Bridging functional and anatomical neural connectivity through cluster synchronization.


Journal

Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288

Informations de publication

Date de publication:
17 Dec 2023
Historique:
received: 01 06 2023
accepted: 11 12 2023
medline: 17 12 2023
pubmed: 17 12 2023
entrez: 16 12 2023
Statut: epublish

Résumé

The dynamics of the brain results from the complex interplay of several neural populations and is affected by both the individual dynamics of these areas and their connection structure. Hence, a fundamental challenge is to derive models of the brain that reproduce both structural and functional features measured experimentally. Our work combines neuroimaging data, such as dMRI, which provides information on the structure of the anatomical connectomes, and fMRI, which detects patterns of approximate synchronous activity between brain areas. We employ cluster synchronization as a tool to integrate the imaging data of a subject into a coherent model, which reconciles structural and dynamic information. By using data-driven and model-based approaches, we refine the structural connectivity matrix in agreement with experimentally observed clusters of brain areas that display coherent activity. The proposed approach leverages the assumption of homogeneous brain areas; we show the robustness of this approach when heterogeneity between the brain areas is introduced in the form of noise, parameter mismatches, and connection delays. As a proof of concept, we apply this approach to MRI data of a healthy adult at resting state.

Identifiants

pubmed: 38104227
doi: 10.1038/s41598-023-49746-2
pii: 10.1038/s41598-023-49746-2
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

22430

Informations de copyright

© 2023. The Author(s).

Références

Gilson, M., Moreno-Bote, R., Ponce-Alvarez, A., Ritter, P. & Deco, G. Estimation of directed effective connectivity from fMRI functional connectivity hints at asymmetries of cortical connectome. PLoS Comput. Biol. 12, e1004762 (2016).
pubmed: 26982185 pmcid: 4794215 doi: 10.1371/journal.pcbi.1004762
Bassett, D. S. et al. Reflections on the past two decades of neuroscience. Nat. Rev. Neurosci. 21, 524–534 (2020).
pubmed: 32879507 doi: 10.1038/s41583-020-0363-6
Liégeois, R., Santos, A., Matta, V., Van De Ville, D. & Sayed, A. H. Revisiting correlation-based functional connectivity and its relationship with structural connectivity. Netw. Neurosci. 4, 1235–1251 (2020).
pubmed: 33409438 pmcid: 7781609 doi: 10.1162/netn_a_00166
Schilling, K. G. et al. Limits to anatomical accuracy of diffusion tractography using modern approaches. Neuroimage 185, 1–11 (2019).
pubmed: 30317017 doi: 10.1016/j.neuroimage.2018.10.029
Deco, G., Jirsa, V., McIntosh, A. R., Sporns, O. & Kötter, R. Key role of coupling, delay, and noise in resting brain fluctuations. Proc. Natl. Acad. Sci. 106, 10302–10307 (2009).
pubmed: 19497858 pmcid: 2690605 doi: 10.1073/pnas.0901831106
Sporns, O. The human connectome: a complex network. Ann. N. Y. Acad. Sci. 1224, 109–125 (2011).
pubmed: 21251014 doi: 10.1111/j.1749-6632.2010.05888.x
Alexander-Bloch, A. et al. The discovery of population differences in network community structure: new methods and applications to brain functional networks in schizophrenia. Neuroimage 59, 3889–3900 (2012).
pubmed: 22119652 doi: 10.1016/j.neuroimage.2011.11.035
Bassett, D. S. & Sporns, O. Network neuroscience. Nat. Neurosci. 20, 353–364 (2017).
pubmed: 28230844 pmcid: 5485642 doi: 10.1038/nn.4502
Sporns, O. & Bassett, D. S. New trends in connectomics. Netw. Neurosci. 2(02), 125–127 (2018).
pubmed: 30215029 pmcid: 6130434 doi: 10.1162/netn_e_00052
Lynn, C. W. & Bassett, D. S. The physics of brain network structure, function and control. Nat. Rev. Phys. 1, 318–332 (2019).
doi: 10.1038/s42254-019-0040-8
Hahn, G. et al. Signature of consciousness in brain-wide synchronization patterns of monkey and human fMRI signals. Neuroimage 226, 117470 (2021).
pubmed: 33137478 doi: 10.1016/j.neuroimage.2020.117470
Oswal, A. et al. Neural signatures of hyperdirect pathway activity in Parkinson’s disease. Nat. Commun. 12, 1–14 (2021).
doi: 10.1038/s41467-021-25366-0
Nowak, A. K., Vallacher, R. R., Praszkier, R., Rychwalska, A. & Zochowski, M. In Sync: The emergence of function in minds, groups and societies (Springer Nature, 2020).
Shadlen, M. N. & Newsome, W. T. Noise, neural codes and cortical organization. Curr. Opin. Neurobiol. 4, 569–579 (1994).
pubmed: 7812147 doi: 10.1016/0959-4388(94)90059-0
Wang, X.-J. Neurophysiological and computational principles of cortical rhythms in cognition. Physiol. Rev. 90, 1195–1268 (2010).
pubmed: 20664082 doi: 10.1152/physrev.00035.2008
Ponce-Alvarez, A. et al. Resting-state temporal synchronization networks emerge from connectivity topology and heterogeneity. PLoS Comput. Biol. 11, e1004100 (2015).
pubmed: 25692996 pmcid: 4333573 doi: 10.1371/journal.pcbi.1004100
Suárez, L. E., Markello, R. D., Betzel, R. F. & Misic, B. Linking structure and function in macroscale brain networks. Trends Cogn. Sci. 24, 302–315 (2020).
pubmed: 32160567 doi: 10.1016/j.tics.2020.01.008
Mišić, B. et al. Network-level structure-function relationships in human neocortex. Cereb. Cortex 26, 3285–3296 (2016).
pubmed: 27102654 pmcid: 4898678 doi: 10.1093/cercor/bhw089
Deligianni, F., Carmichael, D. W., Zhang, G. H., Clark, C. A. & Clayden, J. D. Noddi and tensor-based microstructural indices as predictors of functional connectivity. PLoS ONE 11, e0153404 (2016).
pubmed: 27078862 pmcid: 4831788 doi: 10.1371/journal.pone.0153404
Rosenthal, G. et al. Mapping higher-order relations between brain structure and function with embedded vector representations of connectomes. Nat. Commun. 9, 2178 (2018).
pubmed: 29872218 pmcid: 5988787 doi: 10.1038/s41467-018-04614-w
Avena-Koenigsberger, A., Misic, B. & Sporns, O. Communication dynamics in complex brain networks. Nat. Rev. Neurosci. 19, 17–33 (2018).
doi: 10.1038/nrn.2017.149
Deco, G., Jirsa, V. K. & McIntosh, A. R. Emerging concepts for the dynamical organization of resting-state activity in the brain. Nat. Rev. Neurosci. 12, 43–56 (2011).
pubmed: 21170073 doi: 10.1038/nrn2961
Breakspear, M. Dynamic models of large-scale brain activity. Nat. Neurosci. 20, 340–352 (2017).
pubmed: 28230845 doi: 10.1038/nn.4497
Cabral, J., Kringelbach, M. L. & Deco, G. Functional connectivity dynamically evolves on multiple time-scales over a static structural connectome: Models and mechanisms. Neuroimage 160, 84–96 (2017).
pubmed: 28343985 doi: 10.1016/j.neuroimage.2017.03.045
Honey, C. J. et al. Predicting human resting-state functional connectivity from structural connectivity. Proc. Natl. Acad. Sci. 106, 2035–2040 (2009).
pubmed: 19188601 pmcid: 2634800 doi: 10.1073/pnas.0811168106
Robinson, P., Sarkar, S., Pandejee, G. M. & Henderson, J. Determination of effective brain connectivity from functional connectivity with application to resting state connectivities. Phys. Rev. E 90, 012707 (2014).
doi: 10.1103/PhysRevE.90.012707
Abdelnour, F., Dayan, M., Devinsky, O., Thesen, T. & Raj, A. Functional brain connectivity is predictable from anatomic network’s Laplacian Eigen-structure. Neuroimage 172, 728–739 (2018).
pubmed: 29454104 doi: 10.1016/j.neuroimage.2018.02.016
Sorrentino, F., Pecora, L. M., Hagerstrom, A. M., Murphy, T. E. & Roy, R. Complete characterization of the stability of cluster synchronization in complex dynamical networks. Sci. Adv. 2, e1501737 (2016).
pubmed: 27152349 pmcid: 4846448 doi: 10.1126/sciadv.1501737
Zhang, Y., Latora, V. & Motter, A. E. Unified treatment of synchronization patterns in generalized networks with higher-order, multilayer, and temporal interactions. Commun. Phys. 4, 195 (2021).
doi: 10.1038/s42005-021-00695-0
Lodi, M., Sorrentino, F. & Storace, M. One-way dependent clusters and stability of cluster synchronization in directed networks. Nat. Commun. 12, 1–13 (2021).
doi: 10.1038/s41467-021-24363-7
Moran, R., Pinotsis, D. A. & Friston, K. Neural masses and fields in dynamic causal modeling. Front. Comput. Neurosci. 7, 57 (2013).
pubmed: 23755005 pmcid: 3664834 doi: 10.3389/fncom.2013.00057
Schaub, M. T. et al. Graph partitions and cluster synchronization in networks of oscillators. Chaos: Interdiscipl. J. Nonlinear Sci. 26, 094821 (2016).
doi: 10.1063/1.4961065
Siddique, A. B., Pecora, L., Hart, J. D. & Sorrentino, F. Symmetry-and input-cluster synchronization in networks. Phys. Rev. E 97, 042217 (2018).
pubmed: 29758661 doi: 10.1103/PhysRevE.97.042217
Pecora, L. M. & Carroll, T. L. Master stability functions for synchronized coupled systems. Phys. Rev. Lett. 80, 2109 (1998).
doi: 10.1103/PhysRevLett.80.2109
Sporns, O. Networks of the Brain. (MIT Press, 2016).
Liu, X., Zhu, X.-H., Qiu, P. & Chen, W. A correlation-matrix-based hierarchical clustering method for functional connectivity analysis. J. Neurosci. Methods 211, 94–102 (2012).
pubmed: 22939920 pmcid: 3477851 doi: 10.1016/j.jneumeth.2012.08.016
Wang, Y. & Li, T.-Q. Analysis of whole-brain resting-state fMRI data using hierarchical clustering approach. PLoS ONE 8, e76315 (2013).
pubmed: 24204612 pmcid: 3799854 doi: 10.1371/journal.pone.0076315
Warren, K. N. et al. Increased fMRI activity correlations in autobiographical memory versus resting states. Hum. Brain Mapp. 39, 4312–4321 (2018).
pubmed: 29956403 pmcid: 6314301 doi: 10.1002/hbm.24248
Gotts, S. J., Gilmore, A. W. & Martin, A. Brain networks, dimensionality, and global signal averaging in resting-state fMRI: Hierarchical network structure results in low-dimensional spatiotemporal dynamics. Neuroimage 205, 116289 (2020).
pubmed: 31629827 doi: 10.1016/j.neuroimage.2019.116289
Fowlkes, E. B. & Mallows, C. L. A method for comparing two hierarchical clusterings. J. Am. Stat. Assoc. 78, 553–569 (1983).
doi: 10.1080/01621459.1983.10478008
Golubitsky, M. & Stewart, I. Nonlinear dynamics of networks: the groupoid formalism. Bull. Am. Math. Soc. 43, 305–364 (2006).
doi: 10.1090/S0273-0979-06-01108-6
Sorrentino, F. & Pecora, L. Approximate cluster synchronization in networks with symmetries and parameter mismatches. Chaos: Interdiscipl. J. Nonlinear Sci. 26, 094823 (2016).
doi: 10.1063/1.4961967
Pecora, L. M., Sorrentino, F., Hagerstrom, A. M., Murphy, T. E. & Roy, R. Cluster synchronization and isolated desynchronization in complex networks with symmetries. Nat. Commun. 5, 1–8 (2014).
doi: 10.1038/ncomms5079
Wilson, H. R. & Cowan, J. D. Excitatory and inhibitory interactions in localized populations of model neurons. Biophys. J . 12, 1–24 (1972).
pubmed: 4332108 pmcid: 1484078 doi: 10.1016/S0006-3495(72)86068-5
Uhlig, F. Simultaneous block diagonalization of two real symmetric matrices. Linear Algebra Appl. 7, 281–289 (1973).
doi: 10.1016/S0024-3795(73)80001-1
Maehara, T. & Murota, K. A numerical algorithm for block-diagonal decomposition of matrix [Formula: see text]-algebras with general irreducible components. Jpn. J. Ind. Appl. Math. 27, 263–293 (2010).
doi: 10.1007/s13160-010-0007-8
Murota, K., Kanno, Y., Kojima, M. & Kojima, S. A numerical algorithm for block-diagonal decomposition of matrix [Formula: see text]-algebras with application to semidefinite programming. Jpn. J. Ind. Appl. Math. 27, 125–160 (2010).
doi: 10.1007/s13160-010-0006-9
Zhang, Y. & Motter, A. E. Symmetry-independent stability analysis of synchronization patterns. SIAM Rev. 62, 817–836 (2020).
doi: 10.1137/19M127358X
Panahi, S., Klickstein, I. & Sorrentino, F. Cluster synchronization of networks via a canonical transformation for simultaneous block diagonalization of matrices. Chaos: Interdiscipl. J. Nonlinear Sci. 31, 111102 (2021).
doi: 10.1063/5.0071154
Cho, Y. S., Nishikawa, T. & Motter, A. E. Stable chimeras and independently synchronizable clusters. Phys. Rev. Lett. 119, 084101 (2017).
pubmed: 28952757 doi: 10.1103/PhysRevLett.119.084101
MRI Cloud. https://neurodata.io/mri/ . Accessed 21 July 2022.
Kiar, G. et al. A high-throughput pipeline identifies robust connectomes but troublesome variability. bioRxiv 188706 (2018).
Zuo, X.-N. et al. An open science resource for establishing reliability and reproducibility in functional connectomics. Sci. Data 1, 1–13 (2014).
doi: 10.1038/sdata.2014.49
Coluzzi, D. et al. Development and testing of spider-net: An interactive tool for brain connectogram visualization, sub-network exploration and graph metrics quantification. Front. Neurosci. 16, 818385 (2022).
pubmed: 35368253 pmcid: 8968144 doi: 10.3389/fnins.2022.818385
Raichle, M. E. et al. A default mode of brain function. Proc. Natl. Acad. Sci. 98, 676–682 (2001).
pubmed: 11209064 pmcid: 14647 doi: 10.1073/pnas.98.2.676
Greicius, M. D., Krasnow, B., Reiss, A. L. & Menon, V. Functional connectivity in the resting brain: A network analysis of the default mode hypothesis. Proc. Natl. Acad. Sci. 100, 253–258 (2003).
pubmed: 12506194 doi: 10.1073/pnas.0135058100
Buckner, R. L., Andrews-Hanna, J. R. & Schacter, D. L. The brain’s default network: Anatomy, function, and relevance to disease. Ann. N. Y. Acad. Sci. 1124, 1–38 (2008).
pubmed: 18400922 doi: 10.1196/annals.1440.011
Finotelli, P. et al. Exploring resting-state functional connectivity invariants across the lifespan in healthy people by means of a recently proposed graph theoretical model. PLoS ONE 13, e0206567 (2018).
pubmed: 30408067 pmcid: 6224060 doi: 10.1371/journal.pone.0206567
Finotelli, P., Piccardi, C., Miglio, E. & Dulio, P. A graphlet-based topological characterization of the resting-state network in healthy people. Front. Neurosci. 15, 665544 (2021).
pubmed: 33994939 pmcid: 8113409 doi: 10.3389/fnins.2021.665544
Friston, K. J., Harrison, L. & Penny, W. Dynamic causal modelling. Neuroimage 19, 1273–1302 (2003).
pubmed: 12948688 doi: 10.1016/S1053-8119(03)00202-7
Jeurissen, B., Descoteaux, M., Mori, S. & Leemans, A. Diffusion MRI fiber tractography of the brain. NMR Biomed. 32, e3785 (2019).
pubmed: 28945294 doi: 10.1002/nbm.3785
O’Donnell, L. J. & Pasternak, O. Does diffusion MRI tell us anything about the white matter? An overview of methods and pitfalls. Schizophr. Res. 161, 133–141 (2015).
pubmed: 25278106 doi: 10.1016/j.schres.2014.09.007
Jones, D. K., Knösche, T. R. & Turner, R. White matter integrity, fiber count, and other fallacies: The do’s and don’ts of diffusion MRI. Neuroimage 73, 239–254 (2013).
pubmed: 22846632 doi: 10.1016/j.neuroimage.2012.06.081
Shimono, M. & Hatano, N. Efficient communication dynamics on macro-connectome, and the propagation speed. Sci. Rep. 8, 1–15 (2018).
Panchuk, A., Rosin, D. P., Hövel, P. & Schöll, E. Synchronization of coupled neural oscillators with heterogeneous delays. Int. J. Bifurc. Chaos 23, 1330039 (2013).
doi: 10.1142/S0218127413300395
Ranade, S. A common voice for neural data. Nat. Neurosci. 25, 1583 (2022).
pubmed: 36446932 doi: 10.1038/s41593-022-01231-1
Ward, L. M. Synchronous neural oscillations and cognitive processes. Trends Cogn. Sci. 7, 553–559 (2003).
pubmed: 14643372 doi: 10.1016/j.tics.2003.10.012
Ahn, S., Zauber, S. E., Worth, R. M., Witt, T. & Rubchinsky, L. L. Interaction of synchronized dynamics in cortex and basal ganglia in Parkinson’s disease. Eur. J. Neurosci. 42, 2164–2171 (2015).
pubmed: 26154341 doi: 10.1111/ejn.12980
Zhu, J. et al. Abnormal synchronization of functional and structural networks in schizophrenia. Brain Imaging Behav. 14, 2232–2241 (2020).
pubmed: 31376115 doi: 10.1007/s11682-019-00175-8
Farahmand, S., Sobayo, T. & Mogul, D. J. Noise-assisted multivariate EMD-based mean-phase coherence analysis to evaluate phase-synchrony dynamics in epilepsy patients. IEEE Trans. Neural Syst. Rehabil. Eng. 26, 2270–2279 (2018).
pubmed: 30452374 pmcid: 6326379 doi: 10.1109/TNSRE.2018.2881606
Preti, M. G., Bolton, T. A. & Van De Ville, D. The dynamic functional connectome: State-of-the-art and perspectives. Neuroimage 160, 41–54 (2017).
pubmed: 28034766 doi: 10.1016/j.neuroimage.2016.12.061
Friston, K. J., Kahan, J., Biswal, B. & Razi, A. A DCM for resting state fMRI. Neuroimage 94, 396–407 (2014).
pubmed: 24345387 doi: 10.1016/j.neuroimage.2013.12.009
Gilson, M. et al. Model-based whole-brain effective connectivity to study distributed cognition in health and disease. Netw. Neurosci. 4, 338–373 (2020).
pubmed: 32537531 pmcid: 7286310 doi: 10.1162/netn_a_00117
Wu, L. & Calhoun, V. Joint connectivity matrix independent component analysis: Auto-linking of structural and functional connectivities. Hum. Brain Mapp. 44, 1533–1547 (2023).
pubmed: 36420833 doi: 10.1002/hbm.26155
Smith, S. M. et al. Network modelling methods for fMRI. Neuroimage 54, 875–891 (2011).
pubmed: 20817103 doi: 10.1016/j.neuroimage.2010.08.063
Marrelec, G. & Fransson, P. Assessing the influence of different ROI selection strategies on functional connectivity analyses of fMRI data acquired during steady-state conditions. PLoS ONE 6, e14788 (2011).
pubmed: 21533283 pmcid: 3076321 doi: 10.1371/journal.pone.0014788
Cabral, J. et al. Metastable oscillatory modes emerge from synchronization in the brain spacetime connectome. Commun. Phys. 5, 1–13 (2022).
doi: 10.1038/s42005-022-00950-y
Meunier, D., Lambiotte, R., Fornito, A., Ersche, K. & Bullmore, E. T. Hierarchical modularity in human brain functional networks. Front. Neuroinform. 3, 37 (2009).
pubmed: 19949480 pmcid: 2784301 doi: 10.3389/neuro.11.037.2009
Rousseeuw, P. J. Silhouettes: A graphical aid to the interpretation and validation of cluster analysis. J. Comput. Appl. Math. 20, 53–65 (1987).
doi: 10.1016/0377-0427(87)90125-7
Tibshirani, R., Walther, G. & Hastie, T. Estimating the number of clusters in a data set via the gap statistic. J. R. Stat. Soc.: Series B (Stat. Methodol.) 63, 411–423 (2001).
doi: 10.1111/1467-9868.00293
Abeysuriya, R. G. et al. A biophysical model of dynamic balancing of excitation and inhibition in fast oscillatory large-scale networks. PLoS Comput. Biol. 14, e1006007 (2018).
pubmed: 29474352 pmcid: 5841816 doi: 10.1371/journal.pcbi.1006007
Hellyer, P. J., Jachs, B., Clopath, C. & Leech, R. Local inhibitory plasticity tunes macroscopic brain dynamics and allows the emergence of functional brain networks. Neuroimage 124, 85–95 (2016).
pubmed: 26348562 doi: 10.1016/j.neuroimage.2015.08.069
Daffertshofer, A. & van Wijk, B. C. On the influence of amplitude on the connectivity between phases. Front. Neuroinform. 5, 6 (2011).
pubmed: 21811452 pmcid: 3139941 doi: 10.3389/fninf.2011.00006
Luke, T. B., Barreto, E. & So, P. Complete classification of the macroscopic behavior of a heterogeneous network of theta neurons. Neural Comput. 25, 3207–3234 (2013).
pubmed: 24047318 doi: 10.1162/NECO_a_00525
Laing, C. R. Derivation of a neural field model from a network of theta neurons. Phys. Rev. E 90, 010901 (2014).
doi: 10.1103/PhysRevE.90.010901
Montbrió, E., Pazó, D. & Roxin, A. Macroscopic description for networks of spiking neurons. Phys. Rev. X 5, 021028 (2015).
Coombes, S. & Byrne, Á. Next generation neural mass models. In Nonlinear Dynamics in Computational Neuroscience, 1–16 (Springer, 2019).
Taher, H., Torcini, A. & Olmi, S. Exact neural mass model for synaptic-based working memory. PLoS Comput. Biol. 16, e1008533 (2020).
pubmed: 33320855 pmcid: 7771880 doi: 10.1371/journal.pcbi.1008533
Deco, G., Kringelbach, M. L., Jirsa, V. K. & Ritter, P. The dynamics of resting fluctuations in the brain: Metastability and its dynamical cortical core. Sci. Rep. 7, 1–14 (2017).
doi: 10.1038/s41598-017-03073-5
Chizhov, A. V., Zefirov, A. V., Amakhin, D. V., Smirnova, E. Y. & Zaitsev, A. V. Minimal model of interictal and ictal discharges epileptor-2. PLoS Comput. Biol. 14, e1006186 (2018).
pubmed: 29851959 pmcid: 6005638 doi: 10.1371/journal.pcbi.1006186
Liu, F. et al. A neural mass model of basal ganglia nuclei simulates pathological beta rhythm in Parkinson’s disease. Chaos: Interdiscipl. J. Nonlinear Sci. 26, 123113 (2016).
doi: 10.1063/1.4972200
Filipchuk, A., Schwenkgrub, J., Destexhe, A. & Bathellier, B. Awake perception is associated with dedicated neuronal assemblies in the cerebral cortex. Nat. Neurosci., 1–12 (2022).
Bittner, S. R. et al. Population activity structure of excitatory and inhibitory neurons. PLoS ONE 12, e0181773 (2017).
pubmed: 28817581 pmcid: 5560553 doi: 10.1371/journal.pone.0181773
Grubb, R. L. Jr., Raichle, M. E., Eichling, J. O. & Ter-Pogossian, M. M. The effects of changes in PaCO2 cerebral blood volume, blood flow, and vascular mean transit time. Stroke 5, 630–639 (1974).
pubmed: 4472361 doi: 10.1161/01.STR.5.5.630

Auteurs

Valentina Baruzzi (V)

DITEN, University of Genoa, Via Opera Pia 11a, 16145, Genova, Italy.

Matteo Lodi (M)

DITEN, University of Genoa, Via Opera Pia 11a, 16145, Genova, Italy.

Francesco Sorrentino (F)

Mechanical Engineering Department, University of New Mexico, Albuquerque, NM, 87131, USA.

Marco Storace (M)

DITEN, University of Genoa, Via Opera Pia 11a, 16145, Genova, Italy. marco.storace@unige.it.

Classifications MeSH