Multi-modal approach for investigating brain and behavior changes in an animal model of traumatic brain injury

Utilization of novel approaches in imaging modalities are needed for enhancing diagnostic and therapeutic outcomes of persons suffering a traumatic brain injury (TBI). This study explored the feasibility of using functional magnetic resonance imaging (fMRI) in conjunction with behavioral measures to target dynamic changes in specific neural circuitries in an animal model of traumatic brain injury. Wistar rats were randomly assigned to one of two groups (traumatic brain injury / sham operation). TBI rats were subjected to the closed head injury (CHI) model. Any observable motor deficits and cognitive deficits associated with the injury were measured using Beam Walk and Morris Water Maze tests, respectively. fMRI was performed to assess the underlying post-traumatic cerebral anatomy and function in acute (24 hours after the injury) and chronic (7 and 21 days after the injury) phases. Beam Walk test results detected no significant differences in motor deficits between groups. Morris Water Maze test indicated that cognitive deficits persisted for the first week following injury and to a large extent, recovered thereafter. Resting state functional connectivity (rsFC) analysis detected initially diminished connectivity between cortical areas involved in cognition for the TBI group; however the connectivity patterns normalized at one week and remained so at three weeks post-injury timepoint. Taken together, we have demonstrated an objective in vivo marker for mapping functional brain changes correlated with injury-associated cognitive behavior deficits and offer an animal model for testing potential therapeutic interventions options

Functional Connectivity fMRI of the Rodent Brain: Comparison of Functional Connectivity Networks in Rat and Mouse

At present, resting state functional MRI (rsfMRI) is increasingly used in human neuropathological research. The present study aims at implementing rsfMRI in mice, a species that holds the widest variety of neurological disease models. Moreover, by acquiring rsfMRI data with a comparable protocol for anesthesia, scanning and analysis, in both rats and mice we were able to compare findings obtained in both species. The outcome of rsfMRI is different for rats and mice and depends strongly on the applied number of components in the Independent Component Analysis (ICA). The most important difference was the appearance of unilateral cortical components for the mouse resting state data compared to bilateral rat cortical networks. Furthermore, a higher number of components was needed for the ICA analysis to separate different cortical regions in mice as compared to rats

Network-level reorganisation of functional connectivity following arm amputation

AbstractOne of the most striking demonstrations of plasticity in the adult human brain follows peripheral injury, such as amputation. In the primary sensorimotor cortex, arm amputation results in massive local remapping of the missing hands' cortical territory. However, little is known about the consequences of sensorimotor deprivation on global brain organisation. Here, we used resting-state fMRI to identify large-scale reorganisation beyond the primary sensorimotor cortex in arm amputees, compared with two-handed controls. Specifically, we characterised changes in functional connectivity between the cortical territory of the missing hand in the primary sensorimotor cortex (‘missing hand cortex’) and two networks of interest: the sensorimotor network, which is typically strongly associated with the hand cortex, and the default mode network (DMN), which is normally dissociated from it. Functional connectivity values between the missing hand cortex and the sensorimotor network were reduced in amputees, and connectivity was weaker in individuals amputated for longer periods. Lower levels of functional coupling between the missing hand cortex and the sensorimotor network were also associated with emerged coupling of this cortex with the DMN. Our results demonstrate that plasticity following arm amputation is not restricted to local remapping occurring within the sensorimotor homunculus of the missing hand but rather produces a cascade of cortical reorganisation at a network-level scale. These findings may provide a new framework for understanding how local deprivation following amputation could elicit complex perceptual experiences of phantom sensations, such as phantom pain

Identifying Respiration-Related Aliasing Artifacts in the Rodent Resting-State fMRI

Resting-state functional magnetic resonance imaging (rs-fMRI) combined with optogenetics and electrophysiological/calcium recordings in animal models is becoming a popular platform to investigate brain dynamics under specific neurological states. Physiological noise originating from the cardiac and respiration signal is the dominant interference in human rs-fMRI and extensive efforts have been made to reduce these artifacts from the human data. In animal fMRI studies, physiological noise sources including the respiratory and cardiorespiratory artifacts to the rs-fMRI signal fluctuation have typically been less investigated. In this article, we demonstrate evidence of aliasing effects into the low-frequency rs-fMRI signal fluctuation mainly due to respiration-induced B0 offsets in anesthetized rats. This aliased signal was examined by systematically altering the fMRI sampling rate, i.e., the time of repetition (TR), in free-breathing conditions and by adjusting the rate of ventilation. Anesthetized rats under ventilation showed a significantly narrower frequency bandwidth of the aliasing effect than free-breathing animals. It was found that the aliasing effect could be further reduced in ventilated animals with a muscle relaxant. This work elucidates the respiration-related aliasing effects on the rs-fMRI signal fluctuation from anesthetized rats, indicating non-negligible physiological noise needed to be taken care of in both awake and anesthetized animal rs-fMRI studies

THE EFFECTS OF MODERATE PRENATAL ALCOHOL EXPOSURE ON RESTING STATE FUNCTIONAL CONNECTIVITY AND ITS RELATIONSHIP TO BEHAVIOR

It is well established that heavy ethanol exposure during prenatal brain development leads to drastic morphological, cognitive and behavioral consequences. In contrast to heavy exposure, the effects of moderate prenatal alcohol exposure (PAE) are less severe yet continue well into adulthood. Animal models of PAE have been of immense importance to researchers for their ability to control for extraneous variables such as socio economic status, age, nutrition, stress, and co-exposure to other substances. Studies of moderate PAE have investigated several discrete brain regions, neurotransmitter systems, and animal behaviors. However, the effects of moderate PAE on resting state functional network connectivity (FNC) have not been well characterized. Moreover, the relationship between PAE, functional connectivity, and animal behavior has not been previously investigated. The present study determined whether moderate PAE alters whole brain FNC. Furthermore, the relationship between hippocampal FNC and behavior was investigated. Long-Evans rats were exposed to 5% ethanol or saccharin throughout the entire gestational period. In adulthood, rats were anesthetized (1.0-2.3% isoflurane) and BOLD signals were acquired during a 10 min echoplanar imaging sequence in a 4.7T Bruker Biospin scanner. Following motion correction, spatial normalization and smoothing, spatial group independent component analysis (gICA) was performed using the Infomax algorithm implemented in the GIFT toolbox. A total of 17 non-artifactual components were retained for analysis of spectral power and connectivity. Components were observed in cortical, hippocampal, striatal, thalamic, and cerebellar structures. Cortical, hippocampal, and midbrain regions frequently stood out as areas that displayed more significant prenatal treatment differences. PAE animals displayed reductions in low frequency spectral power for several components. PAE animals often displayed a loss of strength in connectivity. Furthermore, analyses of social behaviors with hippocampal related connectivity showed that cortex-to-hippocampus (Cx-H) connectivity is most sensitive to alcohol exposure. PAE females and males displayed more negative correlations compared to their respective saccharin comparison groups. The results indicated that moderate fetal ethanol exposure can have long-lasting consequences on functional connectivity and that hippocampal-containing connectivity was linked to alterations in social behavior

Novel Neuromodulation Techniques to Assess Interhemispheric Communication in Neural Injury and Neurodegenerative Diseases

Interhemispheric interaction has a major role in various neurobehavioral functions. Its disruption is a major contributor to the pathological changes in the setting of brain injury such as traumatic brain injury, peripheral nerve injury, and stroke, as well as neurodegenerative diseases. Because interhemispheric interaction has a crucial role in functional consequence in these neuropathological states, a review of noninvasive and state-of-the-art molecular based neuromodulation methods that focus on or have the potential to elucidate interhemispheric interaction have been performed. This yielded approximately 170 relevant articles on human subjects or animal models. There has been a recent surge of reports on noninvasive methods such as transcranial magnetic stimulation and transcranial direct current stimulation. Since these are noninvasive techniques with little to no side effects, their widespread use in clinical studies can be easily justified. The overview of novel neuromodulation methods and how they can be applied to study the role of interhemispheric communication in neural injury and neurodegenerative disease is provided. Additionally, the potential of each method in therapeutic use as well as investigating the pathophysiology of interhemispheric interaction in neurodegenerative diseases and brain injury is discussed. New technologies such as transcranial magnetic stimulation or transcranial direct current stimulation could have a great impact in understanding interhemispheric pathophysiology associated with acquired injury and neurodegenerative diseases, as well as designing improved rehabilitation therapies. Also, advances in molecular based neuromodulation techniques such as optogenetics and other chemical, thermal, and magnetic based methods provide new capabilities to stimulate or inhibit a specific brain location and a specific neuronal population

Functional networks and network perturbations in rodents

Synchronous low-frequency oscillation in the resting human brain has been found to form networks of functionally associated areas and hence has been widely used to map the functional connectivity of the brain using techniques such as resting-state functional MRI (rsfMRI). Interestingly, similar resting-state networks can also be detected in the anesthetized rodent brain, including the default mode-like network. This opens up opportunities for understanding the neurophysiological basis of the rsfMRI signal, the behavioral relevance of the network characteristics, connectomic deficits in diseases and treatment effects on brain connectivity using rodents, particularly transgenic mouse models. In this review, we will provide an overview on the resting-state networks in the rat and mouse brains, the effects of pharmacological agents, brain stimulation, structural connectivity, genetics on these networks, neuroplasticity after behavioral training and applications in models of neurological disease and psychiatric disorders. The influence of anesthesia, strain difference, and physiological variation on the rsfMRI-based connectivity measure will be discussed