Decreased Resting Functional Connectivity after Traumatic Brain Injury in the Rat

Traumatic brain injury (TBI) contributes to about 10% of acquired epilepsy. Even though the mechanisms of post-traumatic epileptogenesis are poorly known, a disruption of neuronal networks predisposing to altered neuronal synchrony remains a viable candidate mechanism. We tested a hypothesis that resting state BOLD-fMRI functional connectivity can reveal network abnormalities in brain regions that are connected to the lesioned cortex, and that these changes associate with functional impairment, particularly epileptogenesis. TBI was induced using lateral fluid-percussion injury in seven adult male Sprague-Dawley rats followed by functional imaging at 9.4T 4 months later. As controls we used six sham-operated animals that underwent all surgical operations but were not injured. Electroencephalogram (EEG)-functional magnetic resonance imaging (fMRI) was performed to measure resting functional connectivity. A week after functional imaging, rats were implanted with bipolar skull electrodes. After recovery, rats underwent pentyleneterazol (PTZ) seizure-susceptibility test under EEG. For image analysis, four pairs of regions of interests were analyzed in each hemisphere: ipsilateral and contralateral frontal and parietal cortex, hippocampus, and thalamus. High-pass and low-pass filters were applied to functional imaging data. Group statistics comparing injured and sham-operated rats and correlations over time between each region were calculated. In the end, rats were perfused for histology. None of the rats had epileptiform discharges during functional imaging. PTZ-test, however revealed increased seizure susceptibility in injured rats as compared to controls. Group statistics revealed decreased connectivity between the ipsilateral and contralateral parietal cortex and between the parietal cortex and hippocampus on the side of injury as compared to sham-operated animals. Injured animals also had abnormal negative connectivity between the ipsilateral and contralateral parietal cortex and other regions. Our data provide the first evidence on abnormal functional connectivity after experimental TBI assessed with resting state BOLD-fMRI.

[1]  Y Ge,et al.  Brain Iron Quantification in Mild Traumatic Brain Injury: A Magnetic Field Correlation Study , 2011, American Journal of Neuroradiology.

[2]  D. G. Watts,et al.  Spectral analysis and its applications , 1968 .

[3]  Christian Windischberger,et al.  Toward discovery science of human brain function , 2010, Proceedings of the National Academy of Sciences.

[4]  B. Biswal,et al.  Functional connectivity in the motor cortex of resting human brain using echo‐planar mri , 1995, Magnetic resonance in medicine.

[5]  Lei Zhou,et al.  BOLD study of stimulation-induced neural activity and resting-state connectivity in medetomidine-sedated rat , 2008, NeuroImage.

[6]  D. Corbett,et al.  Coaccumulation of Calcium and β-Amyloid in the Thalamus after Transient Middle Cerebral Artery Occlusion in Rats , 2008, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[7]  A. Pitkänen,et al.  From traumatic brain injury to posttraumatic epilepsy: What animal models tell us about the process and treatment options , 2009, Epilepsia.

[8]  Shobini L. Rao,et al.  Reduction of functional brain connectivity in mild traumatic brain injury during working memory. , 2009, Journal of neurotrauma.

[9]  L. Noble,et al.  Traumatic brain injury in the rat: Characterization of a lateral fluid-percussion model , 1989, Neuroscience.

[10]  E. Bullmore,et al.  Human brain networks in health and disease , 2009, Current opinion in neurology.

[11]  Asla Pitkänen,et al.  Magnetic Resonance Imaging of Regional Hemodynamic and Cerebrovascular Recovery after Lateral Fluid-Percussion Brain Injury in Rats , 2011, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[12]  M. Lowe,et al.  Functional Connectivity in Single and Multislice Echoplanar Imaging Using Resting-State Fluctuations , 1998, NeuroImage.

[13]  Juha-Pekka Niskanen,et al.  Monitoring functional impairment and recovery after traumatic brain injury in rats by FMRI. , 2013, Journal of neurotrauma.

[14]  Steven A Prescott,et al.  Explaining pathological changes in axonal excitability through dynamical analysis of conductance-based models , 2011, Journal of neural engineering.

[15]  Fahmeed Hyder,et al.  Focal BOLD fMRI changes in bicuculline-induced tonic–clonic seizures in the rat , 2010, NeuroImage.

[16]  M. Fox,et al.  Spontaneous fluctuations in brain activity observed with functional magnetic resonance imaging , 2007, Nature Reviews Neuroscience.

[17]  H. van Oostrom,et al.  Evaluation of analgesic and sedative effects of continuous infusion of dexmedetomidine by measuring somatosensory- and auditory-evoked potentials in the rat. , 2008, Veterinary anaesthesia and analgesia.

[18]  A. Pitkänen,et al.  Epileptogenesis after cortical photothrombotic brain lesion in rats , 2007, Neuroscience.

[19]  A. Pitkänen,et al.  Anti-epileptogenesis in rodent post-traumatic epilepsy models , 2011, Neuroscience Letters.

[20]  K. Blennow,et al.  The Neuropathology and Neurobiology of Traumatic Brain Injury , 2012, Neuron.

[21]  A. Pitkänen,et al.  A model of posttraumatic epilepsy induced by lateral fluid-percussion brain injury in rats , 2006, Neuroscience.

[22]  Matthew N. DeSalvo,et al.  Where fMRI and Electrophysiology Agree to Disagree: Corticothalamic and Striatal Activity Patterns in the WAG/Rij Rat , 2011, The Journal of Neuroscience.

[23]  R T Constable,et al.  Resting functional connectivity between the hemispheres in childhood absence epilepsy , 2011, Neurology.

[24]  Jean Daunizeau,et al.  Concepts of Connectivity and Human Epileptic Activity , 2011, Front. Syst. Neurosci..

[25]  H N Mallick,et al.  Stereotaxic assembly and procedures for simultaneous electrophysiological and MRI study of conscious rat , 2003, Magnetic resonance in medicine.

[26]  G. Jackson,et al.  Functional connectivity networks are disrupted in left temporal lobe epilepsy , 2006, Annals of neurology.

[27]  Asla Pitkänen,et al.  Quantitative diffusion MRI of hippocampus as a surrogate marker for post-traumatic epileptogenesis. , 2007, Brain : a journal of neurology.

[28]  F. Hyder,et al.  Remote Effects of Focal Hippocampal Seizures on the Rat Neocortex , 2008, The Journal of Neuroscience.

[29]  Fahmeed Hyder,et al.  Increased resting functional connectivity in spike‐wave epilepsy in WAG/Rij rats , 2013, Epilepsia.

[30]  Christophe Bernard,et al.  Hyperexcitability of the CA1 Hippocampal Region during Epileptogenesis , 2007, Epilepsia.

[31]  Hal Blumenfeld,et al.  Impaired attention and network connectivity in childhood absence epilepsy , 2011, NeuroImage.

[32]  Vladislav Volman,et al.  Computer Modeling of Mild Axonal Injury: Implications for Axonal Signal Transmission , 2013, Neural Computation.

[33]  Asla Pitkänen,et al.  MRI biomarkers for post-traumatic epileptogenesis. , 2013, Journal of neurotrauma.

[34]  Rakesh K. Gupta,et al.  Serial Changes in Diffusion Tensor Imaging Metrics of Corpus Callosum in Moderate Traumatic Brain Injury Patients and Their Correlation With Neuropsychometric Tests: A 2‐Year Follow‐up Study , 2010, The Journal of head trauma rehabilitation.

[35]  Fahmeed Hyder,et al.  Dynamic fMRI and EEG Recordings during Spike-Wave Seizures and Generalized Tonic-Clonic Seizures in WAG/Rij Rats , 2004, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[36]  M. D’Esposito,et al.  Alterations in the BOLD fMRI signal with ageing and disease: a challenge for neuroimaging , 2003, Nature Reviews Neuroscience.

[37]  Christopher P. Pawela,et al.  Long-term vascular access ports as a means of sedative administration in a rodent fMRI survival model , 2011, Journal of Neuroscience Methods.

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

[39]  Asla Pitkänen,et al.  Association of chronic vascular changes with functional outcome after traumatic brain injury in rats. , 2010, Journal of neurotrauma.

[40]  A. Turken,et al.  The Neural Architecture of the Language Comprehension Network: Converging Evidence from Lesion and Connectivity Analyses , 2011, Front. Syst. Neurosci..

[41]  Yitzhak Schiller,et al.  Network Dynamics during Development of Pharmacologically Induced Epileptic Seizures in Rats In Vivo , 2010, The Journal of Neuroscience.

[42]  David R. Pickens,et al.  Experimental model for functional magnetic resonance imaging of somatic sensory cortex in the unanesthetized rat , 2003, NeuroImage.