**5. Mechanics of hydraulic fracturing**

As used classically in petroleum engineering, hydraulic fracturing involves sealing off an interval of a borehole at depth in an oil or gas bearing horizon, subjecting the interval to increasing fluid pressure until a fracture is generated, injecting some form of granular proppant into the fracture as it extends a considerable distance from the borehole into the

5 Hydraulic fractures generated in classical petroleum applications typically extend (2b) of the order of 25m ~ 50m from a wellbore. The fracture aperture (2a) at the wellbore then will be typically of the order of 0.01 m. Thus, the tensile stress concentration at the tip is very high of the order of 103.

6 In his second paper, Griffith (1924), demonstrated that tensile stresses also developed around similar cracks loaded in compression, provided the cracks were inclined to the direction of the major principal (compressive) stress.(He also assumed that the cracks did not close under the compression.) For the optimum crack inclination, an applied compressive stress of eight times the magnitude of the tensile strength was required to develop a tensile stress on the crack boundary (close to, but not at the apex of the crack) equal to the limiting value in the tensile test. He concluded that the uniaxial compressive strength of a brittle material should be eight times greater than the tensile strength. Interestingly, he did not invoke his second (minimum potential energy) criterion. It was later determined that although a tensile crack could initiate in a compressive stress regime as predicted by Griffith (1924), the crack was stable (i.e., did not satisfy the minimum potential energy criterion). The compressive/tensile strength ratio is greater than 8 (see Hoek and Bieniawski, 1966).

petroleum bearing formation, and then releasing the pressure. This causes the sides of the fracture to compress onto the proppant, creating a high-permeability pathway to allow oil and/ or natural gas to flow back to the well and to the surface.

tion\_models. Several differences between the stationary crack assumed by Inglis (1913) and a hydraulic fracture introduce significant difficulties in developing an accurate model of the fracturing process. Thus, the fracture is generated by application of an increasing fluid pressure until the fracture is initiated and extends away from the injection point. Flow of fluid in the fracture is governed by classical fluid flow equations of Poiseuille and Reynolds (lubrication); the pressure drop along the fracture depends on the viscosity of the fluid, and the permeability of the rock (leading to fluid 'leak-off'); the fracture aperture depends on the stiffness of the rock mass and the fluid pressure distribution along the crack; and fracture extension depends on the mechanical energy supplied to the region around the crack tip. The tip may propagate ahead of the fluid, leading to a 'lag,'a dry region between the crack tip and fluid front.

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**Figure 2.** Radial Model of Axi-symmetric Flow and Deformation associated with Hydraulic Fracturing.

(least compressive) principal in-situ stress, σ0.

Figure 2 illustrates these features for the classical Radial Model in which it is assumed that the fracture propagates symmetrically away from the borehole in a plane normal to the minimum

Development of efficient and robust Hydraulic Fracturing (HF) simulators is central to successful practical HF treatment of petroleum reservoirs. As noted earlier, competing physical processes are operative during the fracturing operation. This has led to a sustained effort over many years to understand and map the multi-scale nature of the tip asymptotics that arise as a result of these competing physical processes in fluid-driven fracture. These asymptotics solutions are critical to the construction of efficient and robust HF simulators. For example, in an impermeable medium, the viscous energy dissipation associated with driving fluid through the fracture competes with the energy required to break the solid material. Breaking of the bonds corresponds to the familiar asymptotic form of linear elastic fracture mechanics (LEFM), i.e., the opening in the tip region is of the form, e.g., (Rice, 1968), with denoting the distance from the tip. However, under conditions where viscous dissipation dominates, the coupling between the fluid flow and solid deformation leads to (Spence and Sharp, 1985; Lister, 1990; Desroches et al., 1994), on a scale that is considerably larger than the size of the LEFMdominated region, but still small relative to the overall fracture size. In other words, in the viscosity-dominated regime, the zone governed by the LEFM asymptote is negligibly small

Figure 1 shows a simple two-dimensional cross-section through an idealized hydraulic fracture. The borehole injection point is at the center of the fracture, which is assumed to be a narrow ellipse that has extended in a plane normal to the direction of the maximum7 (least compressive) in-situ stress.

**Figure 1.** Left) Major and (right) minor principal stresses in the vicinity of an internally pressurized elliptical crack in an impermeable rock.

In the case shown, the crack major/minor axis ratio a/b is 10:1. The internal fluid pressure p = 1.2, while the least compressive principal stress σx = 1.0. This results in a tensile stress concentration at the crack tip. The magnitude of the elastic stress concentration at the crack tip increases directly with 2a/b, (Inglis, 1913). Hence for the case of a>>b, i.e., a 'sharp' crack8 , the concentration is very high, and the crack will extend essentially as soon as the fluid pressure exceeds the magnitude of the least compressive principal stress (σx in Figure 3) it begins to extend, and there will be a pressure gradient from the injection point towards the crack tip as the fluid flows towards the tips. This gradient will depend on the fluid viscosity. Also, since the rock will exhibit some level of permeability, fluid will also flow (or 'leak–off') into the formation as it flows under pressure along the fracture; the rock has a finite strength, or 'toughness' so that energy will be required to extend the crack.

An analytical solution for the stresses in the elastic medium and the crack-opening displace‐ ment along the crack was first published by Inglis (1913) and served as the basis for early applications to hydraulic fracturing and fracture treatment design. The Perkins, Kern (1961) and Nordgren (1972) (PKN) and Geertsma and de Klerk (1969) (GDK) models are still used, although numerical models and combinations are now popular. Details of the PKN and GDK models can be found on the SPE website: http://petrowiki.spe.org/Fracture\_propaga‐

7 Tension is assumed to be positive in Figure 3.

8 A typical hydraulic fracture may have a length (2a) of the order of 50m and a maximum aperture (2b) of 5mm, so that the stress concentration will be of the order of 2000:1.

tion\_models. Several differences between the stationary crack assumed by Inglis (1913) and a hydraulic fracture introduce significant difficulties in developing an accurate model of the fracturing process. Thus, the fracture is generated by application of an increasing fluid pressure until the fracture is initiated and extends away from the injection point. Flow of fluid in the fracture is governed by classical fluid flow equations of Poiseuille and Reynolds (lubrication); the pressure drop along the fracture depends on the viscosity of the fluid, and the permeability of the rock (leading to fluid 'leak-off'); the fracture aperture depends on the stiffness of the rock mass and the fluid pressure distribution along the crack; and fracture extension depends on the mechanical energy supplied to the region around the crack tip. The tip may propagate ahead of the fluid, leading to a 'lag,'a dry region between the crack tip and fluid front.

petroleum bearing formation, and then releasing the pressure. This causes the sides of the fracture to compress onto the proppant, creating a high-permeability pathway to allow oil and/

Figure 1 shows a simple two-dimensional cross-section through an idealized hydraulic fracture. The borehole injection point is at the center of the fracture, which is assumed to be a narrow ellipse that has extended in a plane normal to the direction of the maximum7 (least

**Figure 1.** Left) Major and (right) minor principal stresses in the vicinity of an internally pressurized elliptical crack in an

In the case shown, the crack major/minor axis ratio a/b is 10:1. The internal fluid pressure p = 1.2, while the least compressive principal stress σx = 1.0. This results in a tensile stress concentration at the crack tip. The magnitude of the elastic stress concentration at the crack tip increases directly with 2a/b, (Inglis, 1913). Hence for the case of a>>b, i.e., a 'sharp' crack8

concentration is very high, and the crack will extend essentially as soon as the fluid pressure exceeds the magnitude of the least compressive principal stress (σx in Figure 3) it begins to extend, and there will be a pressure gradient from the injection point towards the crack tip as the fluid flows towards the tips. This gradient will depend on the fluid viscosity. Also, since the rock will exhibit some level of permeability, fluid will also flow (or 'leak–off') into the formation as it flows under pressure along the fracture; the rock has a finite strength, or

An analytical solution for the stresses in the elastic medium and the crack-opening displace‐ ment along the crack was first published by Inglis (1913) and served as the basis for early applications to hydraulic fracturing and fracture treatment design. The Perkins, Kern (1961) and Nordgren (1972) (PKN) and Geertsma and de Klerk (1969) (GDK) models are still used, although numerical models and combinations are now popular. Details of the PKN and GDK models can be found on the SPE website: http://petrowiki.spe.org/Fracture\_propaga‐

8 A typical hydraulic fracture may have a length (2a) of the order of 50m and a maximum aperture (2b) of 5mm, so that

'toughness' so that energy will be required to extend the crack.

7 Tension is assumed to be positive in Figure 3.

the stress concentration will be of the order of 2000:1.

, the

or natural gas to flow back to the well and to the surface.

compressive) in-situ stress.

52 Effective and Sustainable Hydraulic Fracturing

impermeable rock.

**Figure 2.** Radial Model of Axi-symmetric Flow and Deformation associated with Hydraulic Fracturing.

Figure 2 illustrates these features for the classical Radial Model in which it is assumed that the fracture propagates symmetrically away from the borehole in a plane normal to the minimum (least compressive) principal in-situ stress, σ0.

Development of efficient and robust Hydraulic Fracturing (HF) simulators is central to successful practical HF treatment of petroleum reservoirs. As noted earlier, competing physical processes are operative during the fracturing operation. This has led to a sustained effort over many years to understand and map the multi-scale nature of the tip asymptotics that arise as a result of these competing physical processes in fluid-driven fracture. These asymptotics solutions are critical to the construction of efficient and robust HF simulators. For example, in an impermeable medium, the viscous energy dissipation associated with driving fluid through the fracture competes with the energy required to break the solid material. Breaking of the bonds corresponds to the familiar asymptotic form of linear elastic fracture mechanics (LEFM), i.e., the opening in the tip region is of the form, e.g., (Rice, 1968), with denoting the distance from the tip. However, under conditions where viscous dissipation dominates, the coupling between the fluid flow and solid deformation leads to (Spence and Sharp, 1985; Lister, 1990; Desroches et al., 1994), on a scale that is considerably larger than the size of the LEFMdominated region, but still small relative to the overall fracture size. In other words, in the viscosity-dominated regime, the zone governed by the LEFM asymptote is negligibly small compared to the crack length. Thus, in the viscosity-dominated regime, the HF simulator should embed a 2/3 power law asymptote rather than the classic 1/2 asymptote of LEFM. Garagash et al.(2011) discuss the generalized asymptotics near the tip an advancing hydraulic fracture, an extension of two particular asymptotics obtained at Schlumberger Cambridge Research Laboratory in the early 1990's (Desroches et al., 1994; Lenoach, 1995).

**6. Hydroshear**

resistance of the fracture to (shear) sliding, τr, will be:

t

also presented as an argument in favor of hydroshearing.

**7. Deformation and failure of rock in situ**

fractures from different tectonic epochs.

Hydraulic fracturing is considered to be initiated from a packed–off interval borehole when the net state of stress around the well bore reaches the tensile strength of the rock. It is important to recognize that fluid pressurization of a well in permeable rock will result in flow of the fluid into the rock as soon as the fluid pressure stimulation process is started. This changes the effective stress state in the rock mass and can lead to slip on pre-existing fractures at fluid pressures below the pressure required to crate and extend a hydraulic fracture. This process of inducing slip on pre-existing fractures is termed 'Hydro-shear'. Flow of pressurized fluid into the rock reduces the effective normal stress (σn – p) everywhere in the rock { σn = normal stress at any point; p = fluid pressure.] If c and μ respectively represent the cohesion and coefficient of friction acting across the surfaces of a fracture in the rock, then the effective

> s

Thus, if the pressure p is raised progressively then τr will be reduced correspondingly until it reaches the limit at which sliding will occur. The situation is illustrated graphically in Figure 3. The rock is subjected to a three-dimensional state of stress represented by the principal stresses σ1, σ2, σ3 and the fluid pressure p. The series of points 'X' indicate the effective state of stress on an array of pre-existing fractures in the rock. As illustrated in Figure 5, the effect of increasing the fluid pressure in the medium is to move the stress state on these cracks close to the limiting shear resistance, i.e., to the limiting value represented by the Mohr-Coulomb limit. As the stress state reaches this limit, the cracks will slip. In order to initiate a hydraulic fracture, the fluid pressure would need to be increased further, until the limiting Mohr circle reaches the tensile strength limit of the failure envelope. Since crack surfaces are often not smooth, shear slip will tend to result in crack dilation, and an associated increase in fluid conductivity. It is suggested that hydro-shearing could be more effective than hydraulic fracturing as a stimulation technique in certain applications, e.g., in stimulation of hightemperature geothermal reservoirs. Cladouhos et al. (2011) discuss the application of hydroshearing as a geothermal stimulation technique. The possibility that silica proppant may dissolve in the aggressive high-temperature fluid environment of some geothermal reservoirs whereas slip on rough fractures develops aperture increase without the need for proppant is

As with fabricated materials, the deformation and failure of brittle rock is also dependent strongly on fractures and discontinuities. In a rock mass, however, the fractures occur over a very wide range of scales from sub-microscopic to the size of tectonic plates. A large specimen of rock will probably include some large fractures, and as the scale of the rock mass increases,

r c n – p = + *µ* ( ) (1)

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Three classes of numerical algorithms for HF simulators have now been built: (i) a moving grid for KGD, radial, PKN and P3D fracture simulators; (ii) a fixed grid for plane strain and axisymmetric HF with allowance for a lag between the fluid front and the crack tip, and fracture curving (a versatile code has been developed at CSIRO9 Melbourne to simulate the interaction of a hydraulic fracture with other discontinuities); and (iii) fixed grid for simulating a arbitrary shape planar fracture in a homogenous elastic rock. These codes rely on the displacement discontinuity method (Crouch and Starfield, 1983) for solving the elastic component of the problem, i.e., the relationship between the fracture aperture and the fluid pressure.

**Figure 3.** Fluid Pressure Distribution along the Central Axis (Ox) of Figure 1 for a permeable rock due to pressurization and de-pressurization of the borehole.

Figure 3 is presented to illustrate that the fluid pressure in a permeable rock can continue to flow away from the point of injection even after the borehole pressure is reduced to zero. The example shows the distribution of fluid pressure in the rock mass (permeability 5 mD) after (i) 2 days of pressurization up to the peak pressure of 20 MPa in the fracture; (ii) stop pumping and reduce fluid pressure quickly to 12MPa at the point of injection; (iii) hold the pressure constant for 2 days; and (iv) drop the pressure to zero.

It is seen that the pressure in the rock (red curve) has a maximum at some distance from the borehole such that fluid continues to flow into the rock for some time after the pressure in the borehole is reduced to zero. Different combinations of rock permeability, pumping rates and durations can lead to higher peak pressure values in the rock, and longer periods during which fluid can continue to flow away from the well. Such flow may contribute to slip on pre-existing fractures after the pressure in the borehole is reduced to zero.

9 Commonwealth Scientific and Industrial Research Organization.

#### **6. Hydroshear**

compared to the crack length. Thus, in the viscosity-dominated regime, the HF simulator should embed a 2/3 power law asymptote rather than the classic 1/2 asymptote of LEFM. Garagash et al.(2011) discuss the generalized asymptotics near the tip an advancing hydraulic fracture, an extension of two particular asymptotics obtained at Schlumberger Cambridge

Three classes of numerical algorithms for HF simulators have now been built: (i) a moving grid for KGD, radial, PKN and P3D fracture simulators; (ii) a fixed grid for plane strain and axisymmetric HF with allowance for a lag between the fluid front and the crack tip, and fracture

of a hydraulic fracture with other discontinuities); and (iii) fixed grid for simulating a arbitrary shape planar fracture in a homogenous elastic rock. These codes rely on the displacement discontinuity method (Crouch and Starfield, 1983) for solving the elastic component of the

**Figure 3.** Fluid Pressure Distribution along the Central Axis (Ox) of Figure 1 for a permeable rock due to pressurization

Figure 3 is presented to illustrate that the fluid pressure in a permeable rock can continue to flow away from the point of injection even after the borehole pressure is reduced to zero. The example shows the distribution of fluid pressure in the rock mass (permeability 5 mD) after (i) 2 days of pressurization up to the peak pressure of 20 MPa in the fracture; (ii) stop pumping and reduce fluid pressure quickly to 12MPa at the point of injection; (iii) hold the pressure

It is seen that the pressure in the rock (red curve) has a maximum at some distance from the borehole such that fluid continues to flow into the rock for some time after the pressure in the borehole is reduced to zero. Different combinations of rock permeability, pumping rates and durations can lead to higher peak pressure values in the rock, and longer periods during which fluid can continue to flow away from the well. Such flow may contribute to slip on pre-existing

problem, i.e., the relationship between the fracture aperture and the fluid pressure.

Melbourne to simulate the interaction

Research Laboratory in the early 1990's (Desroches et al., 1994; Lenoach, 1995).

curving (a versatile code has been developed at CSIRO9

54 Effective and Sustainable Hydraulic Fracturing

constant for 2 days; and (iv) drop the pressure to zero.

fractures after the pressure in the borehole is reduced to zero.

9 Commonwealth Scientific and Industrial Research Organization.

and de-pressurization of the borehole.

Hydraulic fracturing is considered to be initiated from a packed–off interval borehole when the net state of stress around the well bore reaches the tensile strength of the rock. It is important to recognize that fluid pressurization of a well in permeable rock will result in flow of the fluid into the rock as soon as the fluid pressure stimulation process is started. This changes the effective stress state in the rock mass and can lead to slip on pre-existing fractures at fluid pressures below the pressure required to crate and extend a hydraulic fracture. This process of inducing slip on pre-existing fractures is termed 'Hydro-shear'. Flow of pressurized fluid into the rock reduces the effective normal stress (σn – p) everywhere in the rock { σn = normal stress at any point; p = fluid pressure.] If c and μ respectively represent the cohesion and coefficient of friction acting across the surfaces of a fracture in the rock, then the effective resistance of the fracture to (shear) sliding, τr, will be:

$$
\tau \mathbf{r} = \mathbf{c} + \mu \left( \sigma \mathbf{n} - \mathbf{p} \right) \tag{1}
$$

Thus, if the pressure p is raised progressively then τr will be reduced correspondingly until it reaches the limit at which sliding will occur. The situation is illustrated graphically in Figure 3. The rock is subjected to a three-dimensional state of stress represented by the principal stresses σ1, σ2, σ3 and the fluid pressure p. The series of points 'X' indicate the effective state of stress on an array of pre-existing fractures in the rock. As illustrated in Figure 5, the effect of increasing the fluid pressure in the medium is to move the stress state on these cracks close to the limiting shear resistance, i.e., to the limiting value represented by the Mohr-Coulomb limit. As the stress state reaches this limit, the cracks will slip. In order to initiate a hydraulic fracture, the fluid pressure would need to be increased further, until the limiting Mohr circle reaches the tensile strength limit of the failure envelope. Since crack surfaces are often not smooth, shear slip will tend to result in crack dilation, and an associated increase in fluid conductivity. It is suggested that hydro-shearing could be more effective than hydraulic fracturing as a stimulation technique in certain applications, e.g., in stimulation of hightemperature geothermal reservoirs. Cladouhos et al. (2011) discuss the application of hydroshearing as a geothermal stimulation technique. The possibility that silica proppant may dissolve in the aggressive high-temperature fluid environment of some geothermal reservoirs whereas slip on rough fractures develops aperture increase without the need for proppant is also presented as an argument in favor of hydroshearing.

#### **7. Deformation and failure of rock in situ**

As with fabricated materials, the deformation and failure of brittle rock is also dependent strongly on fractures and discontinuities. In a rock mass, however, the fractures occur over a very wide range of scales from sub-microscopic to the size of tectonic plates. A large specimen of rock will probably include some large fractures, and as the scale of the rock mass increases, fractures from different tectonic epochs.

**Figure 4.** Hydro-shearing — a procedure to generate slip on pre-existing fractures by increasing the fluid pressure to a level below that required to generate a hydraulic fracture.

of joint sets in DFN's is the formation of bridges of intact rock Figure 4 within the SRM. These bridges provide regions of intact rock, and of stress concentration, in the SRM and account for a significant part of the overall strength of the rock mass. Earlier models of a rock mass, considered to consist of several sets of through-going fractures, exhibited much lower rock

**Figure 5.** The Synthetic Rock Mass (SRM ) representation of a fractured rock mass (in two dimensions). Damjanac et al. (2013) present a discussion of the 'construction' of an SRM in three dimensions. Pierce (2011) presents a comprehen‐

*Fracture Representation (DFN)*

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Figure 5 presents selected extracts from a two–dimensional *PFC* simulation of the development of a hydraulic fracture in a jointed Synthetic Rock Mass. The SRM model was developed following the procedure outlined in Figure 5. The joint distribution was based on a DFN obtained at the Northparkes Mine in Australia.11 Figure 5(a) shows the location of a vertical borehole that was pressurized by fluid until a hydraulic fracture was initiated. The rock mass is assumed to be impermeable. (The path of the fracture has been traced in blue for clarity.) Displacements in the rock mass produced by the hydraulic fracture are shown as vectors on each side of the fracture. It is seen that the fracture started more or less symmetrically on each side of the borehole, but propagation of the right wing was arrested when the hydraulic fracture encountered an adversely oriented pre-existing joint (Figure 5(b)). With increasing pressure, in the borehole, the hydraulic fracture continued to extend asymmetrically towards the left (Figures 5(c) and 5(d) Figure 5(d) is simply an enlarged view of Figure 5(c)). It is seen that the propagating fracture extended partially by opening existing fractures and partially by developing new fractures through intact rock. Although local deviations occur, the overall path of fracture growth is approximately perpendicular to the direction of the minimum compression stress. The existing fractures introduce an asymmetry to the rock mass. In terms of the idealized symmetric crack of Figure 2, the system in Figure 3 can be considered as two cracks, one extending to the right and one to the left of the borehole with a higher 'fracture

11 A number of important subsurface engineering problems involve borehole access only. This often means difficulty in establishing reliable, realistic DFN's. In such cases there is no recourse, at least at the start of the project, other than to try to infer fracture networks from borehole observations, perhaps supplemented by local observations of structural geological features . The DFN for Northparkes was available and convenient to use in the example shown in Figure 5.

mass strength (Hoek and Brown, 1980).

• *2,890 faults and 37,335 joints i.e. 40,225 discontinuities*

sive discussion of practical guidelines and factors involved in the construction of DFN's.

• *~330,000 particles*  • *38,656 blocks (clusters \*)*  • *A cluster is defined as a group of particles , each of which may be reached from any other in the group without crossing a joint face.*

*Intact Rock Representation (PFC)*

particle

bond

toughness' on the right compared to the left, etc.

Study of fracture systems underground in mines and in civil engineering projects allow systems of fractures to be identified and classified statistically into discrete fracture networks (DFN's). The network will include intersecting sets of planar fractures, but individual fractures will tend to be of different lengths, and though organized in two or three spatial orientations, of variable, finite length and not collinear.

Figure 7 presents a two-dimensional illustration of the application of DFN's to the numerical modeling of a fractured rock mass. The in-situ rock mass is considered as a large specimen of intact rock that has been transected by the DFN determined from field observations and fracture mapping underground or at surface outcrops. The properties of the intact rock are built into a Bonded Particle Model of the rock (using the Particle Flow Code (*PFC*) code) based on results of laboratory tests of the intact rock deformability and strength. The intact rock representation is shown on the left of Figure 6. The DFN (shown on the upper right in Figure 6) then is superimposed onto the intact rock.

Cohesion and friction values are assigned to the joint planes.10 The 'unconfined' strength of a typical large SRM is of the order of a few percent of an intact rock specimen of the same rock (Cundall, 2008). Much of the in-situ strength is derived, of course, from the in-situ stresses imposed on the SRM in situ. One of the consequences of the finite length and lack of collinearity

10 Typically, computer tests indicate the unconfined strength of a Synthetic Rock Mass of the order of 50-m to 100-m side length, to be a few percent of the unconfined strength of the laboratory specimen.

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**Figure 5.** The Synthetic Rock Mass (SRM ) representation of a fractured rock mass (in two dimensions). Damjanac et al. (2013) present a discussion of the 'construction' of an SRM in three dimensions. Pierce (2011) presents a comprehen‐ sive discussion of practical guidelines and factors involved in the construction of DFN's.

of joint sets in DFN's is the formation of bridges of intact rock Figure 4 within the SRM. These bridges provide regions of intact rock, and of stress concentration, in the SRM and account for a significant part of the overall strength of the rock mass. Earlier models of a rock mass, considered to consist of several sets of through-going fractures, exhibited much lower rock mass strength (Hoek and Brown, 1980).

Study of fracture systems underground in mines and in civil engineering projects allow systems of fractures to be identified and classified statistically into discrete fracture networks (DFN's). The network will include intersecting sets of planar fractures, but individual fractures will tend to be of different lengths, and though organized in two or three spatial orientations,

**Figure 4.** Hydro-shearing — a procedure to generate slip on pre-existing fractures by increasing the fluid pressure to a

Figure 7 presents a two-dimensional illustration of the application of DFN's to the numerical modeling of a fractured rock mass. The in-situ rock mass is considered as a large specimen of intact rock that has been transected by the DFN determined from field observations and fracture mapping underground or at surface outcrops. The properties of the intact rock are built into a Bonded Particle Model of the rock (using the Particle Flow Code (*PFC*) code) based on results of laboratory tests of the intact rock deformability and strength. The intact rock representation is shown on the left of Figure 6. The DFN (shown on the upper right in Figure

Cohesion and friction values are assigned to the joint planes.10 The 'unconfined' strength of a typical large SRM is of the order of a few percent of an intact rock specimen of the same rock (Cundall, 2008). Much of the in-situ strength is derived, of course, from the in-situ stresses imposed on the SRM in situ. One of the consequences of the finite length and lack of collinearity

10 Typically, computer tests indicate the unconfined strength of a Synthetic Rock Mass of the order of 50-m to 100-m side

of variable, finite length and not collinear.

level below that required to generate a hydraulic fracture.

56 Effective and Sustainable Hydraulic Fracturing

6) then is superimposed onto the intact rock.

length, to be a few percent of the unconfined strength of the laboratory specimen.

Figure 5 presents selected extracts from a two–dimensional *PFC* simulation of the development of a hydraulic fracture in a jointed Synthetic Rock Mass. The SRM model was developed following the procedure outlined in Figure 5. The joint distribution was based on a DFN obtained at the Northparkes Mine in Australia.11 Figure 5(a) shows the location of a vertical borehole that was pressurized by fluid until a hydraulic fracture was initiated. The rock mass is assumed to be impermeable. (The path of the fracture has been traced in blue for clarity.) Displacements in the rock mass produced by the hydraulic fracture are shown as vectors on each side of the fracture. It is seen that the fracture started more or less symmetrically on each side of the borehole, but propagation of the right wing was arrested when the hydraulic fracture encountered an adversely oriented pre-existing joint (Figure 5(b)). With increasing pressure, in the borehole, the hydraulic fracture continued to extend asymmetrically towards the left (Figures 5(c) and 5(d) Figure 5(d) is simply an enlarged view of Figure 5(c)). It is seen that the propagating fracture extended partially by opening existing fractures and partially by developing new fractures through intact rock. Although local deviations occur, the overall path of fracture growth is approximately perpendicular to the direction of the minimum compression stress. The existing fractures introduce an asymmetry to the rock mass. In terms of the idealized symmetric crack of Figure 2, the system in Figure 3 can be considered as two cracks, one extending to the right and one to the left of the borehole with a higher 'fracture toughness' on the right compared to the left, etc.

11 A number of important subsurface engineering problems involve borehole access only. This often means difficulty in establishing reliable, realistic DFN's. In such cases there is no recourse, at least at the start of the project, other than to try to infer fracture networks from borehole observations, perhaps supplemented by local observations of structural geological features . The DFN for Northparkes was available and convenient to use in the example shown in Figure 5.

**Figure 7.** Hydraulic fracture (green plastic) crossing a shear zone on the face of a tunnel excavated through the frac‐ ture. "The arrows indicate the trace of the fracture with green plastic contained in it. There is no clear fracture be‐ tween points 1 and 2 but the fracture may have crossed this zone either deeper into the rock or in the rock that has

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59

(a)

(b) (c)

**Figure 8.** Energy changes during propagation of a fracture through heterogeneous rock.

been excavated. Approximately 2 m of fracture extent is visible" (Jeffrey et al., 2009).

**Figure 6.** Extracts from simulation of the propagation of a hydraulic fracture in a two-dimensional impermeable SRM (Synthetic Rock Mass). (The horizontal stress σmax is 29 MPa and the vertical stress σmin is 12 MPa – Figure 5(a)). Note that the intact rock between the fractures has a finite strength and can break by rupture of the cemented bonded particles shown in Figure 5. The pressure required to propagate the fracture after breakdown was approximately 10 MPa above the minimum (i.e., least compressive) principal.

Jeffrey et al. (2009) conducted an underground test in the Northparkes Mine, Australia to observe the propagation of a hydraulic fracture in naturally fractured tock. Figure 7 shows part of the path of the fracture, as seen in a tunnel excavated into the fractured rock. The fracture path shows similar characteristics to those shown in the *PFC* simulation in Figure 6.

**Figure 7.** Hydraulic fracture (green plastic) crossing a shear zone on the face of a tunnel excavated through the frac‐ ture. "The arrows indicate the trace of the fracture with green plastic contained in it. There is no clear fracture be‐ tween points 1 and 2 but the fracture may have crossed this zone either deeper into the rock or in the rock that has been excavated. Approximately 2 m of fracture extent is visible" (Jeffrey et al., 2009).

**Figure 8.** Energy changes during propagation of a fracture through heterogeneous rock.

Jeffrey et al. (2009) conducted an underground test in the Northparkes Mine, Australia to observe the propagation of a hydraulic fracture in naturally fractured tock. Figure 7 shows part of the path of the fracture, as seen in a tunnel excavated into the fractured rock. The fracture

(c) (d)

**Figure 6.** Extracts from simulation of the propagation of a hydraulic fracture in a two-dimensional impermeable SRM (Synthetic Rock Mass). (The horizontal stress σmax is 29 MPa and the vertical stress σmin is 12 MPa – Figure 5(a)). Note that the intact rock between the fractures has a finite strength and can break by rupture of the cemented bonded particles shown in Figure 5. The pressure required to propagate the fracture after breakdown was approximately 10

(a) (b)

path shows similar characteristics to those shown in the *PFC* simulation in Figure 6.

MPa above the minimum (i.e., least compressive) principal.

58 Effective and Sustainable Hydraulic Fracturing

The energy required to initiate crack propagation is represented by the area OAC in Figure 7(a). Whether or not the crack will extend depends on the energy that becomes available from the intact rock around the crack. If the energy released from the rock mass, represented by the area under the red curve AB, is greater than the energy required to extend the crack, repre‐ sented by the area under curve AE, then the crack will extend; the excess energy represented by the shaded area serves to accelerate the crack and release seismic energy. If the energy required to extend the crack is represented by the area under the green curve AD, it is greater than the energy that would be released from the rock mass, and hence the crack would not extend. It is possible that the crack could exhibit some form of time-dependent weakening (e.g., due to fluid flow to the crack, viscous behavior, etc.) such that the energy required to extend the crack would be reduced. This could lead to crack extension, i.e., as the slope AD increased to overlap AB, but with no excess energy to produce seismicity. Figures 7(b) and 7(c)12 illustrate another feature of crack extension on the granular scale. The energy required to extend a crack through or around a grain will be variable; the fracture may encounter pore spaces where no crack energy is required. Application of a constant load to such a heteroge‐ neous system will result in local acceleration and deceleration of the crack-producing bursts of microseismicity. Similar effects can arise in rock fracture propagation at all scales.

It is worth noting that all of these processes of fracture propagation, albeit complex, develop in accordance with the principle of seeking the minimum potential energy of the system.

Much of the preceding discussion has focused on two-dimensional analysis or models. In reality, we are dealing with three- dimensional space (as noted in Figure 6), plus the influence of time (e.g., with respect to fluid flow, or time-dependent rock properties). Figure 8 provides an example from an actual record of hydraulic fracture propagation.

Figure 8 shows the sequence of microseismic events observed during hydraulic fracture stimulation ('treatment' in Figure 8(a)) of a borehole. Early time events are shown as green dots; later events are in red. The microseismic pattern indicates that fracturing started on both sides of the borehole at the injection horizon, but then moved up some 100 m to a higher horizon. As pumping continued, fracturing continued (red locations) on both horizons. It was concluded that the initial fracture in the lower horizon had intercepted a high-angle fault, allowing injection fluid to move to the higher level where it opened up and extended another fracture. Continued pumping led to fracture extension on both horizons. Numerical analysis Figure 8(b) indicated that initial fracture propagation at the lower level resulted in induced tension on the fault above the horizon, but compression on the fault below the lower injection horizon. This explains why injection fluid did not penetrate along the fault below the horizon, and provides a good illustration of the benefit of combining numerical analysis with field observation in understanding fracturing processes.

some cases, it is tacitly assumed that absence of microseismicity indicates absence of slip or deformation. In fact, there is growing evidence that microseismicity does not present a complete picture of deformations induced by stimulation or other effects leading to stress change. Figure 9, reproduced from Cornet (2012) (with permission from the author), shows Pwave velocity changes observed by 4D (time-dependent) tomography during the stimulation of the borehole GPK2 in the year 2000. A detailed discussion of the procedure used to observe

**Figure 9.** a) Microseismicity observed during hydraulic fracturing in a deep borehole; (b) numerical 'explanation' of

(a) (b)

Fractures and Fracturing: Hydraulic Fracturing in Jointed Rock

http://dx.doi.org/10.5772/56366

61

It is seen that the region of detected microseismicity (the cloud of black dots is small compared to the region where the P-wave velocity is reduced by as much as 20% in some regions). Some of the changes in velocity were temporary, suggesting that they may be related to temporal

and determine the P-wave changes is presented by Calo et al. (2012).

the behavior observed in (a).


**4. Conclusions**

262 Biogas

The untreated "raw" dairy wastewater with low value of pH (4.27) was completely nonactive in hydrogen generation by microbiological method. However, we assumed that the same wastewater under controlled pH can generate hydrogen similarly as a sterilized one. Therefore, in order to achieve similar conditions like in bioreactor operating under controlled pH we performed our batch tests in small photoreactors (capacity of 60 ml with working capacity of 30 ml) correcting pH with 0.5M solution of NaOH every 12 h. Medium containing non-sterilized dairy wastewater with concentration of 40 v/v % was inoculated with bacteria at two different concentrations: 0.086g dry wt/l (10 vol.%) or 0.36 g dry wt/l (30 vol.%). Data presented in table 5 indicate that stabilization of the system at pH close to 7 allows for hydrogen generation even from the untreated dairy wastewater. Application of inoculums with concentration at the 0.36 g dry wt/l level generates 3.6 l H2/l. The four-fold dilution of microorganisms reduces the volume of hydrogen to 2.6 l H2/l. Although the starting time was relatively long (about 20 h) savings which could arise from the application of untreated waste can be significant. Performing the same experiment with brewery waste II ( concentration 40 v/v % ) the yield of the generated hydrogen has not been improved. In this case the value of pH rapidly grew to 7.5- 7.9 in the first two days. However , it can not be excluded that in the system with controlled pH this yield could be much higher. Preliminary experiments performed under such

**3.5 The influence of pH correction on hydrogen production**

conditions confirm this assumption.

**3.6 Kinetic of hydrogen generation**

reaction rate and prolongation of the lag phase.

Rmax,H2 (l/l/h)

0.038±0.005 0.056±0.009 λH2 (h)

20.7±3.6 17.0±4.5 Y (l H2/l waste)

> 6.0 8.6

Table 5. Kinetic parameters of cumulative hydrogen production for non-treated 40 % dairy wastewater, with correction of pH for different concentration of inoculums (Seifert, 2010).

The results presented in this section suggest that hydrogen generation can be effectively performed under solar radiation in photobioreactor operating under continuous

The results of kinetic considerations based on modified Gompertz equation (Eq. 4) are shown in table 6. Independently from the kind of food waste (in the active of concentration) it was observed that the increase of the volume of generated hydrogen, small drops in

These results showed that higher substrate yield increases the reaction rate. Moreover, these values are well correlated with the lag phase in systems with higher concentration of wastes

are caused probably by longer adaptation of microorganisms to the bed.

pH final

> 6.8 6.7

COD loss (g O2/l)

> 3.8 4.6

COD loss (%)

> 20 23

Biomass (g/l)

> 2.2 2.8

Hmax (l/l)

2.58±0.16 3.62±0.24

\* expressed in g dry wt/l \*\* biomass increase

Inoculum conc.

> 0.086 0.36

conditions.

The presented results shows that the waste studied in this paper represent a vary good substrate in photophermentation by *Rhodobacter sphaeroides.* Light intensity of 9 klx and inoculum concentration of 0.36 g dry wt/l (30% v/v) were used as the most effective (high light conversion efficiency and short duration of the process). The studied wastes has to be treated with high temperature (20 min in 120oC). This pretreatment significantly increases H2 production. The optimum concentrations of wastes were estimated: 40% v/v for dairy waste and 10% v/v for brewery waste with high COD. These wastes represent the effective (comparable with L-malic acid) nutrient for hydrogen production. Higher wastes concentrations inhibit the process as it initiate fermentation which starts to compete with hydrogen production and additionally increases NH4 + concentration, which also negatively affect the process. Brewery waste with low COD shows low efficiencies and needs to be concentrated to supply sufficient concentration of organic compounds. An application of untreated dairy wastewater containing suspensions in efficient hydrogen generation process can be performed only at controlled acidity (pH = 7.0). Kinetic measurements proved that the rate of hydrogen generation drops with concentration of the waste and prolongs the lag phase.


**5.1 Laboratory and microbiology test**

 There are no specific analytical tests that suggest the presence of an NBTE. Depending on the causative disease, we can find analytical alterations that support or not a diagnosis.  In some patients with NBTE, data of disseminated intravascular coagulation can be evidenced. In case of suspicion of autoimmune disease, a complete immunological study should be requested, mainly from SLE and APS (including antinuclear antibody, anti-doublestranded DNA, and antiphospholipid antibodies). It will be necessary to carry out a screening of the most frequent types of neoplasms taking into account the sex, the comorbidities, and the age range of the patient.

 Many authors suggest that before diagnosing an NBTE, it is essential to rule out an IE after carrying out different microbiological tests. In fact, at least three sets of blood cultures must be made before any suspicion of IE. Sometimes blood cultures in the presence of valvular vegetations can be persistently negative and do not rule out the presence of IE (called "culture-negative endocarditis"). For this reason, cultures of other biological fluids (urine, feces, etc.) should be performed, and serology and PCR should be performed on those less frequent or "atypical" microorganisms that can also cause IE (e.g., *Brucella* spp., *Coxiella burnetii*, *Legionella*, etc.) (**Table 2**).


Preface

Modern societies have recently experienced several transitions in dietary habits. The last few centuries have emerged from famine by increasing the consumption of cereals. Also, food production has been industrialized, which enhances the diversity of food products. However, food industrialization also induces a rise in saturated fats and sugars in the diet, paralleled by a reduction in physical activity. More developed countries are now in a new transition phase fueled by the desire for healthier and less processed food. With these dietary transitions, human health has evolved, following the famous adage "We are what we eat." The most obvious example is the important escalation in diabetes occurrence over the last 30 years or so. Therefore, nutrition is a critical environmental factor modulating health throughout life.

Over the past decades, scientific interest has been focused on the impact of nutrition specifically on brain function.

Most nutrients can cross the blood–brain barrier to impact brain physiology. Nutrients in the brain can either fuel brain cells, contribute to tissue architecture, or initiate signaling pathways through their derivatives. Nutrients ultimately participate in brain development, cognitive and emotional behaviors, and can influence the susceptibility to develop brain pathologies. Despite the huge amount of knowledge brought about by the scientific community, a lot still needs to be unraveled.

Beyond dietary habits, nutrients can also be isolated and formulated to serve as therapeutic agents. Indeed, they are less prone to develop secondary effects than pharmaceuticals since the organism has the machinery to metabolize them. In addition, they can enter the brain more easily than synthetic molecules, which is essential to reach therapeutic efficacy for brain-related disorders.

More recently, the field of brain nutrition has been enlarged by considering bidirectional interactions between the brain and the periphery, including microbiota and the enteric system. For example, some microbiota species release derivatives following digestion and can have a direct effect on brain function. In the other direction, it is now clear that the brain can control digestion and metabolism, not only through the hypothalamus, but also through mechanisms and circuits that are highly sophisticated, which delay their precise understanding. In addition, these bidirectional interactions between the brain and the periphery for nutrition are interdependent, which further complicates the picture.

*Feed Your Mind: How Does Nutrition Modulate Brain Function throughout Life?* is a selection of current research on the impact of diet on brain function. The book is organized into five chapters, opening with the editor's Introductory chapter.

Chapter 2 is dedicated to the role of lipids in the brain. In particular, polyunsaturated fatty acids are highly enriched in the brain and brain cells. This chapter

focuses on these polyunsaturated fatty acids and their derivatives, involved in the resolution of neuroinflammation.

Chapter 3 focuses on the role of glucose in fueling the brain, and how some hypothalamic neurons are sensitive to glycemia, to participate in its regulation. Indeed, the brain represents approximately 2% of body weight but consumes approximately 20% of its total energy. Therefore, blood glucose is essential for brain function. This chapter also discusses the role of fructose in brain function, since the current industrialized diet contains abnormally high levels of fructose.

Chapter 4 presents the concept of autophagy and how nutrition can modulate it. Autophagy is a process of protein degradation in cells that allow control of cell integrity. Autophagy is stimulated by caloric restriction; however, the global trend in industrialized countries is toward calories over consumption. Therefore, this chapter presents how modern dietary habits can favor neuropathologies associated with autophagy defects, such as in Alzheimer's disease.

Finally, Chapter 5 concentrates on brain–gut interactions in the context of enteral feeding. Some chronic pathologies require non-oral feeding, which basically bypasses the brain in the control of feeding. This particular situation highlights the role of the brain in different steps of feeding, from appetite to digestion. This chapter also points out strategies to improve digestion in enteral feeding.

We would like to thank all the authors for their valuable contributions and for their constructive interplay throughout the editorial process.

> **Clémentine Bosch-Bouju, Sophie Layé and Véronique Pallet** NutriNeuro Lab UMR1286, INRA/Bordeaux University/Bordeaux INP, France

> > **1**

Section 1

Introduction

Section 1 Introduction

**3**

**Chapter 1**

Introductory Chapter: Feed Your

Nutrition is a transdisciplinary science that aims at studying the role of food and physical exercise on health and diseases. It includes notably biochemistry, metabolism, behavioural and social studies. Nutrition science is highly diverse and

• The control of energy balance is a primary need for humans and for all ani-

related to the diversity of culture, even in one single country.

industrialisation has engendered a profound dietary imbalance.

obesity, cardiovascular disorders and depressive disorders.

• In human societies, alimentation participates to social behaviour.

• A high diversity of dietary models throughout the world exists, which is closely

• Modern societies have been hugely transformed since food industrialization.

The last point has critically changed the way of life for people in industrialised countries. Food industrialisation was originally designed to ease life and feed the growing population following the First and Second World Wars. Unexpectedly,

For the first time in history, people with industrialised diet are facing food with high quantities of sugar and saturated fats. This diet can also lead to deficiency in essential nutrients, such as vitamins, minerals and polyunsaturated fatty acids. This change in diet has been paralleled by an increase in sedentariness, which contributes to energy imbalance. This change in the last 70 years leads to global epidemics as

In this context, the brain appears as a structure highly sensitive to dietary imbalance [1]. In addition, the brain can participate to dietary imbalance by controlling feeding behaviours and through its interaction with peripheral organs and hormones involved in the control of energy balance. Thus, the impact of nutrition on brain function is a specific field of research that has gain interest in the recent years, and the role of the brain appears central in nutrition. Nutrition will impact the brain from early-developmental stages to adolescence, when the brain tissue is built and modelled. Nutrition also appears critical at adult age, to maintain optimal brain function. Finally, nutrition appears as an important environmental factor that

Mind - How Does Nutrition

Modulate Brain Function

throughout Life?

constantly evolving for several reasons:

mals, which implies it is of high importance.

*Clémentine Bosch-Bouju*

**1. Introduction**

## **Chapter 1**

## Introductory Chapter: Feed Your Mind - How Does Nutrition Modulate Brain Function throughout Life?

*Clémentine Bosch-Bouju*

## **1. Introduction**

Nutrition is a transdisciplinary science that aims at studying the role of food and physical exercise on health and diseases. It includes notably biochemistry, metabolism, behavioural and social studies. Nutrition science is highly diverse and constantly evolving for several reasons:

The last point has critically changed the way of life for people in industrialised countries. Food industrialisation was originally designed to ease life and feed the growing population following the First and Second World Wars. Unexpectedly, industrialisation has engendered a profound dietary imbalance.

For the first time in history, people with industrialised diet are facing food with high quantities of sugar and saturated fats. This diet can also lead to deficiency in essential nutrients, such as vitamins, minerals and polyunsaturated fatty acids. This change in diet has been paralleled by an increase in sedentariness, which contributes to energy imbalance. This change in the last 70 years leads to global epidemics as obesity, cardiovascular disorders and depressive disorders.

In this context, the brain appears as a structure highly sensitive to dietary imbalance [1]. In addition, the brain can participate to dietary imbalance by controlling feeding behaviours and through its interaction with peripheral organs and hormones involved in the control of energy balance. Thus, the impact of nutrition on brain function is a specific field of research that has gain interest in the recent years, and the role of the brain appears central in nutrition. Nutrition will impact the brain from early-developmental stages to adolescence, when the brain tissue is built and modelled. Nutrition also appears critical at adult age, to maintain optimal brain function. Finally, nutrition appears as an important environmental factor that should be controlled through ageing, to prevent neurodegenerative processes. In this introductory chapter, we will take the example of vitamin A, which is a nutrient that has been demonstrated as critical for brain function throughout life [2–5].

### **2. Vitamin A and its active metabolite: retinoic acid**

Vitamin A is a lipophilic vitamin that cannot be synthesised de novo by organism. Food sources are animal products for the preformed vitamin A and vegetables for provitamin A. Preformed vitamin A and provitamin A are found in sufficient quantities in most diets, but strong deficiency may occur in undernourished populations, mainly in sub-Saharan Africa. Vitamin A deficiency in children can cause blindness and growth retardation and can ultimately lead to death. Besides, vitamin A deficiency may occur with ageing, since its bioavailability can be reduced. In both cases, vitamin A supplementation can reverse this deficiency, which emphasises the need to study the impact of vitamin A supplementation for pregnant women and children, as well as for elderly.

The active metabolite of vitamin A in the brain is the all-*trans* retinoic acid (a*t*RA), synthesised from vitamin A (retinol) by aldehyde dehydrogenase enzymes [6, 7]. Retinoic acid and its derivatives bind to nuclear receptors, namely, RAR and RXR. These receptors act as homo- or heterodimers to control gene transcription [3, 6]. Therefore, retinoic acid is a powerful morphogen factor, highly involved in embryonic development and growth [8].

### **3. The role of vitamin A during brain development**

During brain development, retinoic acid synthesised from dietary vitamin A binds to nuclear receptors to drive transcription of hundreds of genes. Retinoic acid is a morphogen that acts through a concentration gradient [8]. To carry out the precision of retinoic acid gradient during embryonic development, metabolism and signalling pathways for retinoic acid are multiple and highly robust [8]. Remarkably, retinoic acid is the only morphogen that comes from dietary sources, which highlights the importance of vitamin A intake during pregnancy. Through its action on nuclear receptors, retinoic acid is implicated in the patterning of neural axis along the dorsoventral and anteroposterior axes [2].

In addition to development and growth, retinoic acid in the brain is critical for neuronal differentiation and neurite outgrowth. This is particularly true in the basal ganglia network, which is a group of brain structures involved in the control of action. Indeed, retinoic acid is key in the differentiation of specific subpopulations of neurons, such as the medium size spiny neurons in the striatum, or the dopaminergic neurons from the substantia nigra pars compacta [9–13].

#### **4. The role of vitamin A in the adult brain**

At adult age, vitamin A-derived retinoic acid has two remarkable roles; it is involved in homeostatic plasticity and in neurogenesis [3, 5, 14, 15]. First, retinoic acid induces molecular and morphological changes in neuronal network, to maintain overall synaptic activity constant, despite synaptic plasticity, a process named homeostatic synaptic plasticity [16]. For this, retinoic acid binds to nuclear RAR and RXR receptors, but evidence suggests that non-genomic mechanisms are also

**5**

disease.

**6. Conclusion**

*Introductory Chapter: Feed Your Mind - How Does Nutrition Modulate Brain Function…*

involved [17–19]. Changes induced by retinoic acid to produce homeostatic plasticity include transcription of synaptic proteins, such as AMPA receptors, but also modulation of neuronal morphology, through outgrowth or retraction of synapse

Second, retinoic acid controls neurogenesis. In rodent deficient for vitamin A, neurogenesis in the hippocampus is strongly dampened and can be restored by replenishment with vitamin A or derivatives [20–23]. However, in physiological conditions, retinoic acid applied exogenously can inhibit neurogenesis in the hippocampus and facilitate cell differentiation [3]. The apparent discrepancy between physiological and deficient states may be explained by the finely tuned concentration and timing of retinoic acid that is needed for its control of neurogenesis. In the hypothalamus, neurogenesis is highly dynamic to orchestrate circadian rhythms that govern several hypothalamic functions. In this structure, a similar role has been demonstrated for retinoic acid, inhibiting proliferation of cells and thus neurogenesis [5].

Ageing process is a physiological and unavoidable phenomenon involving the whole body. Related to brain function, ageing is characterised by a cognitive decline, which comprises all molecular and cellular alterations that lead ultimately to decreased performance in cognitive and executive functions [24]. Evidence suggests that bioavailability of retinoic acid in the brain reduces with ageing, likely due to peripheral alterations [4]. Yet several studies have highlighted the parallel between ageing, decrease in brain retinoid signalling and cognitive decline [4, 25–27]. Mechanisms linking retinoid metabolism and cognitive decline are not yet completely unravelled, but evidence suggests the involvement of glucocorticoids

[20] and morphological changes of neuronal trees (unpublished data).

Beyond normal ageing, decreased retinoid signalling in the brain with ageing may be involved in neurodegenerative processes, such as in Alzheimer's and Parkinson's diseases. For Alzheimer's disease, accumulating evidence suggests that the lack of retinoic acid in the hippocampus is a risk factor that precipitates the deposition of β-amyloid plaques, a histological landmark of the disease [28–31]. Therefore, vitamin A and retinoids appear as potential therapeutics [30, 32]. However, mechanisms are not yet sufficiently understood to elaborate such therapeutics. Additionally, retinoids are lipophilic molecules that oxidise rapidly, which

In the context of Parkinson's disease, a similar process has been proposed. Reduced signalling of retinoids in the brain, and particularly in the substantia nigra compacta, may be a risk factor that accelerates the degeneration of dopaminergic neurons [33, 34]. This hypothesis is supported by the fact that rodents deficient for vitamin A or for retinoid receptors display motor impairments close to Parkinson's models [35, 36]. Some studies revealed encouraging results with retinoid supplementation to prevent neurodegeneration in cell culture or in vivo [37, 38], but research is still to preliminary to envisage soon vitamin A-based treatments for this

Through the solely example of vitamin A, we can appreciate the importance of nutrition for brain physiology, from development to adult age. Remarkably, a same

*DOI: http://dx.doi.org/10.5772/intechopen.89349*

**5. The role of vitamin A in the ageing brain**

render their pharmacological use challenging.

boutons and dendrites.

*Introductory Chapter: Feed Your Mind - How Does Nutrition Modulate Brain Function… DOI: http://dx.doi.org/10.5772/intechopen.89349*

involved [17–19]. Changes induced by retinoic acid to produce homeostatic plasticity include transcription of synaptic proteins, such as AMPA receptors, but also modulation of neuronal morphology, through outgrowth or retraction of synapse boutons and dendrites.

Second, retinoic acid controls neurogenesis. In rodent deficient for vitamin A, neurogenesis in the hippocampus is strongly dampened and can be restored by replenishment with vitamin A or derivatives [20–23]. However, in physiological conditions, retinoic acid applied exogenously can inhibit neurogenesis in the hippocampus and facilitate cell differentiation [3]. The apparent discrepancy between physiological and deficient states may be explained by the finely tuned concentration and timing of retinoic acid that is needed for its control of neurogenesis. In the hypothalamus, neurogenesis is highly dynamic to orchestrate circadian rhythms that govern several hypothalamic functions. In this structure, a similar role has been demonstrated for retinoic acid, inhibiting proliferation of cells and thus neurogenesis [5].

## **5. The role of vitamin A in the ageing brain**

Ageing process is a physiological and unavoidable phenomenon involving the whole body. Related to brain function, ageing is characterised by a cognitive decline, which comprises all molecular and cellular alterations that lead ultimately to decreased performance in cognitive and executive functions [24]. Evidence suggests that bioavailability of retinoic acid in the brain reduces with ageing, likely due to peripheral alterations [4]. Yet several studies have highlighted the parallel between ageing, decrease in brain retinoid signalling and cognitive decline [4, 25–27]. Mechanisms linking retinoid metabolism and cognitive decline are not yet completely unravelled, but evidence suggests the involvement of glucocorticoids [20] and morphological changes of neuronal trees (unpublished data).

Beyond normal ageing, decreased retinoid signalling in the brain with ageing may be involved in neurodegenerative processes, such as in Alzheimer's and Parkinson's diseases. For Alzheimer's disease, accumulating evidence suggests that the lack of retinoic acid in the hippocampus is a risk factor that precipitates the deposition of β-amyloid plaques, a histological landmark of the disease [28–31]. Therefore, vitamin A and retinoids appear as potential therapeutics [30, 32]. However, mechanisms are not yet sufficiently understood to elaborate such therapeutics. Additionally, retinoids are lipophilic molecules that oxidise rapidly, which render their pharmacological use challenging.

In the context of Parkinson's disease, a similar process has been proposed. Reduced signalling of retinoids in the brain, and particularly in the substantia nigra compacta, may be a risk factor that accelerates the degeneration of dopaminergic neurons [33, 34]. This hypothesis is supported by the fact that rodents deficient for vitamin A or for retinoid receptors display motor impairments close to Parkinson's models [35, 36]. Some studies revealed encouraging results with retinoid supplementation to prevent neurodegeneration in cell culture or in vivo [37, 38], but research is still to preliminary to envisage soon vitamin A-based treatments for this disease.

### **6. Conclusion**

Through the solely example of vitamin A, we can appreciate the importance of nutrition for brain physiology, from development to adult age. Remarkably, a same

*Feed Your Mind - How Does Nutrition Modulate Brain Function throughout Life?*

**2. Vitamin A and its active metabolite: retinoic acid**

children, as well as for elderly.

embryonic development and growth [8].

**3. The role of vitamin A during brain development**

axis along the dorsoventral and anteroposterior axes [2].

**4. The role of vitamin A in the adult brain**

nergic neurons from the substantia nigra pars compacta [9–13].

should be controlled through ageing, to prevent neurodegenerative processes. In this introductory chapter, we will take the example of vitamin A, which is a nutrient that has been demonstrated as critical for brain function throughout life [2–5].

Vitamin A is a lipophilic vitamin that cannot be synthesised de novo by organism. Food sources are animal products for the preformed vitamin A and vegetables for provitamin A. Preformed vitamin A and provitamin A are found in sufficient quantities in most diets, but strong deficiency may occur in undernourished populations, mainly in sub-Saharan Africa. Vitamin A deficiency in children can cause blindness and growth retardation and can ultimately lead to death. Besides, vitamin A deficiency may occur with ageing, since its bioavailability can be reduced. In both cases, vitamin A supplementation can reverse this deficiency, which emphasises the need to study the impact of vitamin A supplementation for pregnant women and

The active metabolite of vitamin A in the brain is the all-*trans* retinoic acid (a*t*RA), synthesised from vitamin A (retinol) by aldehyde dehydrogenase enzymes [6, 7]. Retinoic acid and its derivatives bind to nuclear receptors, namely, RAR and RXR. These receptors act as homo- or heterodimers to control gene transcription [3, 6]. Therefore, retinoic acid is a powerful morphogen factor, highly involved in

During brain development, retinoic acid synthesised from dietary vitamin A binds to nuclear receptors to drive transcription of hundreds of genes. Retinoic acid is a morphogen that acts through a concentration gradient [8]. To carry out the precision of retinoic acid gradient during embryonic development, metabolism and signalling pathways for retinoic acid are multiple and highly robust [8]. Remarkably, retinoic acid is the only morphogen that comes from dietary sources, which highlights the importance of vitamin A intake during pregnancy. Through its action on nuclear receptors, retinoic acid is implicated in the patterning of neural

In addition to development and growth, retinoic acid in the brain is critical for neuronal differentiation and neurite outgrowth. This is particularly true in the basal ganglia network, which is a group of brain structures involved in the control of action. Indeed, retinoic acid is key in the differentiation of specific subpopulations of neurons, such as the medium size spiny neurons in the striatum, or the dopami-

At adult age, vitamin A-derived retinoic acid has two remarkable roles; it is involved in homeostatic plasticity and in neurogenesis [3, 5, 14, 15]. First, retinoic acid induces molecular and morphological changes in neuronal network, to maintain overall synaptic activity constant, despite synaptic plasticity, a process named homeostatic synaptic plasticity [16]. For this, retinoic acid binds to nuclear RAR and RXR receptors, but evidence suggests that non-genomic mechanisms are also

**4**

nutrient can have different roles depending on the timing, the brain structure and even the cell type. The field of research on nutrition applied to neurosciences is growing, to better encompass the impact of industrialised diet on brain function and also to consider nutrients and their derivatives as potential therapeutic strategies. In this way, it is to expect that nutritional approaches will give rise in the future to new therapeutics to prevent, and in some case cure, neurological disorders.

## **Author details**

Clémentine Bosch-Bouju INRA, Bordeaux INP, NutriNeuro, University of Bordeaux, Bordeaux, France

\*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.

**7**

*Introductory Chapter: Feed Your Mind - How Does Nutrition Modulate Brain Function…*

Opinion in Genetics and Development.

[10] Occhi G, Regazzo D, Albiger NM, Ceccato F, Ferasin S, Scanarini M, et al. Activation of the dopamine receptor Type-2 (DRD2) promoter by 9-cis retinoic acid in a cellular model of Cushing's disease mediates the inhibition of cell proliferation and ACTH secretion without a complete corticotroph-to-melanotroph transdifferentiation. Endocrinology.

[11] Pedrini S, Bogush A, Ehrlich ME. Phosphatidylinositide 3-kinase and protein kinase C zeta mediate retinoic acid induction of DARPP-32 in medium size spiny neurons in vitro. Journal of Neurochemistry. 2008;**106**(2):917-924

[12] Podleśny-Drabiniok A, Sobska J, de Lera AR, Gołembiowska K, Kamińska K, Dollé P, et al. Distinct retinoic acid receptor (RAR) isotypes control

differentiation of embryonal carcinoma cells to dopaminergic or striatopallidal medium spiny neurons. Scientific

[13] Rataj-Baniowska M, Niewiadomska-Cimicka A, Paschaki M, Szyszka-Niagolov M, Carramolino L, Torres M, et al. Retinoic acid receptor β controls development of Striatonigral projection neurons through FGF-dependent and Meis1-dependent mechanisms. Journal of Neuroscience: The Official Journal of the Society for Neuroscience.

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## **References**

*Feed Your Mind - How Does Nutrition Modulate Brain Function throughout Life?*

nutrient can have different roles depending on the timing, the brain structure and even the cell type. The field of research on nutrition applied to neurosciences is growing, to better encompass the impact of industrialised diet on brain function and also to consider nutrients and their derivatives as potential therapeutic strategies. In this way, it is to expect that nutritional approaches will give rise in the future to new therapeutics to prevent, and in some case cure, neurological disorders.

**6**

**Author details**

Clémentine Bosch-Bouju

provided the original work is properly cited.

INRA, Bordeaux INP, NutriNeuro, University of Bordeaux, Bordeaux, France

© 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,

\*Address all correspondence to<EMAIL_ADDRESS>
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**9**

*Introductory Chapter: Feed Your Mind - How Does Nutrition Modulate Brain Function…*

[37] Esteves M, Cristóvão AC, Saraiva T, Rocha SM, Baltazar G, Ferreira L, et al.

nanoparticles induce neuroprotection in a mouse model for Parkinson's disease. Frontiers in Aging Neuroscience.

He Y, Bae E, Wang Y. 9-cis retinoic acid protects against methamphetamineinduced neurotoxicity in nigrostriatal dopamine neurons. Neurotoxicity Research. 2014;**25**(3):248-261

Retinoic acid-loaded polymeric

[38] Reiner DJ, Yu S-J, Shen H,

2015;**7**:20

*DOI: http://dx.doi.org/10.5772/intechopen.89349*

synthesis exacerbating Alzheimer disease pathology which can be attenuated by an retinoic acid receptor α agonist. The European Journal of Neuroscience. 2013;**37**(7):1182-1192

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[31] Goodman AB, Pardee AB. Evidence for defective retinoid transport and function in late onset Alzheimer's disease. Proceedings of the National Academy of Sciences of the United States of America.

2003;**100**(5):2901-2905

[32] Sodhi RK, Singh N. Retinoids as potential targets for Alzheimer's disease. Pharmacology, Biochemistry, and Behavior. 2014;**120**:117-123

[33] Cai H, Liu G, Sun L, Ding J. Aldehyde dehydrogenase 1 making molecular inroads into the differential

vulnerability of nigrostriatal dopaminergic neuron subtypes in Parkinson's disease. Translational Neurodegeneration. 2014;**3**:27

[34] Liu G, Yu J, Ding J, Xie C, Sun L, Rudenko I, et al. Aldehyde dehydrogenase 1 defines and protects a nigrostriatal dopaminergic neuron subpopulation. The Journal of Clinical Investigation. 2014;**124**(7):3032-3046

2006;**139**(4):1163-1172

[35] Carta M, Stancampiano R, Tronci E, Collu M, Usiello A, Morelli M, et al. Vitamin A deficiency induces motor impairments and striatal cholinergic dysfunction in rats. Neuroscience.

[36] Krezel W, Ghyselinck N, Samad TA, Dupé V, Kastner P, Borrelli E, et al. Impaired locomotion and dopamine signaling in retinoid receptor mutant mice. Science. 1998;**279**(5352):863-867

*Introductory Chapter: Feed Your Mind - How Does Nutrition Modulate Brain Function… DOI: http://dx.doi.org/10.5772/intechopen.89349*

synthesis exacerbating Alzheimer disease pathology which can be attenuated by an retinoic acid receptor α agonist. The European Journal of Neuroscience. 2013;**37**(7):1182-1192

*Feed Your Mind - How Does Nutrition Modulate Brain Function throughout Life?*

[23] Touyarot K, Bonhomme D, Roux P, Alfos S, Lafenêtre P, Richard E, et al. A mid-life vitamin A supplementation prevents age-related spatial memory deficits and hippocampal neurogenesis alterations through CRABP-I. PLoS One.

[24] Hedden T, Gabrieli JDE. Insights into the ageing mind: A view from cognitive neuroscience. Nature Reviews.

[25] Bonhomme D, Pallet V, Dominguez G, Servant L, Henkous N, Lafenêtre P,

corticosterone in middle-aged mice: Consequences on hippocampal plasticity and contextual memory. Frontiers in Aging Neuroscience. 2014;**6**:6

Neuroscience. 2004;**5**(2):87-96

et al. Retinoic acid modulates intrahippocampal levels of

[26] Etchamendy N, Enderlin V, Marighetto A, Pallet V, Higueret P, Jaffard R. Vitamin A deficiency and relational memory deficit in adult mice: Relationships with changes in brain retinoid signalling. Behavioural Brain

Research. 2003;**145**(1-2):37-49

[27] Mingaud F, Mormede C, Etchamendy N, Mons N,

2008;**28**(1):279-291

2004;**20**(4):896-902

Niedergang B, Wietrzych M, et al. Retinoid hyposignaling contributes to aging-related decline in hippocampal function in short-term/working memory organization and long-term declarative memory encoding in mice. Journal of Neuroscience: The Official Journal of the Society for Neuroscience.

[28] Corcoran JPT, So PL, Maden M. Disruption of the retinoid signalling pathway causes a deposition of

amyloid beta in the adult rat brain. The European Journal of Neuroscience.

[29] Goncalves MB, Clarke E, Hobbs C, Malmqvist T, Deacon R, Jack J, et al. Amyloid β inhibits retinoic acid

2013;**8**(8):e72101

[15] Olson CR, Mello CV. Significance of vitamin A to brain function, behavior and learning. Molecular Nutrition and Food Research. 2010;**54**(4):489-495

Homeostatic plasticity in the developing nervous system. Nature Reviews. Neuroscience. 2004;**5**(2):97-107

[17] Aoto J, Nam CI, Poon MM, Ting P, Chen L. Synaptic signaling by alltrans retinoic acid in homeostatic synaptic plasticity. Neuron.

[16] Turrigiano GG, Nelson SB.

2008;**60**(2):308-320

[18] Arendt KL, Zhang Y,

Neuron. 2015;**86**(2):442-456

[20] Bonhomme D, Minni AM, Alfos S, Roux P, Richard E, Higueret P, et al. Vitamin A status regulates glucocorticoid availability in Wistar rats: Consequences on cognitive functions and hippocampal neurogenesis? Frontiers in Behavioral

Neuroscience. 2014;**20**:1-13

2008;**3**(10):e3487

[21] Bonnet E, Touyarot K, Alfos S, Pallet V, Higueret P, Abrous DN.

[22] Jacobs S, Lie DC, DeCicco KL, Shi Y, DeLuca LM, Gage FH, et al. Retinoic acid is required early during adult neurogenesis in the dentate gyrus. Proceedings of the National Academy of Sciences of the United States of America. 2006;**103**(10):3902-3907

Retinoic acid restores adult hippocampal neurogenesis and reverses spatial memory deficit in vitamin A deprived rats. In: McCabe BD, editor. PLoS One.

2014;**78**:3-12

Jurado S, Malenka RC, Südhof TC, Chen L. Retinoic acid and LTP recruit postsynaptic AMPA receptors using distinct SNARE-dependent mechanisms.

[19] Chen L, Lau AG, Sarti F. Synaptic retinoic acid signaling and homeostatic synaptic plasticity. Neuropharmacology.

**8**

[30] Goodman AB. Retinoid receptors, transporters, and metabolizers as therapeutic targets in late onset Alzheimer disease. Journal of Cellular Physiology. 2006;**209**(3):598-603

[31] Goodman AB, Pardee AB. Evidence for defective retinoid transport and function in late onset Alzheimer's disease. Proceedings of the National Academy of Sciences of the United States of America. 2003;**100**(5):2901-2905

[32] Sodhi RK, Singh N. Retinoids as potential targets for Alzheimer's disease. Pharmacology, Biochemistry, and Behavior. 2014;**120**:117-123

[33] Cai H, Liu G, Sun L, Ding J. Aldehyde dehydrogenase 1 making molecular inroads into the differential vulnerability of nigrostriatal dopaminergic neuron subtypes in Parkinson's disease. Translational Neurodegeneration. 2014;**3**:27

[34] Liu G, Yu J, Ding J, Xie C, Sun L, Rudenko I, et al. Aldehyde dehydrogenase 1 defines and protects a nigrostriatal dopaminergic neuron subpopulation. The Journal of Clinical Investigation. 2014;**124**(7):3032-3046

[35] Carta M, Stancampiano R, Tronci E, Collu M, Usiello A, Morelli M, et al. Vitamin A deficiency induces motor impairments and striatal cholinergic dysfunction in rats. Neuroscience. 2006;**139**(4):1163-1172

[36] Krezel W, Ghyselinck N, Samad TA, Dupé V, Kastner P, Borrelli E, et al. Impaired locomotion and dopamine signaling in retinoid receptor mutant mice. Science. 1998;**279**(5352):863-867

[37] Esteves M, Cristóvão AC, Saraiva T, Rocha SM, Baltazar G, Ferreira L, et al. Retinoic acid-loaded polymeric nanoparticles induce neuroprotection in a mouse model for Parkinson's disease. Frontiers in Aging Neuroscience. 2015;**7**:20

[38] Reiner DJ, Yu S-J, Shen H, He Y, Bae E, Wang Y. 9-cis retinoic acid protects against methamphetamineinduced neurotoxicity in nigrostriatal dopamine neurons. Neurotoxicity Research. 2014;**25**(3):248-261

**11**

Section 2

PUFA Metabolism

in the Brain

Section 2