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• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01R—MEASURING ELECTRIC VARIABLES; MEASURING MAGNETIC VARIABLES
  • G01R33/00—Arrangements or instruments for measuring magnetic variables
  • G01R33/20—Arrangements or instruments for measuring magnetic variables involving magnetic resonance
  • G01R33/44—Arrangements or instruments for measuring magnetic variables involving magnetic resonance using nuclear magnetic resonance [NMR]
  • G01R33/48—NMR imaging systems
  • G01R33/54—Signal processing systems, e.g. using pulse sequences ; Generation or control of pulse sequences; Operator console
  • G01R33/56—Image enhancement or correction, e.g. subtraction or averaging techniques, e.g. improvement of signal-to-noise ratio and resolution
  • G01R33/565—Correction of image distortions, e.g. due to magnetic field inhomogeneities
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01R—MEASURING ELECTRIC VARIABLES; MEASURING MAGNETIC VARIABLES
  • G01R33/00—Arrangements or instruments for measuring magnetic variables
  • G01R33/20—Arrangements or instruments for measuring magnetic variables involving magnetic resonance
  • G01R33/44—Arrangements or instruments for measuring magnetic variables involving magnetic resonance using nuclear magnetic resonance [NMR]
  • G01R33/48—NMR imaging systems
  • G01R33/54—Signal processing systems, e.g. using pulse sequences ; Generation or control of pulse sequences; Operator console
  • G01R33/56—Image enhancement or correction, e.g. subtraction or averaging techniques, e.g. improvement of signal-to-noise ratio and resolution
  • G01R33/561—Image enhancement or correction, e.g. subtraction or averaging techniques, e.g. improvement of signal-to-noise ratio and resolution by reduction of the scanning time, i.e. fast acquiring systems, e.g. using echo-planar pulse sequences
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01R—MEASURING ELECTRIC VARIABLES; MEASURING MAGNETIC VARIABLES
  • G01R33/00—Arrangements or instruments for measuring magnetic variables
  • G01R33/20—Arrangements or instruments for measuring magnetic variables involving magnetic resonance
  • G01R33/44—Arrangements or instruments for measuring magnetic variables involving magnetic resonance using nuclear magnetic resonance [NMR]
  • G01R33/48—NMR imaging systems
  • G01R33/54—Signal processing systems, e.g. using pulse sequences ; Generation or control of pulse sequences; Operator console
  • G01R33/56—Image enhancement or correction, e.g. subtraction or averaging techniques, e.g. improvement of signal-to-noise ratio and resolution
  • G01R33/563—Image enhancement or correction, e.g. subtraction or averaging techniques, e.g. improvement of signal-to-noise ratio and resolution of moving material, e.g. flow contrast angiography
  • G01R33/56341—Diffusion imaging
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01R—MEASURING ELECTRIC VARIABLES; MEASURING MAGNETIC VARIABLES
  • G01R33/00—Arrangements or instruments for measuring magnetic variables
  • G01R33/20—Arrangements or instruments for measuring magnetic variables involving magnetic resonance
  • G01R33/44—Arrangements or instruments for measuring magnetic variables involving magnetic resonance using nuclear magnetic resonance [NMR]
  • G01R33/48—NMR imaging systems
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01R—MEASURING ELECTRIC VARIABLES; MEASURING MAGNETIC VARIABLES
  • G01R33/00—Arrangements or instruments for measuring magnetic variables
  • G01R33/20—Arrangements or instruments for measuring magnetic variables involving magnetic resonance
  • G01R33/44—Arrangements or instruments for measuring magnetic variables involving magnetic resonance using nuclear magnetic resonance [NMR]
  • G01R33/48—NMR imaging systems
  • G01R33/4818—MR characterised by data acquisition along a specific k-space trajectory or by the temporal order of k-space coverage, e.g. centric or segmented coverage of k-space
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01R—MEASURING ELECTRIC VARIABLES; MEASURING MAGNETIC VARIABLES
  • G01R33/00—Arrangements or instruments for measuring magnetic variables
  • G01R33/20—Arrangements or instruments for measuring magnetic variables involving magnetic resonance
  • G01R33/44—Arrangements or instruments for measuring magnetic variables involving magnetic resonance using nuclear magnetic resonance [NMR]
  • G01R33/48—NMR imaging systems
  • G01R33/54—Signal processing systems, e.g. using pulse sequences ; Generation or control of pulse sequences; Operator console
  • G01R33/56—Image enhancement or correction, e.g. subtraction or averaging techniques, e.g. improvement of signal-to-noise ratio and resolution
  • G01R33/561—Image enhancement or correction, e.g. subtraction or averaging techniques, e.g. improvement of signal-to-noise ratio and resolution by reduction of the scanning time, i.e. fast acquiring systems, e.g. using echo-planar pulse sequences
  • G01R33/5611—Parallel magnetic resonance imaging, e.g. sensitivity encoding [SENSE], simultaneous acquisition of spatial harmonics [SMASH], unaliasing by Fourier encoding of the overlaps using the temporal dimension [UNFOLD], k-t-broad-use linear acquisition speed-up technique [k-t-BLAST], k-t-SENSE
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01R—MEASURING ELECTRIC VARIABLES; MEASURING MAGNETIC VARIABLES
  • G01R33/00—Arrangements or instruments for measuring magnetic variables
  • G01R33/20—Arrangements or instruments for measuring magnetic variables involving magnetic resonance
  • G01R33/44—Arrangements or instruments for measuring magnetic variables involving magnetic resonance using nuclear magnetic resonance [NMR]
  • G01R33/48—NMR imaging systems
  • G01R33/54—Signal processing systems, e.g. using pulse sequences ; Generation or control of pulse sequences; Operator console
  • G01R33/56—Image enhancement or correction, e.g. subtraction or averaging techniques, e.g. improvement of signal-to-noise ratio and resolution
  • G01R33/561—Image enhancement or correction, e.g. subtraction or averaging techniques, e.g. improvement of signal-to-noise ratio and resolution by reduction of the scanning time, i.e. fast acquiring systems, e.g. using echo-planar pulse sequences
  • G01R33/5615—Echo train techniques involving acquiring plural, differently encoded, echo signals after one RF excitation, e.g. using gradient refocusing in echo planar imaging [EPI], RF refocusing in rapid acquisition with relaxation enhancement [RARE] or using both RF and gradient refocusing in gradient and spin echo imaging [GRASE]

Definitions

• the present invention relates to a method for magnetic resonance (MR) and/or MR imaging, comprising acquisition of signals and MR images originating from a RF and gradient sequence causing isotropic diffusion weighting of signal attenuation.
• MR magnetic resonance
• Anisotropy of the pore structure renders the water self-diffusion anisotropic, a fact that is utilized for three-dimensional mapping of nerve fiber orientations in the white matter of the brain where the fibers have a
• Mean diffusivity can be determined from the trace of the diffusion tensor, which requires diffusion measurements in several directions.
• MRI magnetic resonance imaging
• MRS magnetic resonance spectroscopy
• One aim of the present invention is to provide a method improving inter alia the time needed for using a sequence in MR(I) for obtaining isotropic diffusion weighting and where the signal-to-noise ratio also is improved in comparison to the known methods disclosed above. Summary of the invention
• a method for magnetic resonance (MR) and/or MR imaging comprising acquisition of signals and MR images originating from a radio frequency (RF) and gradient sequence causing isotropic diffusion weighting of signal attenuation, wherein the isotropic diffusion weighting is proportional to the trace of a diffusion tensor D, and wherein the isotropic diffusion weighting is achieved by one time-dependent dephasing vector q(f) having an orientation, and wherein the orientation of the time-dependent dephasing vector q(f) is either varied discretely in more than three directions in total, or changed continuously, or changed in a
• RF radio frequency
• time-dependent dephasing vector implies that both the magnitude and the direction of the dephasing vector are time-dependent.
• the aim of the present invention is to provide a method for achieving isotropic diffusion weighting with a single or multiple spin-echo pulse sequence with reduced echo times compared to the present known methods giving higher signal-to-noise ratio and enabling isotropic diffusion weighting on systems with shorter characteristic length scale of micro-anisotropy.
• An important characteristic of the new protocol is that it can be implemented with standard diffusion MR(I) equipment with reduced or comparable demands on the gradient system hardware compared to the present methods.
• the isotropic weighting protocol disclosed herein can be used to obtain data with isotropic diffusion weighting and thus determine the mean diffusivity with high precision (high signal to noise) at minimum scan times.
• the protocol can be used as a building block, e.g. isotropic diffusion filter, of different NMR or MRI experiments. For example, it could be used in molecular exchange measurements (FEXSY, FEXI) as a low pass diffusion filter. It can also be used within multi-dimensional (2D, 3D ...) correlation experiments to achieve isotropic diffusion weighting or signal filtering.
• the protocol could be used in diffusion-diffusion or diffusion- relaxation correlation experiments, where isotropic and non-isotropic diffusion contributions are correlated and analysed by an inverse Laplace transform to yield information about degree of anisotropy for different diffusion
• the protocol could also be used in combination with other NMR or MRI methods.
• the protocol could be combined with the diffusion tensor and/or diffusion kurtosis measurement to provide additional information about morphology and micro-anisotropy as well as information about anisotropic orientation dispersion.
• the protocol can be used to facilitate and strengthen the interpretation of diffusion tensor and diffusion kurtosis measurements in vivo.
• the protocol can provide information on the degree of anisotropy and on multi-exponential signal decays detected in kurtosis tensor measurements by attributing kurtosis to different isotropic and/or anisotropic diffusion contributions.
• Figs. 1 A-D to 6A-D show examples of different gradient modulation schemes for isotropic diffusion weighting according to the present invention.
• Insets A depict components of the normalized dephasing vector, q ⁇ q
• Insets B depict components of the normalized effective gradient vector, g x / ⁇ g ⁇ (dashed line), g y / ⁇ g ⁇ (dotted line) and g ⁇ g
• Insets C depict time dependence of the azimuth angle.
• Insets D depict the evolution of the anisotropic diffusion weighting terms (16) as a function of time; the first term in Eq. (16) is shown as a dotted line, the second term is shown as a dashed dotted line, the third term as a solid line and the fourth term is shown as a dashed line.
• Fig. 7A-C show schematic representations of signal decays vs. b for isotropic (dashed line) and non-isotropic (solid line) diffusion weighting for different types of materials.
• the inset A depicts signal attenuation curves in case of anisotropic materials with 1 D or 2D curvilinear diffusion.
• the attenuation curves are multi-exponential for non-isotropic diffusion weighting, while they are mono-exponential for isotropic diffusion weighting.
• the deviation between the attenuation curves for isotropic and non-isotropic diffusion weighting provides a measure of anisotropy.
• the inset B depicts an example of isotropic material with several apparent diffusion contributions resulting in identical and multi-exponential signal attenuation curves for isotropic and non-isotropic diffusion weighting.
• the inset C depicts an example of material with a mixture of isotropic and anisotropic components resulting in multi-exponential signal decays for both isotropic and non- isotropic diffusion weighting, while the deviation between the attenuation curves for isotropic and non-isotropic diffusion weighting provides a measure of anisotropy.
• Fig.8A-C show experimental results with analysis for different types of materials. Experimental results for isotropic (circles) and for non-isotropic (crosses) diffusion weighting are shown in all the insets. Experimental results and analysis are shown for a sample with free isotropic diffusion (inset A), for a sample with restricted isotropic diffusion (inset B) and for a sample with high degree of anisotropy (inset C).
• Fig. 9A and 9B show a Monte-Carlo error analysis for the investigation of systematic deviations and precision as a function of the range of diffusion weighting b for estimating the degree of micro-anisotropy with the disclosed analytical method.
• the evolution of the complex transverse magnetization m(r,t) during a diffusion encoding experiment is given by the Bloch-Torrey equation.
• the Bloch-Torrey equation applies for arbitrary diffusion encoding schemes, e.g. pulse gradient spin-echo (PGSE), pulse gradient stimulated echo (PGSTE) and other modulated gradient spin- echo (MGSE) schemes.
• PGSE pulse gradient spin-echo
• PGSTE pulse gradient stimulated echo
• MGSE modulated gradient spin- echo
• the macroscopic magnetization is a superposition of contributions from all the domains with different D.
• the echo magnitude (3) can be rewritten in terms of the diffusion weighting matrix
• Integral of the time-dependent waveform F(t) 2 defines the effective diffusion time, i d , for an arbitrary diffusion encoding scheme in a spin-echo experiment
• gradient modulations g(f) can be designed to yield isotropic diffusion weighting, invariant under rotation of D, i.e. the echo attenuation is proportional to the isotropic mean diffusivity,
• the isotropic diffusion weighting is invariant under rotation of the diffusion tensor D.
• D diffusion tenor D is expressed as a sum of its isotropic contribution, Dl , where I is the identity matrix, and the
• the unit vector q(t) is expressed by the inclination ⁇ and azimuth angle y/ as
• Equation (13) can be rearranged to
• the first term in Eq. (14) is the mean diffusivity, while the remaining terms are time-dependent through the angles ⁇ ( ⁇ ) and ⁇ ( ⁇ ) which define the direction of the dephasing vector (4). Furthermore, the second term in Eq. (14) is independent of ⁇ , while the third and the forth terms are harmonic functions of y/ and 2 ⁇ , respectively (compare with Eq. (4) in [13]).
• the corresponding integrals of the second, third and fourth terms in Eq. (14) must vanish.
• the condition for the second term of Eq. (14) to vanish upon integration leads to one possible solution for the angle ⁇ ( ⁇ ), i.e. the time-independent "magic angle"
• the isotropic diffusion weighting scheme is thus determined by the dephasing vector q(f) with a normalized magnitude F(t) and a continuous orientation sweep through the angles m (15) and ⁇ ) (20). Note that since the isotropic weighting is invariant upon rotation of D, orientation of the vector q(f) and thus also orientation of the effective gradient g(f) can be arbitrarily offset relative to the laboratory frame in order to best suit the particular experimental conditions.
• the isotropic diffusion weighting is achieved by a continuous sweep of the time-dependent dephasing vector q(f) where the azimuth angle y/(f) and the magnitude thereof is a continuous function of time so that the time-dependent dephasing vector q(f) spans an entire range of orientations parallel to a right circular conical surface and so that the orientation of the time-dependent dephasing vector q(f) at time 0 is identical to the orientation aatt ttiimmee ff EE .
• ⁇ is chosen to be time-dependent, as far as condition (10) is fulfilled, however, this is not a preferred implementation.
• the time-dependent normalized magnitude F(t) of the dephasing vector is
• US20081 16889 is required to achieve higher spectroscopic resolution (reduce anisotropic susceptibility broadening).
• the method does no relate to diffusion weighting.
• the dephasing vector may be turned around the magic angle to achieve isotropic diffusion weighting, and is hence not related to turning the magnetic field or sample around the magic angle as described in US20081 16889.
• the isotropic weighting can also be achieved by g-modulations with discrete steps in azimuth angle ⁇ , providing q(f) vector steps through at least four orientations with unique values of e"'', such that ⁇ modulus 2 ⁇ are equally spaced values.
• the pulsed gradient spin-echo (PGSE) sequence with short pulses offers a simplest implementation of the isotropic weighting scheme according to the present invention.
• the short gradient pulses at times approximately 0 and f E cause the magnitude of the dephasing vector to instantaneously acquire its maximum value approximately at time 0 and vanish at time f E .
• the dephasing vector is given by
• the first term, 9PGSE represents the effective gradient in a regular PGSE two pulse sequence, while the second term, g iS o, might be called the "iso-pulse" since it is the effective gradient modulation which can be added to achieve isotropic weighting.
• the method is performed in a single shot, in which the latter should be understood to imply a single MR excitation.
• FA Fractional anisotropy
• E(b) 1(b)/ h
• Multi- exponential echo attenuation is commonly observed in diffusion experiments.
• the multi exponential attenuation might be due to isotropic diffusion contributions, e.g. restricted diffusion with non- Gaussian diffusion, as well as due to the presence of multiple anisotropic domains with varying orientation of main diffusion axis.
• the inverse Laplace transform of E(b) provides a distribution of apparent diffusion coefficients P(D), with possibly overlapping isotropic and anisotropic contributions.
• the diffusion weighting b is often limited to a low-Jb regime, where only an initial deviation from mono-exponential attenuation may be observed.
• Such behaviour may be quantified in terms of the kurtosis coefficient K (Jensen, J. H. , and Helpern, J. A. (2010). MRI quantification of non-Gaussian water diffusion by kurtosis analysis. NMR Biomed 23, 698- 710.),
• Eq. (28) can be expressed by the second central moment of the distribution P(D).
• the distribution P(D) is completely determined by the mean value and by the central moments
• the third central moment, ⁇ 3 gives the skewness or asymmetry of the distribution P(D).
• the echo intensity can be expressed as a cumulant expansion (Frisken, B. (2001 ). Revisiting the method of cumulants for the analysis of dynamic light-scattering data. Appl Optics 40) by
• the first-order deviation from the mono-exponential decay is thus given by the variance of P(D).
• the non-isotropic diffusion weighting results in a relatively broad distribution of diffusion coefficients, although reduced four-fold when measured with a double PGSE compared to the single PGSE.
• the isotropic weighting results in
• the mean diffusivity/J is expected to be identical for both isotropically and non-isotropically weighted data.
• the difference ⁇ 2- ⁇ 2 ⁇ 0 is thus obtained by using the ⁇ 2 ' 50 and ⁇ 2 as free fit parameters when Eq. (44) is fitted to isotropically and non-isotropically weighted data sets, respectively, while a common parameter D is used to fit both data sets.
• the ⁇ is defined so that the ⁇ values correspond to the values of the well-established FA when diffusion is locally purely anisotropic and
• the difference ⁇ 2- ⁇ 2 ⁇ 0 in Eq. (45) ensures that the micro-anisotropy can be quantified even when isotropic diffusion components are present.
• Isotropic restrictions e.g. spherical cells, characterised by non-Gaussian restricted diffusion, are expected to cause a relative increase of both ⁇ 2 and ⁇ 2 ' 50 by the same amount, thus providing the difference ⁇ 2- ⁇ 2 ⁇ 0 independent of the amount of isotropic contributions.
• the amount of non-Gaussian contributions could be quantified for example as the ratio ⁇ ⁇ ° ID For anisotropic diffusion with finite orientation dispersion, i.e.
• the D and ⁇ 2 - ⁇ 2 ' 50 are expected to depend on the gradient orientation in the non-isotropic diffusion weighting experiment.
• variation of the apparent diffusion coefficient (ADC), i.e. volume weighted average diffusivity, dependent on the gradient orientation and given by the initial echo decay of the non-isotropic diffusion weighting experiment may indicate a finite orientation dispersion.
• Non-isotropic weighting experiment performed in several directions similar to the diffusion tensor and diffusion kurtosis tensor measurements, performed with a range of b values to detect possibly multi- exponential decays, combined with the isotropic weighting experiment, is thus expected to yield additional information about micro-anisotropy as well as information related to the orientation dispersion of anisotropic domains.
• Eq. (44) could be expanded by additional terms in cases where this is appropriate.
• CSF cerebrospinal fluid
• D isotropic CSF diffusivity
• the method may involve the use of additional terms in Eq. (44), such as Eq. (46), applied to the analysis described in the above paragraphs. Eq.
• Eq. (46) comprises two additional parameters, i.e. fraction of the additional diffusion contribution (f) and diffusivity of the additional contribution (D-i).
• One such example may be the analysis of data from the human brain, where the additional term in Eq. (46) could be assigned to the signal from the cerebrospinal fluid (CSF).
• CSF cerebrospinal fluid
• the parameter D in Eq. (46) would in this case be assigned to the mean diffusivity in tissue while the parameter D would be assigned to the diffusivity of the CSF.
• the isotropic diffusion weighting could thus be used to obtain the mean diffusivity in the brain tissue without the contribution of the CSF.
• the ratio of the non-isotropically and the isotropically weighted signal or their logarithms might be used to estimate the difference between the radial (Z ) ⁇ ) and the axial (£> ) diffusivity in the human brain tissue due to the diffusion restriction effect by the axons.
• Extracting the information about microscopic anisotropy from the ratio of the signals might be advantageous, because the isotropic components with high diffusivity, e.g. due to the CSF, are suppressed at higher Jb-values.
• Such a signal ratio or any parameters derived from it might be used for generating parameter maps in MRI or for generating MR image contrast.
• Figs 1 to 6 show examples of different gradient modulation schemes for isotropic diffusion weighting according to the present invention. In all of the figures 1 -6 the following is valid: A) Normalized dephasing magnitude F(t)
• Eq. (16) The anisotropic weighting contributions from Eq. (16) as a function of time; the first term in Eq. (16) is shown as a dotted line, the second term is shown as a dashed dotted line, the third terms as a solid line and the fourth term is shown as a dashed line.
• the different presented gradient modulation schemes were constructed by first choosing the dephasing magnitude modulation, F(t) , then calculating the corresponding time-dependent azimuth angle, y/(f), followed by the calculation of the different components of the dephasing and gradient vectors.
• the gradient sequence is
• the non-isotropic diffusion weighting is achieved when x and y gradients are not active.
• the gradient modulations are identical in the intervals 0 ⁇ t ⁇ t ⁇ l2 and f E /2 ⁇ t ⁇ t E , when a 180° refocusing RF pulse is used, which is a preferred implementation for many applications, e.g. to achieve spectroscopic resolution. This may be advantageous due to possible asymmetries in gradient generating equipment.
• the second example may be viewed as a PGSE with long gradient pulses in z-direction or a spin-echo experiment in a constant z-gradient (which may be provided by a stray field of the magnet) augmented with the gradient modulation in x and y directions for isotropic diffusion weighting.
• a constant z-gradient which may be provided by a stray field of the magnet
• the possible need for fast rising and vanishing of some of the gradient components may be disadvantageous also in this case.
• modulations of some gradient components are not identical in the intervals 0 ⁇ t ⁇ f E /2 and f E /2 ⁇ t ⁇ f E .
• examples 3-6 we make use of harmonic gradient modulations for all gradient and dephasing components. These examples may be advantageous compared to the first two examples by using a more gradual variation in the dephasing magnitude. However, these examples do suffer from non- identical modulations of some gradient components in the intervals 0 ⁇ t ⁇ f E /2 and f E /2 ⁇ t ⁇ f E . While in examples 3-5 there may be the need for fast rising and vanishing of some of the gradient components immediately after and before the application of the RF pulses, the situation is more favourable in the sixth example, since all the gradient components conveniently vanish at times 0, f E /2 and f E .
• the time-dependent normalized magnitude F(t) is chosen as a harmonic function of time. It should, however, be noted that this is not a must, as may be seen in fig. 1 and 2, where this is not the case.
• fig. 7A-C there is shown a schematic representation of signal decays vs. b for isotropic and non-isotropic diffusion weighting for different types of materials.
• fig. 7 the following is valid:
• A) Solid lines represent decays in a non-isotropic diffusion weighting experiment for 1 D and 2D curvilinear diffusion (e.g. diffusion in reversed hexagonal phase H2 (tubes) and in lamellar phase La (planes), respectively). Dashed lines are the corresponding decays with isotropic diffusion weighting.
• the initial decay (D ) is identical for the isotropic weighting as for the non-isotropic diffusion weighting.
• the results of the Monte-Carlo error analysis show systematic deviations and precision of the D (A) and ⁇ (B) parameters estimated for the 1 D (dots) and 2D (circles) curvilinear diffusion according to what has been disclosed above.
• the ratio of the estimated mean diffusivity to the exact values D _ labelled as DI D (A) with the corresponding standard deviation values and the estimated ⁇ ⁇ values (B) with the corresponding standard deviations are shown as dots/circles and error bars, respectively, as a function of the maximum attenuation factor b ⁇ J) for signal to noise level of 30.
• the optimal choice of the Jb-values is important.
• a Monte-Carlo error analysis depicted in figs. 9A and 9B has been performed.
• the echo-signal was generated as a function of 16 equally spaced Jb-values between 0 and J-W for the cases of 1 D and 2D curvilinear diffusion with randomly oriented domains.
• the upper limit, £> m ax, was varied and the attenuation factors bD ⁇ were chosen to be identical for the 1 D and 2D case.
• the optimal range of the diffusion weighting b is given by a

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