and spreading of neurodegeneration. Our group has long been working on discovering herbal medicine as neuroprotective agents and investigating their underlying mechanisms. Since most of the herbal medicines are in decoction form, for oral consumption, the effective components in different herbs are not limited to one single chemical. The small molecules being extracted from one herb can also be found from other herbs. There are many laboratories investigating those small molecules and have Research and Development (R&D) to be commercial products. In contrast, big molecules such as polysaccharides have been an unexplored area. In fact, a large portion of components from herbs is polysaccharides. When we use hot water to prepare decoction, what we can easily absorb is polysaccharides. Therefore, we have investigated polysaccharides extracted from different herbs [23].

We have first found that polysaccharides from *Nerium indicum* exert neuroprotective effects against β-amyloid (Aβ) neurotoxicity cultured neurons [24, 25]. Then, we also found that neuroprotective effects of *Verbena officinalis* and *Ganoderma lucidum* [26, 27]. Having investigated different herbal medicine, we found that the polysaccharides from *Lycium barbarum* (Wolfberry) are potent [28, 29]. Polysaccharides can be extracted in hot water or from alkaline condition and elicit neuroprotection [30]. It should be noted that not all polysaccharides, but only some sub-fractions provide neuroprotective effects. Apart from neurons in the brain, polysaccharides from wolfberry can also protect the retina against experimental glaucoma and stroke [31–33]. As harvesting and planting processes have good agricultural practice and the extraction can be done under stringent control of good manufacturing practice, we choose wolfberry as our long-term study. Wolfberry is indeed an anti-aging Chinese herbal medicine. We would like to understand the concept of "anti-aging." Therefore, we have investigated its application in different aging-associated neurodegenerative diseases [34]. In fact, not all aging-associated neurodegenerative diseases can be attenuated by the polysaccharide fraction of Wolfberry. In Parkinson's disease (PD), more potent antioxidants are required to provide neuroprotection.

In experimental PD using 6-hydroxydopamine (6-OHDA) as toxin agent, we employed oxyresveratrol, which is a natural product but a structural analog of resveratrol, and found that it can attenuate neurodegeneration [35, 36]. For this kind of neurodegenerative disease requiring high levels and high capacity of antioxidant, another method is to employ pro-drug approach so that oxidant cleave the precursor and the product becomes potent antioxidant. Interestingly, polyphenol (-)-epigallocatechin-3-gallate (EGCG) from green tea falls in this category [37].

The advantages of using herbal medicine or natural products are to make use of their multiple effects. In neurodegenerative diseases, a wide array of stress responses is stimulated because of free radicals or accumulation of misfolded or

badly folded proteins. Most of the herbal medicine and natural products attenuate many stress kinases. They may not be a good candidate to clear accumulation of bad proteins; however, they can inhibit the cascades of stress responses (e.g., activation of c-Jun-N-terminal kinase, JNK; endoplasmic reticulum stress pathways), which usually lead to neuronal apoptosis. Some of the herbal medicine or natural products can even strengthen the survival signaling pathways such as mTOR or Akt pathways.

In addition to their direct effects on neurons, there are many herbal medicine or natural products that can modulate body immune responses. For example, polysaccharides fraction from *Prunella vulgaris* L. can modulate innate immune responses of macrophages [8, 9]. It has been increasingly aware that activation of body (systemic) immune responses are the origin of our sickness responses leading to low appetites and even fever [38]. Long-term effects of systemic immune responses can even result in psychological depression or acute delirium [39]. Experimentally, we have shown that infection in the body or immune responses triggered by surgery (laparotomy) can modulate cognitive functions because of stimulation of neuroimmune responses [40, 41]. Therefore, modulation of body immunity can be a powerful method to minimize neuroimmune responses and then reduce cognitive dysfunctions.

#### **3. Aerobic and resistance exercises**

As emphasized above, the advantages of herbal medicine and natural products are their multiples and wide array effects. Similarly, exercise is another method to achieve this goal. Exercise can stimulate production of different trophic/growth factors, e.g., vascular endothelial growth factor (VEGF), brain-derived neurotrophic factor (BDNF), insulin-like growth factor-1 (IGF-1), peroxisome proliferatoractivated receptor gamma coactivator-1α (PGC-1α)/neuronal fibronectin type III domain-containing protein 5 (FNDC5). Some trophic factors can be secreted by muscles or liver, which is collectively called myokines. It has been shown that muscle cells can produce PGC-1α, irisin, cathepsin B, myostatin (growth differentiation factor 8), fibroblast growth factor 21 (FGF-21), IL-6, IL-15, myonectin, and SPARC (osteonectin) as novel brain-beneficial myokines [10, 42]. Some of them, such as FGF21, can also be secreted by the liver or even in the brain upon exercise [43]. They all can affect muscle, liver, adipose tissues, and brain cells, leading to preservation of cognitive functions, modulating the lipid metabolism, and immune responses [44]. This kind of myokine can pass through the blood-brain barrier.

For motor-healthy subject, aerobic exercise is beneficial to majority of people. As discussed above, myokines can be induced so that they provide neuroprotective effects to the brain and attenuate any systemic immune responses. While aerobic exercise is known to be good, a great number of elderly and demented patients could not enjoy the benefit of aerobic exercise. Those patients may have prior knee replacement or fall down hurting the legs. They may be lying down on the bed. No matter how we advocate the beneficial effects of aerobic exercise, this will not be beneficial to this group of patients. Does it mean that they will not have any beneficial effects of exercise? This question leads us to investigate the beneficial effects of resistance exercise.

In a systematic review, aerobic exercise shows beneficial effects on cognitive functions and executive functions, which is better than that from resistance exercise [45]. Furthermore, aerobic exercise seems to elicit strong anti-inflammatory effect than that of resistance exercise [46]. However, resistance exercise seems to particularly increase the volume of hippocampus [47]. A study in laboratory animal

**7**

**Author details**

provided the original work is properly cited.

Hong Kong, Pokfulam, Hong Kong SAR

Raymond Chuen-Chung Chang1,2\* and Yuen-Shan Ho3

the way for our effective neuroprotective strategies.

University of Hong Kong, Pokfulam, Hong Kong SAR

Polytechnic University, Kowloon, Hong Kong SAR

\*Address all correspondence to<EMAIL_ADDRESS>
*Introductory Chapter: Concept of Neuroprotection - A New Perspective*

has shown that aerobic exercise can markedly increase BDNF; whereas, resistance exercise can significantly increase IGF-1 [48]. Although resistance exercise may have some limitations, this is still a good choice for those elderly and dementia patients to have this form of exercise. IGF-1 can still elicit multiple functions in the

Since this is an introductory chapter, we do not intend to discuss every single method of neuroprotection in detail. We should keep in mind that neurodegenerative diseases are multiple-hit processes. Therefore, no single biological target can afford all neuroprotective needs. Approaches in using herbal medicine and natural products remind us that multiple biological targets may be the way to exert effective neuroprotection. Therefore, any non-pharmacological approaches including exercise and even the new stem cell approaches exert multiple effects. This can be

*DOI: http://dx.doi.org/10.5772/intechopen.85631*

brain to preserve neurons.

**4. Concluding remarks**

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

1 Laboratory of Neurodegenerative Diseases, LKS Faculty of Medicine, The

2 State Key Laboratory of Brain and Cognitive Sciences, The University of

3 Faculty of Health and Social Sciences, School of Nursing, The Hong Kong

*Introductory Chapter: Concept of Neuroprotection - A New Perspective DOI: http://dx.doi.org/10.5772/intechopen.85631*

has shown that aerobic exercise can markedly increase BDNF; whereas, resistance exercise can significantly increase IGF-1 [48]. Although resistance exercise may have some limitations, this is still a good choice for those elderly and dementia patients to have this form of exercise. IGF-1 can still elicit multiple functions in the brain to preserve neurons.

#### **4. Concluding remarks**

*Neuroprotection*

pathways.

dysfunctions.

**3. Aerobic and resistance exercises**

badly folded proteins. Most of the herbal medicine and natural products attenuate many stress kinases. They may not be a good candidate to clear accumulation of bad proteins; however, they can inhibit the cascades of stress responses (e.g., activation of c-Jun-N-terminal kinase, JNK; endoplasmic reticulum stress pathways), which usually lead to neuronal apoptosis. Some of the herbal medicine or natural products can even strengthen the survival signaling pathways such as mTOR or Akt

In addition to their direct effects on neurons, there are many herbal medicine or natural products that can modulate body immune responses. For example, polysaccharides fraction from *Prunella vulgaris* L. can modulate innate immune responses of macrophages [8, 9]. It has been increasingly aware that activation of body

(systemic) immune responses are the origin of our sickness responses leading to low appetites and even fever [38]. Long-term effects of systemic immune responses can even result in psychological depression or acute delirium [39]. Experimentally, we have shown that infection in the body or immune responses triggered by surgery (laparotomy) can modulate cognitive functions because of stimulation of neuroimmune responses [40, 41]. Therefore, modulation of body immunity can be a powerful method to minimize neuroimmune responses and then reduce cognitive

As emphasized above, the advantages of herbal medicine and natural products are their multiples and wide array effects. Similarly, exercise is another method to achieve this goal. Exercise can stimulate production of different trophic/growth factors, e.g., vascular endothelial growth factor (VEGF), brain-derived neurotrophic factor (BDNF), insulin-like growth factor-1 (IGF-1), peroxisome proliferatoractivated receptor gamma coactivator-1α (PGC-1α)/neuronal fibronectin type III domain-containing protein 5 (FNDC5). Some trophic factors can be secreted by muscles or liver, which is collectively called myokines. It has been shown that muscle cells can produce PGC-1α, irisin, cathepsin B, myostatin (growth differentiation factor 8), fibroblast growth factor 21 (FGF-21), IL-6, IL-15, myonectin, and SPARC (osteonectin) as novel brain-beneficial myokines [10, 42]. Some of them, such as FGF21, can also be secreted by the liver or even in the brain upon exercise [43]. They all can affect muscle, liver, adipose tissues, and brain cells, leading to preservation of cognitive functions, modulating the lipid metabolism, and immune responses [44]. This kind of myokine can pass through the blood-brain barrier. For motor-healthy subject, aerobic exercise is beneficial to majority of people. As discussed above, myokines can be induced so that they provide neuroprotective effects to the brain and attenuate any systemic immune responses. While aerobic exercise is known to be good, a great number of elderly and demented patients could not enjoy the benefit of aerobic exercise. Those patients may have prior knee replacement or fall down hurting the legs. They may be lying down on the bed. No matter how we advocate the beneficial effects of aerobic exercise, this will not be beneficial to this group of patients. Does it mean that they will not have any beneficial effects of exercise? This question leads us to investigate the beneficial effects of

In a systematic review, aerobic exercise shows beneficial effects on cognitive functions and executive functions, which is better than that from resistance exercise [45]. Furthermore, aerobic exercise seems to elicit strong anti-inflammatory effect than that of resistance exercise [46]. However, resistance exercise seems to particularly increase the volume of hippocampus [47]. A study in laboratory animal

**6**

resistance exercise.

Since this is an introductory chapter, we do not intend to discuss every single method of neuroprotection in detail. We should keep in mind that neurodegenerative diseases are multiple-hit processes. Therefore, no single biological target can afford all neuroprotective needs. Approaches in using herbal medicine and natural products remind us that multiple biological targets may be the way to exert effective neuroprotection. Therefore, any non-pharmacological approaches including exercise and even the new stem cell approaches exert multiple effects. This can be the way for our effective neuroprotective strategies.

#### **Author details**

Raymond Chuen-Chung Chang1,2\* and Yuen-Shan Ho3

1 Laboratory of Neurodegenerative Diseases, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR

2 State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong, Pokfulam, Hong Kong SAR

3 Faculty of Health and Social Sciences, School of Nursing, The Hong Kong Polytechnic University, Kowloon, Hong Kong SAR

\*Address all correspondence to<EMAIL_ADDRESS>
© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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[16] Zhang F, Zhong R, Li S, Chang RCC, Le W. The missing link between sleep disorders and age-related dementia: Recent evidence and plausible mechanisms. Journal of Neural Transmission. 2017;**124**:559-568

[17] Cox SR, Bak TH, Allerhand M, Redmond P, Starr JM, Deary IJ, et al. Bilingualism, social cognition and executive functions: A tale of chickens and eggs. Neuropsychologia. 2016;**91**:299-306

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[23] Ho YS, Poon DCH, Chan TF, Chang RCC. From small to big molecules: How do we prevent and delay progression of aging-related neurodegeneration? Current Pharmaceutical Design. 2012;**18**:15-26

[24] Yu MS, Lai SW, Lin KF, Fang JN, Yuen WH, Chang RCC. Characterization of polysaccharides from the flowers of *Nerium indicum* and their neuroprotective effects. International Journal of Molecular Medicine. 2004;**14**:917-924

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**8**

*Neuroprotection*

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[9] Fang X, RCC C, Yuen WH, Zee SY. Immune modulatory effects of *Prunella Valgaris L*. International Journal of Molecular Medicine.

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Neurology. 2016;**75**:955-962

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In press

[2] Caetano L, Pinheiro H, Patrício P, et al. Adenosine A2A receptor

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Chapter 2

Abstract

Current Therapeutic Approaches

Liliana Mititelu-Tartau, Maria Bogdan, Victor Gheorman,

Liliana Foia, Ancuta Goriuc, Gabriela Rusu, Beatrice Buca,

Due to brain plasticity, the nervous system is capable of manifesting behavioral variations, adapted to the influences from both external and internal environment. Multiple neurotransmitters are involved in the mediation of pathological processes at the molecular, cellular, regional, and interregional levels participating in cerebral plasticity, their intervention being responsible for various structural, functional, and behavioral disturbances. The current therapeutic strategies in neuroprotection aim at blocking on different levels, the molecular cascades of the pathophysiological mechanisms responsible for neuronal dysfunctions and ultimately for neuronal death. Different agents influencing these neurotransmitters have demonstrated beneficial effects in neurogenesis and neuroprotection, proved in experimental animal models of focal and global ischemic injuries. Serotonin, dopamine, glutamate, N-methyl-D-aspartate, and nitric oxide have been shown to play a significant role in modulating nervous system injuries. The imidazoline system is one of the important systems involved in human brain functioning. Experimental investigations have revealed the cytoprotective effects of imidazoline I2 receptor ligands against neuronal injury induced by hypoxia in experimental animals. The

neuroprotective effects were also highlighted for kappa and delta receptors, whose agonists demonstrated the ability to reduce architectural lesions and to recover neuronal functions of animals with experimentally induced brain ischemia.

Increase in life expectancy has led to aging of the population and consequently

to an expansion of the prevalence of neurodegenerative diseases (NDDs) [1].

Keywords: neuroprotection, neurodegenerative diseases, ischemic stroke,

Liliana Pavel, Ana Cristofor, Cosmin-Gabriel Tartau

from Imidazoline and Opioid

Receptors Modulators in

Neuroprotection

and Gratiela Eliza Popa

imidazoline, opioids, nitric oxide

1. Introduction

13

#### Chapter 2


**Jeremy Mitonga-Monga and Claude-Hélène Mayer \***

Department of Industrial Psychology & People Management, University of Johannesburg, Johannesburg 2006, South Africa<EMAIL_ADDRESS>
**\*** Correspondence<EMAIL_ADDRESS>Tel.: +277-6372-1263

Received: 24 February 2020; Accepted: 14 May 2020; Published: 10 June 2020

**Abstract:** Research on coping, sense of coherence, burnout, and work engagement is well documented in western countries. However, a void of studies exists on how coping mechanisms can moderate the relationship among sense of coherence, burnout, and work engagement in a manufacturing company in the Democratic Republic of Congo (DRC). The objective of this research was to examine the moderating effect of coping (COP) in the relationship between sense of coherence (SOC), burnout (BO), and work engagement (WE). The study employed a quantitative research approach, while participants were recruited through convenience sampling. A total of 197 employees (*n* = 197; females 40%) who are permanently employed in a manufacturing organisation in the DRC participated in the study voluntarily. The results indicate that coping related positively to a sense of coherence. Moreover, the results indicate that sense of coherence and work engagement related negatively to burnout. Furthermore, the results show that coping acted as a moderator in the relationships between variables. The study adds value to the WE theory by suggesting that an employee who has a high level of COP, high SOC, low level of BO, will positively engage, perform, and be productive.

**Keywords:** sense of coherence; employee participation; burnout; work engagement; Democratic Republic of Congo (DRC)


**4. Clinical manifestations in children**

Moyamoya disease presents with ischemic symptoms in children, an incidence of 68% and adults usually present with a hemorrhagic stroke, about 42% [10].

Amongst the ischemic symptoms, completed strokes are more common in children, a possible explanation being their inability to identify and complain about TIAs [15]. They can be transient or fixed. Most commonly occur in the territory of the internal carotid artery and proximal middle and anterior cerebral arteries [10].

Underlying mechanism:

Progressive stenosis of the internal carotid and middle cerebral arteries are responsible for most of the symptoms [10].

Maximally dilated cortical vessels in patients with chronic ischemia, constrict in response to the decreased carbon dioxide due to hyperventilation, resulting in reduced cerebral perfusion and thus exacerbating the symptoms [16].

Precipitating factors: [16].

Crying (In the paediatric population). Hyperventilation (In paediatric population). Exercise. Anaesthesia. Dehydration. Altitude. Eating a hot meal. Focal Symptoms: [10]. Hemiparesis. Dysarthria. Aphasia. Visual deficits. Chorea. Non-focal symptoms: [10].

Headache: Approximately 20% of the paediatric patients under the age of 14 years suffer from headache. Likely explanantion for the headache was the reduction of cerebral blood flow or cerebral blood flow reserve and diffusive cortical inhibition [17]. Dilatation of meningeal and leptomeningeal collateral vessels may stimulate dural nociceptors. Every refractory headache, especially in the paediatric population should be thoroughly worked up for moyamoya disease [17] Headaches can be migraine-like episodes which may respond to revascularization surgery or remain refractory to surgery [17].

Cognitive impairment, learning disability, and attention deficits.

Seizures.

Syncope.

Personality change, mistaken for a psychiatric illness like schizophrenia, acute transient psychosis, and mania [18].

Symptoms and signs which serve as biomarkers in MMD/MMS:

Orthostatic intolerance (also termed "orthostatic dysregulation"): [19] Orthostatic intolerance is defined as" a disturbance in the physiological adjustment mechanism compensating for physical stresses, such as standing, and causes a variety of symptoms associated with hemodynamic or autonomic nervous system compromise". These symptoms can have a potential impact on the quality of life of paediatric MMD patients. In a study done by H. Uchino et al., 59% of children 10–15 years old suffered from orthostatic intolerance. These symptoms usually go unnoticed, and thus a thorough history from the patients and their caretakers become mandatory.

Symptoms which are suggestive of orthostatic intolerance:

Frequent headache.

Susceptibility to vertigo & dizziness on standing.

Fatigue.

Difficulty while getting out of bed.

Motion sickness.

Palpitation &/or dyspnea after mild exercise.

Tendency for fainting in the standing position.

Anorexia.

Occasional umbilical colic (severe abdominal pain).

Nausea on taking a hot bath or encountering unpleasant experiences.

Absent from school due to the above symptoms.

Pallor.

Fundus: Retinovascular anomalies and "morning glory disk" an enlargement of the optic disk should compel the clinician to look for moyamoya vasculopathy [20]. Morning glory syndrome or Morning glory disc anomaly is an unusual

### **Figure 2.**

*Showing morning glory disc [courtesy:Indian J Radiol imaging. 2018 Apr-Jun] [22]. MRI brain CISS sequence of orbit region may further confirm funnel-shaped excavation of the posterior globein morning glory syndrome of Moyamoya disease (Figure 3) [22].*

**Figure 3.** *Showing funnel-shaped excavation of posterior globe [courtesy: Indian J Radiol imaging. 2018 Apr-Jun] [22].*

congenital optic disc anomaly characterised by a funnel-shaped excavation of the posterior globe that incorporates the optic disc [21]. Kindler described it in 1970 because it resembled the morning glory flower. The disc itself is enlarged, and orange or pink in colour within a surrounding area of peripapillary chorioretinal pigmentary changes. Alteration of lamina cribrosa and posterior sclera due to embryonic developmental defect leads to this fundus's flowery appearanace.

Presence of this sign indicates an association with systemic or intracranial vasculopathies such as MMD. Morning glory disc occurs in 50% of patients with the MMD (**Figure 2**).

Sequelae of MMD: [16]. Refractory headaches. Recurrent TIAs. Posterior cerebral artery (PCA) involvement. Recurrent intracranial aneurysms. Unstable MMD.

In children with MMD, recurrent ischemias can result in cerebral atrophy and thus emanate the onset of learning difficulties, cognitive impairment and mental retardation.