The impact of vasomotion on analysis of rodent fMRI data

Introduction Small animal fMRI is an essential part of translational research in the cognitive neurosciences. Due to small dimensions and animal physiology preclinical fMRI is prone to artifacts that may lead to misinterpretation of the data. To reach unbiased translational conclusions, it is, therefore, crucial to identify potential sources of experimental noise and to develop correction methods for contributions that cannot be avoided such as physiological noise. Aim of this study was to assess origin and prevalence of hemodynamic oscillations (HDO) in preclinical fMRI in rat, as well as their impact on data analysis. Methods Following the development of algorithms for HDO detection and suppression, HDO prevalence in fMRI measurements was investigated for different anesthetic regimens, comprising isoflurane and medetomidine, and for both gradient echo and spin echo fMRI sequences. In addition to assessing the effect of vasodilation on HDO, it was studied if HDO have a direct neuronal correlate using local field potential (LFP) recordings. Finally, the impact of HDO on analysis of fMRI data was assessed, studying both the impact on calculation of activation maps as well as the impact on brain network analysis. Overall, 303 fMRI measurements and 32 LFP recordings were performed in 71 rats. Results In total, 62% of the fMRI measurements showed HDO with a frequency of (0.20 ± 0.02) Hz. This frequent occurrence indicated that HDO cannot be generally neglected in fMRI experiments. Using the developed algorithms, HDO were detected with a specificity of 95%, and removed efficiently from the signal time courses. HDO occurred brain-wide under vasoconstrictive conditions in both small and large blood vessels. Vasodilation immediately interrupted HDO, which, however, returned within 1 h under vasoconstrictive conditions. No direct neuronal correlate of HDO was observed in LFP recordings. HDO significantly impacted analysis of fMRI data, leading to altered cluster sizes and F-values for activated voxels, as well as altered brain networks, when comparing data with and without HDO. Discussion We therefore conclude that HDO are caused by vasomotion under certain anesthetic conditions and should be corrected during fMRI data analysis to avoid bias.

[1]  Georgios A. Keliris,et al.  Combining magnetic resonance imaging with readout and/or perturbation of neural activity in animal models: Advantages and pitfalls , 2022, Frontiers in Neuroscience.

[2]  C. Faber,et al.  Fiber-based lactate recordings with fluorescence resonance energy transfer sensors by applying an magnetic resonance-informed correction of hemodynamic artifacts , 2022, Neurophotonics.

[3]  Francisca F. Fernandes,et al.  StandardRat: A multi-center consensus protocol to enhance functional connectivity specificity in the rat brain , 2022, bioRxiv.

[4]  M. Rudin,et al.  Hybrid fiber optic-fMRI for multimodal cell-specific recording and manipulation of neural activity in rodents , 2022, Neurophotonics.

[5]  Yang Liu,et al.  The Origin of Vasomotion and Stochastic Resonance in Vasomotion , 2022, Frontiers in Bioengineering and Biotechnology.

[6]  A. Hess,et al.  Combined resting state-fMRI and calcium recordings show stable brain states for task-induced fMRI in mice under combined ISO/MED anesthesia , 2021, NeuroImage.

[7]  Nicolas C. Pégard,et al.  Spectral fiber photometry derives hemoglobin concentration changes for accurate measurement of fluorescent sensor activity , 2021, bioRxiv.

[8]  T. Budde,et al.  Retrosplenial Cortex Contributes to Network Changes during Seizures in the GAERS Absence Epilepsy Rat Model , 2021, Cerebral cortex communications.

[9]  Na Ji,et al.  High-speed volumetric two-photon fluorescence imaging of neurovascular dynamics , 2020, Nature Communications.

[10]  Yujian Diao,et al.  Synchronous nonmonotonic changes in functional connectivity and white matter integrity in a rat model of sporadic Alzheimer's disease , 2020, NeuroImage.

[11]  Xenophon Papademetris,et al.  Simultaneous cortex-wide fluorescence Ca2+ imaging and whole-brain fMRI , 2020, Nature Methods.

[12]  M. Clarke,et al.  The Pharmacokinetics of Medetomidine Administered Subcutaneously during Isoflurane Anaesthesia in Sprague-Dawley Rats , 2020, Animals : an open access journal from MDPI.

[13]  Franziska Albers,et al.  A cortical rat hemodynamic response function for improved detection of BOLD activation under common experimental conditions , 2019, NeuroImage.

[14]  Cornelius Faber,et al.  Functional MRI Readouts From BOLD and Diffusion Measurements Differentially Respond to Optogenetic Activation and Tissue Heating , 2019, Front. Neurosci..

[15]  Cornelius Faber,et al.  Anesthesia differentially modulates neuronal and vascular contributions to the BOLD signal , 2019, NeuroImage.

[16]  Nikoloz Sirmpilatze,et al.  Temporal stability of fMRI in medetomidine-anesthetized rats , 2019, Scientific Reports.

[17]  M. Frosz,et al.  MRI-guided robotic arm drives optogenetic fMRI with concurrent Ca2+ recording , 2019, Nature Communications.

[18]  Olli Gröhn,et al.  Functional connectivity under six anesthesia protocols and the awake condition in rat brain , 2018, NeuroImage.

[19]  A. Kubatiev,et al.  Application of wavelet analysis to detect dysfunction in cerebral blood flow autoregulation during experimental hyperhomocysteinaemia , 2018, Lasers in Medical Science.

[20]  Cornelius Faber,et al.  Multimodal Functional Neuroimaging by Simultaneous BOLD fMRI and Fiber-Optic Calcium Recordings and Optogenetic Control , 2018, Molecular Imaging and Biology.

[21]  D. Kleinfeld,et al.  Entrainment of Arteriole Vasomotor Fluctuations by Neural Activity Is a Basis of Blood-Oxygenation-Level-Dependent “Resting-State” Connectivity , 2017, Neuron.

[22]  Klaus Scheffler,et al.  The impact of vessel size, orientation and intravascular contribution on the neurovascular fingerprint of BOLD bSSFP fMRI , 2017, NeuroImage.

[23]  Aaron T. Winder,et al.  Weak correlations between hemodynamic signals and ongoing neural activity during the resting state , 2017, Nature Neuroscience.

[24]  Zhifeng Liang,et al.  Time to wake up: Studying neurovascular coupling and brain-wide circuit function in the un-anesthetized animal , 2016, NeuroImage.

[25]  Ying Ma,et al.  Wide-field optical mapping of neural activity and brain haemodynamics: considerations and novel approaches , 2016, Philosophical Transactions of the Royal Society B: Biological Sciences.

[26]  Mariel G Kozberg,et al.  Rapid Postnatal Expansion of Neural Networks Occurs in an Environment of Altered Neurovascular and Neurometabolic Coupling , 2016, The Journal of Neuroscience.

[27]  Esther Pogatzki-Zahn,et al.  Characterization of incisional and inflammatory pain in rats using functional tools of MRI , 2016, NeuroImage.

[28]  Valerio Zerbi,et al.  Mapping the mouse brain with rs-fMRI: An optimized pipeline for functional network identification , 2015, NeuroImage.

[29]  Chris J. Martin,et al.  A systematic review of physiological methods in rodent pharmacological MRI studies , 2015, Psychopharmacology.

[30]  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.

[31]  Ludovica Griffanti,et al.  Automatic denoising of functional MRI data: Combining independent component analysis and hierarchical fusion of classifiers , 2014, NeuroImage.

[32]  S. Keilholz,et al.  Time‐dependent effects of isoflurane and dexmedetomidine on functional connectivity, spectral characteristics, and spatial distribution of spontaneous BOLD fluctuations , 2014, NMR in biomedicine.

[33]  Matthew B. Bouchard,et al.  Direct, intraoperative observation of ~0.1Hz hemodynamic oscillations in awake human cortex: Implications for fMRI , 2014, NeuroImage.

[34]  Kevin Murphy,et al.  Resting-state fMRI confounds and cleanup , 2013, NeuroImage.

[35]  R. Buxton The physics of functional magnetic resonance imaging (fMRI) , 2013, Reports on progress in physics. Physical Society.

[36]  Dieter Jaeger,et al.  Infraslow LFP correlates to resting-state fMRI BOLD signals , 2013, NeuroImage.

[37]  Seong-Gi Kim,et al.  Effects of the α2‐adrenergic receptor agonist dexmedetomidine on neural, vascular and BOLD fMRI responses in the somatosensory cortex , 2013, The European journal of neuroscience.

[38]  F. Helmchen,et al.  Simultaneous BOLD fMRI and fiber-optic calcium recording in rat neocortex , 2012, Nature Methods.

[39]  Yevgeniy B. Sirotin,et al.  Spatial homogeneity and task-synchrony of the trial-related hemodynamic signal , 2012, NeuroImage.

[40]  K. Grieve,et al.  Vasomotion and Neurovascular Coupling in the Visual Thalamus In Vivo , 2011, PloS one.

[41]  C. Aalkjær,et al.  Vasomotion – what is currently thought? , 2011, Acta physiologica.

[42]  Edward T. Bullmore,et al.  Network-based statistic: Identifying differences in brain networks , 2010, NeuroImage.

[43]  D. Kleinfeld,et al.  Chronic optical access through a polished and reinforced thinned skull , 2010 .

[44]  S. Keilholz,et al.  Functional connectivity in blood oxygenation level‐dependent and cerebral blood volume‐weighted resting state functional magnetic resonance imaging in the rat brain , 2010, Journal of magnetic resonance imaging : JMRI.

[45]  Waqas Majeed,et al.  Simultaneous FMRI and electrophysiology in the rodent brain. , 2010, Journal of visualized experiments : JoVE.

[46]  Arend Heerschap,et al.  Isoflurane anesthesia is a valuable alternative for α‐chloralose anesthesia in the forepaw stimulation model in rats , 2009, NMR in biomedicine.

[47]  Yevgeniy B. Sirotin,et al.  Anticipatory Hæmodynamic Signals in Sensory Cortex , 2009, Nature.

[48]  A. Mak,et al.  Effects of prolonged surface pressure on the skin blood flowmotions in anaesthetized rats—an assessment by spectral analysis of laser Doppler flowmetry signals , 2006, Physics in medicine and biology.

[49]  Dirk Wiedermann,et al.  A fully noninvasive and robust experimental protocol for longitudinal fMRI studies in the rat , 2006, NeuroImage.

[50]  M. Sinclair A review of the physiological effects of alpha2-agonists related to the clinical use of medetomidine in small animal practice. , 2003, The Canadian veterinary journal = La revue veterinaire canadienne.

[51]  Reinhold Ludwig,et al.  Corticothalamic Modulation during Absence Seizures in Rats: A Functional MRI Assessment , 2003, Epilepsia.

[52]  H. Nilsson,et al.  Vasomotion: mechanisms and physiological importance. , 2003, Molecular interventions.

[53]  P. Marchiafava,et al.  Phentolamine suppresses the increase in arteriolar vasomotion frequency due to systemic hypoxia in hamster skeletal muscle microcirculation , 2001, Autonomic Neuroscience.

[54]  A. Villringer,et al.  Spontaneous Low Frequency Oscillations of Cerebral Hemodynamics and Metabolism in Human Adults , 2000, NeuroImage.

[55]  D. Kleinfeld,et al.  Fluctuations and stimulus-induced changes in blood flow observed in individual capillaries in layers 2 through 4 of rat neocortex. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[56]  Hiroki Iida,et al.  Isoflurane and Sevoflurane Induce Vasodilation of Cerebral Vessels via ATP‐sensitive K+ Channel Activation , 1998, Anesthesiology.

[57]  A. Hudetz,et al.  Region‐specific and Agent‐specific Dilation of Intracerebral Microvessels by Volatile Anesthetics in Rat Brain Slices , 1997, Anesthesiology.

[58]  P. Mitra,et al.  The nature of spatiotemporal changes in cerebral hemodynamics as manifested in functional magnetic resonance imaging , 1997, Magnetic resonance in medicine.

[59]  J. Mayhew,et al.  Cerebral Vasomotion: A 0.1-Hz Oscillation in Reflected Light Imaging of Neural Activity , 1996, NeuroImage.

[60]  Z. Bosnjak,et al.  Isoflurane produces endothelium-independent relaxation in canine middle cerebral arteries. , 1992, Anesthesiology.

[61]  D. Heistad,et al.  Vasomotion of basilar arteries in vivo. , 1990, The American journal of physiology.

[62]  S. Ogawa,et al.  Oxygenation‐sensitive contrast in magnetic resonance image of rodent brain at high magnetic fields , 1990, Magnetic resonance in medicine.

[63]  Marcos Intaglietta,et al.  The effects of α- or β-adrenergic receptor agonists and antagonists and calcium entry blockers on the spontaneous vasomotion ☆ , 1984 .

[64]  P. Skovsted,et al.  The effects of isoflurane on arterial pressure, pulse rate, autonomic nervous activity, and barostatic reflexes , 1977, Canadian Anaesthetists' Society journal.

[65]  Hanbing Lu,et al.  Physiological characterization of a robust survival rodent fMRI method. , 2017, Magnetic resonance imaging.

[66]  J. Pillai Functional Connectivity. , 2017, Neuroimaging clinics of North America.

[67]  Bharat B. Biswal,et al.  SPONTANEOUS FLUCTUATIONS IN CEREBRAL OXYGEN SUPPLY , 1998 .

[68]  Karl J. Friston,et al.  Statistical parametric maps in functional imaging: A general linear approach , 1994 .

[69]  D. Slaaf,et al.  Analysis of vasomotion waveform changes during pressure reduction and adenosine application. , 1990, The American journal of physiology.

[70]  W. Halpern,et al.  Spontaneous vasomotion in pressurized cerebral arteries from genetically hypertensive rats. , 1988, The American journal of physiology.

[71]  H. Kontos,et al.  Vasomotion in cerebral microcirculation of awake rabbits. , 1988, The American journal of physiology.