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Three-Dimensional Fractal Analysis of the Interstitial Cells of Cajal Networks of Gastrointestinal Tissue Specimens

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Abstract

Introduction

Several functional gastrointestinal disorders (FGIDs) have been associated with the degradation or remodeling of the network of interstitial cells of Cajal (ICC). Introducing fractal analysis to the field of gastroenterology as a promising data analytics approach to extract key structural characteristics that may provide insightful features for machine learning applications in disease diagnostics. Fractal geometry has advantages over several physically based parameters (or classical metrics) for analysis of intricate and complex microstructures that could be applied to ICC networks.

Methods

In this study, three fractal structural parameters: Fractal Dimension, Lacunarity, and Succolarity were employed to characterize scale-invariant complexity, heterogeneity, and anisotropy; respectively of three types of gastric ICC network structures from a flat-mount transgenic mouse stomach.

Results

The Fractal Dimension of ICC in the longitudinal muscle layer was found to be significantly lower than ICC in the myenteric plexus and circumferential muscle in the proximal, and distal antrum, respectively (both p < 0.0001). Conversely, the Lacunarity parameters for ICC-LM and ICC-CM were found to be significantly higher than ICC-MP in the proximal and in the distal antrum, respectively (both p < 0.0001). The Succolarity measures of ICC-LM network in the aboral direction were found to be consistently higher in the proximal than in the distal antrum (p < 0.05).

Conclusions

The fractal parameters presented here could go beyond the limitation of classical metrics to provide better understanding of the structural-functional relationship between ICC networks and the conduction of gastric bioelectrical slow waves.

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References

  1. Abdelsalam, M. M., and M. A. Zahran. A novel approach of diabetic retinopathy early detection based on multifractal geometry analysis for OCTA macular images using support vector machine. IEEE Access. 9:22844–22858, 2021.

    Article  Google Scholar 

  2. An, W., C. Wang, H. Zhang, and Z. Bi. Measuring the formal complexity of architectural curved surfaces based on 3D box-counting dimension. Nexus Netw. J. 24:753–766, 2022.

    Article  Google Scholar 

  3. Angeli, T. R., L. K. Cheng, P. Du, T.H.-H. Wang, C. E. Bernard, M.-G. Vannucchi, M. S. Faussone-Pellegrini, C. Lahr, R. Vather, J. A. Windsor, G. Farrugia, T. L. Abell, and G. O’Grady. Loss of interstitial cells of cajal and patterns of gastric dysrhythmia in patients with chronic unexplained nausea and vomiting. Gastroenterology. 149:56-66.e5, 2015.

    Article  PubMed  Google Scholar 

  4. Berry, R., T. Miyagawa, N. Paskaranandavadivel, P. Du, T. R. Angeli, M. L. Trew, J. A. Windsor, Y. Imai, G. O’Grady, and L. K. Cheng. Functional physiology of the human terminal antrum defined by highresolution electrical mapping and computational modeling. Am. J. Physiol.-Gastrointest Liver Physiol. 311:G895–G902, 2016.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Bunde, A., and S. Havlin. Fractals in Science. Berlin: Springer, 2013. https://doi.org/10.1007/978-3-642-77953-4.

    Book  Google Scholar 

  6. De Melo, R. H. C., and A. Conci. How succolarity could be used as another fractal measure in image analysis. Telecommun. Syst. 52:1643–1655, 2013.

    Article  Google Scholar 

  7. DePetrillo, P. B., D. Speers, and U. E. Ruttimann. Determining the Hurst exponent of fractal time series and its application to electrocardiographic analysis. Comput. Biol. Med. 29:393–406, 1999.

    Article  CAS  PubMed  Google Scholar 

  8. Du, P., G. O’Grady, S. J. Gibbons, R. Yassi, R. Lees-Green, G. Farrugia, L. K. Cheng, and A. J. Pullan. Tissue-specific mathematical models of slow wave entrainment in wild-type and 5-HT(2B) knockout mice with altered interstitial cells of Cajal networks. Biophys. J. 98:1772–1781, 2010.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  9. Gao, J., P. Du, G. O’Grady, R. Archer, G. Farrugia, S. J. Gibbons, and L. K. Cheng. Numerical metrics for automated quantification of interstitial cell of Cajal network structural properties. J. R. Soc. Interface. 10:20130421, 2013.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Gao, J., P. Du, G. O’Grady, R. Archer, S. J. Gibbons, G. Farrugia, and L. K. Cheng. Cellular automaton model for simulating tissue-specific intestinal electrophysiological activity. Conf. Proc. ... Annu. Int. Conf. IEEE Eng. Med. Biol. Soc. IEEE Eng. Med. Biol. Soc. Annu. Conf. 5537–5540, 2013.

  11. Gkontra, P., K. A. Norton, M. M. Zak, C. Clemente, J. Agüero, B. Ibáñez, A. Santos, A. S. Popel, and A. G. Arroyo. Deciphering microvascular changes after myocardial infarction through 3D fully automated image analysis. Sci. Rep. 81(8):1–19, 2018.

    Google Scholar 

  12. Glenny, R. W., H. T. Robertson, S. Yamashiro, and J. B. Bassingthwaighte. Applications of fractal analysis to physiology. J. Appl. Physiol. 70:2351–2367, 1991.

    Article  CAS  PubMed  Google Scholar 

  13. Goldberger, A. L. Fractal variability versus pathologic periodicity: Complexity loss and stereotypy in disease. Perspect. Biol. Med. 40:543–561, 1997.

    Article  CAS  PubMed  Google Scholar 

  14. Gould, D. J., T. J. Vadakkan, R. A. Poché, and M. E. Dickinson. Multifractal and lacunarity analysis of microvascular morphology and remodeling. Microcirculation. 18:136–151, 2011.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Grover, M., G. Farrugia, M. S. Lurken, C. E. Bernard, M. S. Faussone-Pellegrini, T. C. Smyrk, H. P. Parkman, T. L. Abell, W. J. Snape, W. L. Hasler, A. Ünalp-Arida, L. Nguyen, K. L. Koch, J. Calles, L. Lee, J. Tonascia, F. A. Hamilton, and P. J. Pasricha. Cellular changes in diabetic and idiopathic gastroparesis. Gastroenterology. 140:1575–1585, 2011.

    Article  CAS  PubMed  Google Scholar 

  16. He, C. L., L. Burgart, L. Wang, J. Pemberton, T. Young-Fadok, J. Szurszewski, and G. Farrugia. Decreased interstitial cell of cajal volume in patients with slow-transit constipation. Gastroenterology. 118:14–21, 2000.

    Article  CAS  PubMed  Google Scholar 

  17. Horsfield, K. Morphometry of the small pulmonary arteries in man. Circ. Res. 42:593–597, 1978.

    Article  CAS  PubMed  Google Scholar 

  18. Hughes, A. D., E. Martinez-Perez, A.-S. Jabbar, A. Hassan, N. W. Witt, P. D. Mistry, N. Chapman, A. V. Stanton, G. Beevers, R. Pedrinelli, K. H. Parker, and S. A. M. M. Thom. Quantification of topological changes in retinal vascular architecture in essential and malignant hypertension. J. Hypertens. 24:889–894, 2006.

    Article  CAS  PubMed  Google Scholar 

  19. Huizinga, J. D., N. Zarate, and G. Farrugia. Physiology, injury, and recovery of interstitial cells of Cajal: basic and clinical science. Gastroenterology. 137:1548–1556, 2009.

    Article  PubMed  Google Scholar 

  20. Isozaki, K., S. Hirota, J. Miyagawa, M. Taniguchi, Y. Shinomura, and Y. Matsuzawa. Deficiency of c-kit+ cells in patients with a myopathic form of chronic idiopathic intestinal pseudo-obstruction. Am. J. Gastroenterol. 92:332–334, 1997.

    CAS  PubMed  Google Scholar 

  21. Julián, M., R. Alcaraz, and J. J. Rieta. Application of Hurst exponents to assess atrial reverse remodeling in paroxysmal atrial fibrillation. Physiol. Meas. 36:2231, 2015.

    Article  PubMed  Google Scholar 

  22. Klein, S., B. Seidler, A. Kettenberger, A. Sibaev, M. Rohn, R. Feil, H.-D. Allescher, J.-M. Vanderwinden, F. Hofmann, M. Schemann, R. Rad, M. A. Storr, R. M. Schmid, G. Schneider, and D. Saur. Interstitial cells of Cajal integrate excitatory and inhibitory neurotransmission with intestinal slow-wave activity. Nat. Commun. 4:1630, 2013.

    Article  ADS  PubMed  Google Scholar 

  23. Krohn, S., M. Froeling, A. Leemans, D. Ostwald, P. Villoslada, C. Finke, and F. J. Esteban. Evaluation of the 3D fractal dimension as a marker of structural brain complexity in multiple-acquisition MRI. Hum. Brain Mapp. 40:3299–3320, 2019.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Lee, J., II., H. Park, M. A. Kamm, and I. C. Talbot. Decreased density of interstitial cells of Cajal and neuronal cells in patients with slow-transit constipation and acquired megacolon. J. Gastroenterol. Hepatol. 20:1292–8, 2005.

    Article  PubMed  Google Scholar 

  25. Mah, S. A., R. Avci, L. K. Cheng, and P. Du. Current applications of mathematical models of the interstitial cells of Cajal in the gastrointestinal tract. WIREs Mech. Dis.13:e1507, 2021.

    Article  PubMed  Google Scholar 

  26. Mah, S. A., R. Avci, P. Du, J.-M. Vanderwinden, and L. K. Cheng. Antral variation of murine gastric pacemaker cells informed by confocal imaging and machine learning methods. Annu. Int. Conf. IEEE Eng. Med. Biol. Soc. IEEE Eng. Med. Biol. Soc. Annu. Int. Conf. 2021:3105–3108, 2021.

  27. Mah, S. A., R. Avci, P. Du, J. M. Vanderwinden, and L. K. Cheng. Deciphering stomach myoelectrical slow wave conduction patterns via confocal imaging of gastric pacemaker cells and fractal geometry. Annu. Int. Conf. IEEE Eng. Med. Biol. Soc. IEEE Eng. Med. Biol. Soc. Annu. Int. Conf. 2022:3514–3517, 2022.

  28. Mah, S. A., P. Du, R. Avci, J.-M. Vanderwinden, and L. K. Cheng. Analysis of regional variations of the interstitial cells of Cajal in the Murine distal stomach informed by confocal imaging and machine learning methods. Cell. Mol. Bioeng. 15:193–205, 2022.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Mandelbrot, B. B. The Fractal Geometry of Nature. San Francisco: W.H. Freeman and Company, pp. 394–397, 1982.

    Google Scholar 

  30. Masters, B. R. Fractal analysis of the vascular tree in the human retina. Annu. Rev. Biomed. Eng. 6:427–452, 2004.

    Article  CAS  PubMed  Google Scholar 

  31. Murueta-Goyena, A., M. Barrenechea, A. Erramuzpe, S. Teijeira-Portas, M. Pengo, U. Ayala, D. Romero-Bascones, M. Acera, R. Del Pino, J. C. Gómez-Esteban, and I. Gabilondo. Foveal remodeling of retinal microvasculature in Parkinson’s disease. Front. Neurosci. 15:837, 2021.

    Article  Google Scholar 

  32. Nelson, T. R., and D. K. Manchester. Modeling of lung morphogenesis using fractal geometries. IEEE Trans. Med. Imaging. 7:321–327, 1988.

    Article  CAS  PubMed  Google Scholar 

  33. O’Grady, G., P. Du, L. K. Cheng, J. U. Egbuji, W. J. E. P. Lammers, J. A. Windsor, and A. J. Pullan. Origin and propagation of human gastric slow-wave activity defined by high-resolution mapping. Am. J. Physiol. Gastrointest. Liver Physiol. 299:G585–G592, 2010.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Popovic, N., M. Radunovic, J. Badnjar, and T. Popovic. Fractal dimension and lacunarity analysis of retinal microvascular morphology in hypertension and diabetes. Microvasc. Res. 118:36–43, 2018.

    Article  PubMed  Google Scholar 

  35. Rolle, U., A. P. Piotrowska, L. Nemeth, and P. Puri. Altered distribution of interstitial cells of Cajal in Hirschsprung disease. Arch. Pathol. Lab. Med. 126:928–933, 2002.

    Article  PubMed  Google Scholar 

  36. Smith, T. G., W. B. Marks, G. D. Lange, W. H. Sheriff, and E. A. Neale. A fractal analysis of cell images. J. Neurosci. Methods. 27:173–180, 1989.

    Article  PubMed  Google Scholar 

  37. Souza França, L. G., J. G. Vivas Miranda, M. Leite, N. K. Sharma, M. C. Walker, L. Lemieux, and Y. Wang. Fractal and multifractal properties of electrographic recordings of human brain activity: toward its use as a signal feature for machine learning in clinical applications. Front. Physiol. 9:1767, 2018.

    Article  Google Scholar 

  38. Stošić, T., and B. D. Stošić. Multifractal analysis of human retinal vessels. IEEE Trans. Med. Imaging. 25:1101–1107, 2006.

    Article  PubMed  Google Scholar 

  39. Tolle, C. R., T. R. McJunkin, and D. J. Gorsich. An efficient implementation of the gliding box lacunarity algorithm. Phys. D Nonlinear Phenom. 237:306–315, 2008.

    Article  ADS  MathSciNet  Google Scholar 

  40. Vanderwinden, J.-M., and J. J. Rumessen. Interstitial cells of Cajal in human gut and gastrointestinal disease. Microsc. Res. Tech. 47:344–360, 1999.

    Article  CAS  PubMed  Google Scholar 

  41. West, B. J. Fractal physiology and the fractional calculus: a perspective. Front. Physiol. 1:12, 2010.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Wu, J., X. Jin, S. Mi, and J. Tang. An effective method to compute the box-counting dimension based on the mathematical definition and intervals. Results Eng.6:100106, 2020.

    Article  Google Scholar 

  43. Xia, Y., J. Cai, E. Perfect, W. Wei, Q. Zhang, and Q. Meng. Fractal dimension, lacunarity and succolarity analyses on CT images of reservoir rocks for permeability prediction. J. Hydrol.579:124198, 2019.

    Article  Google Scholar 

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Acknowledgements

The authors thank Perrine Hagué, Faculté de Médecine, Université Libre de Bruxelles, Belgium for technical assistance in mice breeding and tissue clearing, and Prof. Dieter Saur, School of Medicine, Technische Universität München, Germany for providing the KitCreERT2, R26mT-mG mice colony founders.

Funding

This work was supported, in part, by grants from the Marsden Fund Council and Rutherford Foundation managed by The Royal Society Te Apārangi.

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Authors and Affiliations

  1. Auckland Bioengineering Institute, The University of Auckland, Auckland, New Zealand

    Sue Ann Mah, Recep Avci & Peng Du

  2. Laboratoire de Neurophysiologie, Faculté de Médecine, Université Libre de Bruxelles, Brussels, Belgium

    Jean-Marie Vanderwinden

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Contributions

Author SM conducted the conception of the study, technical analysis & statistic, and wrote the manuscript. JM provided the microscopic imaging data. RA and PD supervised the project. All authors took part in reviewing and editing the manuscript.

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Correspondence to Sue Ann Mah or Peng Du.

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Mah, S.A., Avci, R., Vanderwinden, JM. et al. Three-Dimensional Fractal Analysis of the Interstitial Cells of Cajal Networks of Gastrointestinal Tissue Specimens. Cel. Mol. Bioeng. 17, 67–81 (2024). https://doi.org/10.1007/s12195-023-00789-5

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