Functional connectivity hubs of the mouse brain

Recent advances in functional connectivity methods have made it possible to identify brain hubs - a set of highly connected regions serving as integrators of distributed neuronal activity. The integrative role of hub nodes makes these areas points of high vulnerability to dysfunction in brain disorders, and abnormal hub connectivity profiles have been described for several neuropsychiatric disorders. The identification of analogous functional connectivity hubs in preclinical species like the mouse may provide critical insight into the elusive biological underpinnings of these connectional alterations. To spatially locate functional connectivity hubs in the mouse brain, here we applied a fully-weighted network analysis to map whole-brain intrinsic functional connectivity (i.e., the functional connectome) at a high-resolution voxel-scale. Analysis of a large resting-state functional magnetic resonance imaging (rsfMRI) dataset revealed the presence of six distinct functional modules related to known large-scale functional partitions of the brain, including a default-mode network (DMN). Consistent with human studies, highly-connected functional hubs were identified in several sub-regions of the DMN, including the anterior and posterior cingulate and prefrontal cortices, in the thalamus, and in small foci within well-known integrative cortical structures such as the insular and temporal association cortices. According to their integrative role, the identified hubs exhibited mutual preferential interconnections. These findings highlight the presence of evolutionarily-conserved, mutually-interconnected functional hubs in the mouse brain, and may guide future investigations of the biological foundations of aberrant rsfMRI hub connectivity associated with brain pathological states.

[1]  Arthur W. Toga,et al.  Neural Networks of the Mouse Neocortex , 2014, Cell.

[2]  Jonathan D. Power,et al.  Evidence for Hubs in Human Functional Brain Networks , 2013, Neuron.

[3]  Craig K. Jones,et al.  Functional networks in the anesthetized rat brain revealed by independent component analysis of resting-state FMRI. , 2010, Journal of neurophysiology.

[4]  Marleen Verhoye,et al.  Preserved Modular Network Organization in the Sedated Rat Brain , 2014, PloS one.

[5]  Rupert Lanzenberger,et al.  Correlations and anticorrelations in resting-state functional connectivity MRI: A quantitative comparison of preprocessing strategies , 2009, NeuroImage.

[6]  Dennis M. Wilkinson,et al.  A method for finding communities of related genes , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[7]  E. Bullmore,et al.  The hubs of the human connectome are generally implicated in the anatomy of brain disorders , 2014, Brain : a journal of neurology.

[8]  Mathias Hoehn,et al.  Functional connectivity in the rat at 11.7T: Impact of physiological noise in resting state fMRI , 2011, NeuroImage.

[9]  Richard S. J. Frackowiak,et al.  Evidence for Segregated and Integrative Connectivity Patterns in the Human Basal Ganglia , 2008, The Journal of Neuroscience.

[10]  Jean-Loup Guillaume,et al.  Fast unfolding of communities in large networks , 2008, 0803.0476.

[11]  Rafael Delgado y Palacios,et al.  Different anesthesia regimes modulate the functional connectivity outcome in mice , 2014, Magnetic resonance in medicine.

[12]  Francesco Sforazzini,et al.  Deficient neuron-microglia signaling results in impaired functional brain connectivity and social behavior , 2014, Nature Neuroscience.

[13]  Olaf Sporns,et al.  Weight-conserving characterization of complex functional brain networks , 2011, NeuroImage.

[14]  George Paxinos,et al.  The Mouse Brain in Stereotaxic Coordinates , 2001 .

[15]  Allan R. Jones,et al.  A mesoscale connectome of the mouse brain , 2014, Nature.

[16]  Marisa O. Hollinshead,et al.  The organization of the human cerebral cortex estimated by intrinsic functional connectivity. , 2011, Journal of neurophysiology.

[17]  Zhang Nanyin.  Uncovering intrinsic connectional architecture of functional networks in awake rat brain , 2011 .

[18]  Francesco Sforazzini,et al.  Distributed BOLD and CBV-weighted resting-state networks in the mouse brain , 2014, NeuroImage.

[19]  Giuseppe Pagnoni,et al.  A comparison of resting-state brain activity in humans and chimpanzees , 2007, Proceedings of the National Academy of Sciences.

[20]  E. Eger,et al.  Halothane and Isoflurane Have Additive Minimum Alveolar Concentration (MAC) Effects in Rats , 2003, Anesthesia and analgesia.

[21]  Roger Guimerà,et al.  Cartography of complex networks: modules and universal roles , 2005, Journal of statistical mechanics.

[22]  Nora D. Volkow,et al.  Functional connectivity hubs in the human brain , 2011, NeuroImage.

[23]  E. Eger,et al.  Naturally occurring variability in anesthetic potency among inbred mouse strains. , 2000, Anesthesia and analgesia.

[24]  Aileen Schroeter,et al.  Optimization of anesthesia protocol for resting-state fMRI in mice based on differential effects of anesthetics on functional connectivity patterns , 2014, NeuroImage.

[25]  M. Raichle,et al.  Rat brains also have a default mode network , 2012, Proceedings of the National Academy of Sciences.

[26]  Vince D. Calhoun,et al.  Function–structure associations of the brain: Evidence from multimodal connectivity and covariance studies , 2014, NeuroImage.

[27]  Duncan J. Watts,et al.  Collective dynamics of ‘small-world’ networks , 1998, Nature.

[28]  Adam J. Schwarz,et al.  Anti-Correlated Cortical Networks of Intrinsic Connectivity in the Rat Brain , 2013, Brain Connect..

[29]  A. Meyer-Lindenberg,et al.  The low-frequency blood oxygenation level-dependent functional connectivity signature of the hippocampal–prefrontal network in the rat brain , 2013, Neuroscience.

[30]  M. Newman,et al.  Robustness of community structure in networks. , 2007, Physical review. E, Statistical, nonlinear, and soft matter physics.

[31]  O. Sporns,et al.  Network centrality in the human functional connectome. , 2012, Cerebral cortex.

[32]  Olaf Sporns,et al.  Complex network measures of brain connectivity: Uses and interpretations , 2010, NeuroImage.

[33]  O. Sporns,et al.  Network hubs in the human brain , 2013, Trends in Cognitive Sciences.

[34]  Andreas Ludwig,et al.  A Fast Adaptive Layout Algorithm for Undirected Graphs , 1994, GD.

[35]  J Hennig,et al.  RARE imaging: A fast imaging method for clinical MR , 1986, Magnetic resonance in medicine.

[36]  Maurizio Corbetta,et al.  The human brain is intrinsically organized into dynamic, anticorrelated functional networks. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[37]  Olaf Sporns,et al.  Network attributes for segregation and integration in the human brain , 2013, Current Opinion in Neurobiology.

[38]  O. Sporns,et al.  Complex brain networks: graph theoretical analysis of structural and functional systems , 2009, Nature Reviews Neuroscience.

[39]  Jean-Cédric Chappelier,et al.  Finding instabilities in the community structure of complex networks. , 2005, Physical review. E, Statistical, nonlinear, and soft matter physics.

[40]  Takao K. Hensch,et al.  Sensory Integration in Mouse Insular Cortex Reflects GABA Circuit Maturation , 2014, Neuron.

[41]  Angelo Bifone,et al.  Community structure in networks of functional connectivity: Resolving functional organization in the rat brain with pharmacological MRI , 2009, NeuroImage.

[42]  Wei Chen,et al.  Neural origin of spontaneous hemodynamic fluctuations in rats under burst-suppression anesthesia condition. , 2011, Cerebral cortex.

[43]  Walter Schneider,et al.  Identifying the brain's most globally connected regions , 2010, NeuroImage.

[44]  C. J. Honeya,et al.  Predicting human resting-state functional connectivity from structural connectivity , 2009 .

[45]  V. Menon.  Large-scale brain networks and psychopathology: a unifying triple network model , 2011, Trends in Cognitive Sciences.

[46]  Thomas E. Nichols,et al.  Thresholding of Statistical Maps in Functional Neuroimaging Using the False Discovery Rate , 2002, NeuroImage.

[47]  J. Antognini,et al.  The Differential Effects of Halothane and Isoflurane on Electroencephalographic Responses to Electrical Microstimulation of the Reticular Formation , 2006, Anesthesia and analgesia.

[48]  Edward T. Bullmore,et al.  Neuroinformatics Original Research Article , 2022 .

[49]  Kevin Murphy,et al.  The impact of global signal regression on resting state correlations: Are anti-correlated networks introduced? , 2009, NeuroImage.

[50]  Keith A. Johnson,et al.  Cortical Hubs Revealed by Intrinsic Functional Connectivity: Mapping, Assessment of Stability, and Relation to Alzheimer's Disease , 2009, The Journal of Neuroscience.

[51]  R. Guimerà,et al.  Modularity from fluctuations in random graphs and complex networks. , 2004, Physical review. E, Statistical, nonlinear, and soft matter physics.

[52]  Angelo Bifone,et al.  Voxel Scale Complex Networks of Functional Connectivity in the Rat Brain: Neurochemical State Dependence of Global and Local Topological Properties , 2012, Comput. Math. Methods Medicine.

[53]  Jürgen Hennig,et al.  Fine-grained mapping of mouse brain functional connectivity with resting-state fMRI , 2014, NeuroImage.

[54]  M E J Newman,et al.  Finding and evaluating community structure in networks. , 2003, Physical review. E, Statistical, nonlinear, and soft matter physics.

[55]  M. Scattoni,et al.  Erratum to: Altered functional connectivity networks in acallosal and socially impaired BTBR mice , 2014, Brain Structure and Function.

[56]  Angelo Bifone,et al.  A multimodality investigation of cerebral hemodynamics and autoregulation in pharmacological MRI. , 2007, Magnetic resonance imaging.

[57]  Timothy O. Laumann,et al.  Functional Network Organization of the Human Brain , 2011, Neuron.

[58]  Angelo Bifone,et al.  Community structure and modularity in networks of correlated brain activity. , 2007, Magnetic resonance imaging.

[59]  Olaf Sporns,et al.  Towards network substrates of brain disorders. , 2014, Brain : a journal of neurology.

[60]  Nanyin Zhang,et al.  Intrinsic Organization of the Anesthetized Brain , 2012, The Journal of Neuroscience.

[61]  A. Gozzi,et al.  A robust experimental protocol for pharmacological fMRI in rats and mice , 2012, Journal of Neuroscience Methods.

[62]  Angelo Bifone,et al.  Functional connectivity in the rat brain: a complex network approach. , 2010, Magnetic resonance imaging.

[63]  Edward T. Bullmore,et al.  On the use of correlation as a measure of network connectivity , 2012, NeuroImage.

[64]  J. Doye,et al.  Thermodynamics of Community Structure , 2006, cond-mat/0610077.

[65]  Jonathan D. Power,et al.  Functional Brain Networks Develop from a “Local to Distributed” Organization , 2009, PLoS Comput. Biol..

[66]  Brian D. Mills,et al.  Large-scale topology and the default mode network in the mouse connectome , 2014, Proceedings of the National Academy of Sciences.

[67]  Justin L. Vincent,et al.  Intrinsic functional architecture in the anaesthetized monkey brain , 2007, Nature.