Triangulation sensing
Triangulation sensing is a mathematical theory describing the computational steps to recover the location of a source from the fluxes estimated on small windows located on a test surface. The source emits random particles in a medium. The reconstruction steps of the gradient source from the fluxes of diffusing particles arriving to small absorbing receptors are decomposed in several steps:
- Estimating the arrival of Brownian particles to the small windows located on the test surface.
- Inverting the Laplace's equation to estimate the position from the fluxes based on a triplet of windows.
- Reduce the uncertainty by averaging the noise on several triplets.[1]
This theory provides a framework to study neural navigation in the brain.[2][3]
Computing the diffusion fluxes to small window with respect to the source location
The mathematical formulation consists in considering diffusing cues that have to bind to N narrow windows located on the surface of a three dimensional shaped object, typically a ball (in dimension 3) or a disk in dimension 2. M windows ranging between 10 and 50 are located on a ball B(a) of radius a. Individual cue molecules are described as Brownian particles. The cues are released from a source at position [math]\displaystyle{ x_0 }[/math] outside the ball. The triangulation sensing method consists in reconstructing the source position from the steady-state fluxes estimated at each narrow window for fast binding, i.e. the probability density function has an absorbing boundary condition at the windows.[4]
Steady-state Laplace's equation
The steady-state gradient [math]\displaystyle{ P_0(x) }[/math] is obtained by integrating the diffusion equation from 0 to infinity, which is equivalent to resetting the diffusing particles after they disappear through a window. It is given by the solution of the mixed-boundary value problem (where D is the diffusion coefficient)
[math]\displaystyle{ D\Delta P_0(x) = -Q \delta(x-x_0) \hbox{ for } x\, \in \,\R^3 -\Omega }[/math]
[math]\displaystyle{ \frac{\partial P_0}{\partial n}(x) = 0\hbox{ for } x, \in\, \partial\Omega_r }[/math]
[math]\displaystyle{ P_0(x) = 0 \hbox{ for } x \in \partial \Omega_a. }[/math]
The probability fluxes associated with [math]\displaystyle{ P_0(x) }[/math] at each individual window [math]\displaystyle{ \Omega_a(\epsilon_j) }[/math] of size [math]\displaystyle{ \epsilon_j }[/math] can be computed from the fluxes and depend on the specific window arrangement and the surface of the domain [math]\displaystyle{ \Omega }[/math]. The parameter Q>0 can be calibrated so that there are a fixed number of particles located in a given volume. At infinity, the density [math]\displaystyle{ P_0(x) }[/math] has to tend to zero in three dimensions. More complex domains could be studied if their associated Green's function can be found explicitly.
In dimension 2, although the probability density [math]\displaystyle{ P_0(x) }[/math] diverges when [math]\displaystyle{ x\rightarrow\infty }[/math], the splitting probability between windows is finite because it is the ratio of the steady-state flux at each window divided by the total flux through all windows:
[math]\displaystyle{ J_k= \frac{ \int_{\Omega_{k}} \frac{\partial P_0(x)}{\partial n} dS_{x}}{\sum_{q} \int_{\partial \Omega_{q}} \frac{\partial P_0(x)}{\partial n} dS_{x}}. }[/math]
In two-dimensions, due to the recurrent property of the Brownian motion, the probability to hit a window before going to infinity is one, thus the total flux is one:
[math]\displaystyle{ \sum_{q} \int_{\partial\Omega_{q}} \frac{\partial P_0(x)}{\partial n} dS_{x}=1. }[/math]
The construction of the solution uses an inner and outer solution describe below.
Boundary layer analysis in dimension 2
The inner solution is constructed near each small window[5] by scaling the arclength s and the distance to the boundary [math]\displaystyle{ \eta }[/math] by [math]\displaystyle{ \bar \eta=\frac{\eta}{\epsilon} }[/math] and [math]\displaystyle{ \bar s=\frac{s}{\epsilon} }[/math], so that the inner problem reduces to the classical two-dimensional Laplace equation[6]
[math]\displaystyle{ \Delta w=0 \hbox{ in } \R_+^{2}, \frac{\partial w}{\partial n}=0 \hbox{ for } |\bar s|\gt \frac{1}{2}, \bar \eta=0 , w(\bar s, \bar \eta)=0 \hbox{ for } |\bar s|\lt \frac{1}{2}, \bar \eta=0. }[/math]
The far field behavior for [math]\displaystyle{ |x|\rightarrow \infty }[/math] and for each hole i=1, 2 is [math]\displaystyle{ w_i(x) \approx A_i \{\log|x-x_i|-\log \epsilon\} +o(1), }[/math] where A_i is the flux [math]\displaystyle{ A_i=\frac{2}{\pi} \int_0^{1/2} \frac{\partial w(0,\bar s)}{\partial \bar \eta}d\bar s. }[/math]
The general solution of equation for n=2 is obtained from the outer solution of the external Neumann-Green's function
[math]\displaystyle{ -\Delta_{x} G(x,y) = \delta(x-y) \hbox{ for } x \in \,\R_{+}^2 }[/math]
[math]\displaystyle{ \frac{\partial G}{\partial n_{x}}(x,x_0) = 0\hbox{ for } x \in {\partial\R_{+}^2}. }[/math]
Given for [math]\displaystyle{ x, x_0 \in \R_{+}^2 }[/math] by [math]\displaystyle{ G(x,x_0)=\frac{-1}{2\pi }\left(\ln |x-x_0| + \ln \left|x-\bar{x_0}\right| \right), }[/math] where [math]\displaystyle{ \bar{x_0} }[/math]is the symmetric image of [math]\displaystyle{ x_0 }[/math]through the boundary axis 0z.
Construction of the general solution
The uniform solution is the sum of inner and outer solution (Neuman-Green's function) [math]\displaystyle{ P(x,x_0)=G(x,x_0) +A_1 \{\log|x-x_1|-\log \epsilon\}+A_2 \{\log|x-x_2|-\log \epsilon\} +C, }[/math] where [math]\displaystyle{ A_1,A_2,C }[/math] are constants to be determined.
To that purpose, the behavior of the solution near each point [math]\displaystyle{ x_i }[/math] is crutial. In the boundary layer, we get
[math]\displaystyle{ P(x,y) \approx A_i \{\log|x-x_i|-\log \epsilon\}. }[/math]
Using this condition on each window, we obtain the two conditions:
[math]\displaystyle{ G(x_1,x_0)+A_2 \{\log|x_1-x_2|-\log \epsilon\} +C=0 }[/math]
[math]\displaystyle{ G(x_2,x_0) +A_1 \{\log|x_2-x_1|-\log \epsilon\} +C=0. }[/math]
Due to the recursion property of the Brownian motion in dimension 2, there are no fluxes at infinity, thus the conservation of flux gives: [math]\displaystyle{ \int_{\partial\Omega_{1}} \frac{\partial P(x,y)}{\partial n}dS_{x} + \int_{\partial\Omega_{2}} \frac{\partial P(x,y)}{\partial n}dS_{x} =-1. }[/math] In the limit of two well separated windows ([math]\displaystyle{ |x_1-x_2| \gg 1) }[/math], using the condition for the flux, we get for each window i=1,2, [math]\displaystyle{ \int_{\partial \Omega_{i}} \frac{\partial P(x,y))}{\partial n}dS_{x}= -\pi A_i }[/math] (the minus sign is due to the outer normal orientation), thus [math]\displaystyle{ \pi A_1+\pi A_2=1. }[/math] We finally obtain the system
[math]\displaystyle{ \begin{cases} \frac{G(x_1,x_0)-G(x_2,x_0)}{\{\log|x_1-x_2|-\log \epsilon\}} +(A_2-A_1) =0 \\ \\ A_1+ A_2=\frac{1}{\pi}. \end{cases} }[/math]
To conclude, the absorbing probabilities are given by
[math]\displaystyle{ \begin{cases} P_1=\pi A_1=\frac12+ \frac{\pi}{2}\frac{G(x_2,x_0)-G(x_1,x_0)}{\{\log|x_1-x_2|-\log \epsilon\}} =\frac12- \frac{1}{4}\frac{\ln \frac{|x_2-x_0|\left|x_2-\bar{x_0}\right|}{|x_1-x_0|\left|x_1-\bar{x_0}\right|}}{\{\log|x_2-x_1|-\log \epsilon\}}. \\\\ P_2=\pi A_2=\frac12+ \frac{\pi}{2}\frac{G(x_1,x_0)-G(x_2,x_0)}{\{\log|x_1-x_2|-\log \epsilon\}} =\frac12- \frac{1}{4}\frac{\ln \frac{|x_1-x_0|\left|x_1-\bar{x_0}\right|}{|x_2-x_0|\left|x_2-\bar{x_0}\right|}}{\{\log|x_1-x_2|-\log \epsilon\}} . \end{cases} }[/math]
These probabilities precisely depend on the source position [math]\displaystyle{ x_0 }[/math] and the relative position of the two windows. When one of the splitting probabilities (either [math]\displaystyle{ P_1 }[/math] or [math]\displaystyle{ P_2 }[/math]) is known and fixed in [0,1], recovering the position of the source requires inverting the previous equations. For [math]\displaystyle{ P_2=\alpha \in [0,1], }[/math] the position [math]\displaystyle{ x_0 }[/math] lies on the curve
[math]\displaystyle{ S_{source}=\{ x_0 \hbox{ such that} \, \frac{|x_1-x_0|\left|x_1-\bar{x_0}\right|}{|x_2-x_0|\left|x_2-\bar{x_0}\right|}=\exp \left((4\alpha-2)\{\log|x_1-x_2|-\log \epsilon\} \right) \}. }[/math]
To conclude knowing the splitting probability between two windows is not enough to recover the exact the source [math]\displaystyle{ x_0 }[/math] , because it lies on one dimensional curve solution. However the direction can be obtained by simply checking which one of the two probability is the highest.
Inverse problem: computing the source location by triangulation
To reconstruct the location of a source from the measured fluxes, at least three windows are needed. With two windows only, a source located on the line perpendicular to one of the connecting windows would, for example generate the same splitting probability [math]\displaystyle{ P_1=P_2 }[/math], leading to a one dimensional curve degeneracy for the reconstructed source positions [math]\displaystyle{ x_0 }[/math].
Reconstructing the source location [math]\displaystyle{ x_0 }[/math] from the splitting probabilities,[7] requires to invert a system equation. Starting from the general solution as given above, we get for three windows:
[math]\displaystyle{ P(x,x_0)=G(x,x_0) +A_1 \{\log|x-x_1|-\log \epsilon\}+A_2 \{\log|x-x_2|-\log \epsilon\}+A_3 \{\log|x-x_3|-\log \epsilon\} +C, }[/math]
where [math]\displaystyle{ A_1,A_2,A_3,C }[/math] are constants to be determined. The three absorbing boundary conditions for[math]\displaystyle{ P(x,x_0) }[/math]leads to the system of equations
[math]\displaystyle{ G(x_1,x_0) +A_2 \{\log|x_1-x_2|-\log \epsilon\}+A_3 \{\log|x_1-x_3|-\log \epsilon\} +C=0 }[/math]
[math]\displaystyle{ G(x_2,x_0) +A_1 \{\log|x_2-x_1|-\log \epsilon\} +A_3 \{\log|x_2-x_3|-\log \epsilon\}+C=0 }[/math]
[math]\displaystyle{ G(x_3,x_0) +A_1 \{\log|x_1-x_3|-\log \epsilon\}+A_2 \{\log|x_2-x_3|-\log \epsilon\} +C=0, }[/math]
with the normalization condition for the fluxes [math]\displaystyle{ \pi A_1+\pi A_2+\pi A_3=1. }[/math] With [math]\displaystyle{ \Delta_{123}=\left(\log\frac{d_{13}d_{12}}{d_{32}\epsilon}\right)^2-4\log \frac{d_{12}}{\epsilon} \log \frac{d_{13}}{\epsilon} }[/math], and using the notations [math]\displaystyle{ d_{ij}=|x_i-x_j| }[/math], we obtain the solution
[math]\displaystyle{ A_1=\frac{1}{\pi}-A_2 -A_3. }[/math]
[math]\displaystyle{ A_2=\frac{ \log\frac{d_{13}d_{12}}{d_{32}\epsilon}(G_{30}-G_{10} +\frac{1}{\pi} \log\frac{d_{13}}{\epsilon})-( G_{1 0}-G_{2 0}+\frac{1}{\pi}\log\frac{d_{12}}{\epsilon})\log\frac{d_{13}^2}{\epsilon^2 })}{\Delta_{123}}. }[/math]
[math]\displaystyle{ A_3=\frac{ \log\frac{d_{13}d_{12}}{d_{32}\epsilon}(G_{20}-G_{10} +\frac{1}{\pi} \log\frac{d_{12}}{\epsilon})-( G_{1 0}-G_{3 0}+\frac{1}{\pi}\log\frac{d_{13}}{\epsilon}) \log\frac{d_{12}^2}{\epsilon^2})}{\Delta_{123}} }[/math]
To conclude, we can specify the flux values [math]\displaystyle{ \alpha\gt 0 }[/math] and [math]\displaystyle{ \beta\gt 0 }[/math] such that [math]\displaystyle{ \alpha+\beta\lt 1 }[/math], with [math]\displaystyle{ \alpha=\pi A_1=\int_{\partial \Omega_{1}} \frac{\partial P(x,y))}{\partial n}dS_{x} }[/math]and [math]\displaystyle{ \beta=\pi A_2=\int_{\partial \Omega_{2}} \frac{\partial P(x,y))}{\partial n}dS_{x}. }[/math]
To conclude, when two fluxes are know, the flux coefficients [math]\displaystyle{ A_1,A_2,A_3 }[/math]can be computed and the position [math]\displaystyle{ x_0 }[/math] can be reconstructed from the three equations.[8][9]
Generalization to three dimensions
With three windows in a x-y plane in the confirguration [math]\displaystyle{ x_1=(0, 0, 0), x_2=(d, 0, 0)\, \hbox{and} \, x_3=(e, f, 0) }[/math] (window 1 is at the origin and window 2 is on the x-axis). Using the leading order from the expansion of the fluxes, the location of the source is the solution of the three non-linear equations
[math]\displaystyle{ \gamma_1^2 = (x_0^{(1)})^2 + (x_0^{(2)})^2 + (x_0^{(3)})^2 }[/math]
[math]\displaystyle{ \gamma_2^2 = (d-x_0^{(1)})^2 + (x_0^{(2)})^2 + (x_0^{(3)})^2 }[/math]
[math]\displaystyle{ \gamma_3^2 = (e-x_0^{(1)})^2 + (f-x_0^{(2)})^2 + (x_0^{(3)})^2, }[/math]
where [math]\displaystyle{ \gamma_i=\frac{2\epsilon}{\pi\Phi_i} }[/math]. Solving for the coordinates of [math]\displaystyle{ x_0 }[/math] and requiring that [math]\displaystyle{ x_0 }[/math].x >0, leads to the analytical solution
[math]\displaystyle{ x_0^{(1)}=\frac{d^2+\gamma_1-\gamma_2}{2d} }[/math]
[math]\displaystyle{ x_0^{(2)}= \frac{1}{2df}\left[d(e^2+f^2+\gamma_1-\gamma_3)-e(d^2+\gamma_1-\gamma_2)\right] }[/math]
[math]\displaystyle{ x_0^{(3)}= \frac{1}{2df}\left[(e^2+f^2)(\{\gamma_1-\gamma_2\}^2-d^4)+2de(e^2+f^2+\gamma_1-\gamma_3)(d^2+\gamma_1-\gamma_2)\right. \left.-d^2(e^4+f^4+[\gamma_1-\gamma_3]^2+2e^2[f^2+2\gamma_1-\gamma_2-\gamma_3]-2f^2[\gamma_2+\gamma_3])\right]^{1/2}. }[/math]Thus the position can be recovered from the steady-state fluxes.[8][9][10]
Conclusion
In general, with N windows, no explicit inverse is easily available, hence numerical procedures are used to find the position of the source [math]\displaystyle{ x_0 }[/math] at any order in [math]\displaystyle{ \epsilon }[/math]. To find the position of the source [math]\displaystyle{ x_0 }[/math] from the measured fluxes [math]\displaystyle{ \Phi_i, i=1...N, }[/math]we need to invert a system of equations. Each of these equations describe a non-planar surface [math]\displaystyle{ S_{i} }[/math] in three dimensions, corresponding to window i and intersecting the half-plane (in the case of the windows located on the half-plane) or the unit ball (in the case of the windows located on the ball). Each pair of surfaces [math]\displaystyle{ S_{i} }[/math]and [math]\displaystyle{ S_{j} }[/math] intersect, forming three-dimensional curves [math]\displaystyle{ C_{ij} }[/math]and all of these curves intersect at the location of the source [math]\displaystyle{ x_0 }[/math] . In case of N>3 windows, the system is overdetermined and we can simply choose any combination k, l and m of three fluxes from the N available windows. Any combination lead to the same source position.
References
- ↑ Dobramysl, U., & Holcman, D. (2018). Reconstructing the gradient source position from steady-state fluxes to small receptors. Scientific reports, 8(1), 1-8.
- ↑ Kolodkin, A. L.; Tessier-Lavigne, M. (2010-12-01). "Mechanisms and Molecules of Neuronal Wiring: A Primer". Cold Spring Harbor Perspectives in Biology 3 (6): a001727. doi:10.1101/cshperspect.a001727. ISSN 1943-0264. PMID 21123392. PMC 3098670. http://dx.doi.org/10.1101/cshperspect.a001727.
- ↑ Blockus, Heike; Chédotal, Alain (August 2014). "The multifaceted roles of Slits and Robos in cortical circuits: from proliferation to axon guidance and neurological diseases". Current Opinion in Neurobiology 27: 82–88. doi:10.1016/j.conb.2014.03.003. ISSN 0959-4388. PMID 24698714. http://dx.doi.org/10.1016/j.conb.2014.03.003.
- ↑ Shukron, O., Dobramysl, U., & Holcman, D. (2019). Chemical Reactions for Molecular and Cellular Biology. Chemical Kinetics: Beyond The Textbook, 353.
- ↑ Pillay, S.; Ward, M. J.; Peirce, A.; Kolokolnikov, T. (January 2010). "An Asymptotic Analysis of the Mean First Passage Time for Narrow Escape Problems: Part I: Two-Dimensional Domains". Multiscale Modeling & Simulation 8 (3): 803–835. doi:10.1137/090752511. ISSN 1540-3459. http://dx.doi.org/10.1137/090752511.
- ↑ John., Crank (1956). The mathematics of diffusion. Clarendon. OCLC 1120831223. http://worldcat.org/oclc/1120831223.
- ↑ Schuss, Zeev (2009). Theory and applications of stochastic processes : an analytical approach. Springer. ISBN 978-1-4614-2542-7. OCLC 1052813540. http://worldcat.org/oclc/1052813540.
- ↑ 8.0 8.1 Dobramysl, U., & Holcman, D. (2019). Triangulation sensing: how cells recover a source from diffusing particles in three dimensions. arXiv preprint arXiv:1911.02907.
- ↑ 9.0 9.1 Dobramysl, U., & Holcman, D. (2018). Mixed analytical-stochastic simulation method for the recovery of a Brownian gradient source from probability fluxes to small windows. Journal of computational physics, 355, 22-36.
- ↑ DOBRAMYSL, Ulrich et HOLCMAN, David. Triangulation Sensing to Determine the Gradient Source from Diffusing Particles to Small Cell Receptors. Physical Review Letters, 2020, vol. 125, no 14, p. 148102.