Intrinsic organization of the anesthetized brain

The neural mechanism of unconsciousness has been a major unsolved question in neuroscience despite its vital role in brain states like coma and anesthesia. The existing literature suggests that neural connections, information integration, and conscious states are closely related. Indeed, alterations in several important neural circuitries and networks during unconscious conditions have been reported. However, how the whole-brain network is topologically reorganized to support different patterns of information transfer during unconscious states remains unknown. Here we directly compared whole-brain neural networks in awake and anesthetized states in rodents. Consistent with our previous report, the awake rat brain was organized in a nontrivial manner and conserved fundamental topological properties in a way similar to the human brain. Strikingly, these topological features were well maintained in the anesthetized brain. Local neural networks in the anesthetized brain were reorganized with altered local network properties. The connectional strength between brain regions was also considerably different between the awake and anesthetized conditions. Interestingly, we found that long-distance connections were not preferentially reduced in the anesthetized condition, arguing against the hypothesis that loss of long-distance connections is characteristic to unconsciousness. These findings collectively show that the integrity of the whole-brain network can be conserved between widely dissimilar physiologic states while local neural networks can flexibly adapt to new conditions. They also illustrate that the governing principles of intrinsic brain organization might represent fundamental characteristics of the healthy brain. With the unique spatial and temporal scales of resting-state fMRI, this study has opened a new avenue for understanding the neural mechanism of (un)consciousness

Uncovering intrinsic connectional architecture of functional networks in awake rat brain

Intrinsic connectional architecture of the brain is a crucial element in understanding the governing principle of brain organization. To date, enormous effort has been focused on addressing this issue in humans by combining resting-state functional magnetic resonance imaging (rsfMRI) with other techniques. However, this research area is significantly underexplored in animals, perhaps because of confounding effects of anesthetic agents used in most animal experiments on functional connectivity. To bridge this gap, we have systematically investigated the intrinsic connectional architecture in the rodent brain by using a previously established awake-animal imaging model. First, group independent component analysis was applied to the rsfMRI data to extract elementary functional clusters of the brain. The connectional relationships between these clusters, as evaluated by partial correlation analysis, were then used to construct a graph of whole-brain neural network. This network exhibited the typical features of small-worldness and strong community structures seen in the human brain. Finally, the whole-brain network was segregated into community structures using a graph-based analysis. The results of this work provided a functional atlas of intrinsic connectional architecture of the rat brain at both intraregion and interregion levels. More importantly, the current work revealed that functional networks in rats are organized in a nontrivial manner and conserve fundamental topological properties that are also seen in the human brain. Given the high psychopathological relevance of network organization of the brain, this study demonstrated the feasibility of studying mechanisms and therapies of multiple neurological and psychiatric diseases through translational research

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

The development and expression of physical nicotine dependence corresponds to structural and functional alterations in the anterior cingulate-precuneus pathway

INTRODUCTION: Perturbations in neural function provoked by a drug are thought to induce neural adaptations, which, in the absence of the drug, give rise to withdrawal symptoms. Previously published structural data from this study indicated that the progressive development of physical dependence is associated with increasing density of white matter tracts between the anterior cingulum bundle and the precuneus. METHODS: Using functional magnetic resonance imaging, we compared 11 smokers after 11 h of abstinence from nicotine and after satiation, with 10 nonsmoking controls, using independent component analysis for brain network comparisons as well as a whole brain resting-state functional connectivity analysis using the anterior cingulate cortex as a seed. RESULTS: Independent component analysis demonstrated increased functional connectivity in brain networks such as the default mode network associated with the withdrawal state in multiple brain regions. In seed-based analysis, smokers in the withdrawal state showed stronger functional connectivity than nonsmoking controls between the anterior cingulate cortex and the precuneus, caudate, putamen, and frontal cortex (P \u3c 0.05). Among smokers, compared to the satiated state, nicotine withdrawal was associated with increased connectivity between the anterior cingulate cortex and the precuneus, insula, orbital frontal gyrus, superior frontal gyrus, posterior cingulate cortex, superior temporal, and inferior temporal lobe (P \u3c 0.02). The intensity of withdrawal-induced craving correlated with the strength of connectivity between the anterior cingulate cortex and the precuneus, insula, caudate, putamen, middle cingulate gyrus, and precentral gyrus (r = 0.60-0.76; P \u3c 0.05). CONCLUSIONS: In concordance with our previous report that structural neural connectivity between the anterior cingulate area and the precuneus increased in proportion to the progression of physical dependence, resting-state functional connectivity in this pathway increases during nicotine withdrawal in correlation with the intensity of withdrawal-induced craving. These findings suggest that smoking triggers structural and functional neural adaptations in the brain that support withdrawal-induced craving

Three Measures of Tobacco Dependence Independently Predict Changes in Neural Structure

Studies have demonstrated moderate correlations between fractional anisotropy (FA, a measure of white matter organization), and Fagerström Test for Nicotine Dependence (FTND) scores in various white matter brain structures (r=-.52 to -.64). FA increases with smoking in adolescents, but in adult smokers FA declines with the progression of physical dependence. We examined correlations between FA and 3 measures of tobacco dependence: the FTND, Levels of Physical Dependence (PD), and the Hooked on Nicotine Checklist (HONC). The latter 2 measures assess only symptoms rather than behaviors, based on an assumption that a direct assessment of subjective symptoms will better reflect underlying biological conditions than behaviors that might be constrained by sociocultural factors.We compared white matter FA in 8 smokers and 10 nonsmokers and plotted the location of maximal correlation between FA and each dependence measure. FA trended higher in smokers than nonsmokers in the anterior cingulum bundle (ACb) (p=0.05). Among smokers, plots of the maximal correlation for all 3 measures fell within a circumscribed area of the left ACb, showing excellent concordance of results across measures. The maximal correlation with FA was r= -.78 for the FTND, -.85 for Levels of PD, and -.96 for the HONC (

Progressive levels of physical dependence to tobacco coincide with changes in the anterior cingulum bundle microstructure

BACKGROUND: The tobacco withdrawal syndrome indicates the development of neurophysiologic dependence. Clinical evidence indicates that neurophysiologic dependence develops through a set sequence of symptom presentation that can be assessed with a new 3-item survey measure of wanting, craving, and needing tobacco, the Level of Physical Dependence (PD). This study sought to determine if advancing neurophysiologic dependence as measured by the Level of PD correlates with characteristics of white matter structure measured by Fractional Anisotropy (FA). METHODS: Diffusion-MRI based FA and diffusion tensor imaging probabilistic tractography were used to evaluate 11 smokers and 10 nonsmokers. FA was also examined in relation to two additional measures of dependence severity, the Hooked on Nicotine Checklist (HONC), and the Fagerstrom Test for Nicotine Dependence (FTND). RESULTS: Among smokers, FA in the left anterior cingulate bundle (ACb) correlated negatively with the Level of PD (r = -0.68, p = 0.02) and HONC scores (r = -0.65, p = 0.03), but the correlation for the FTND did not reach statistical significance (r = -49, p = 0.12). With advancing Levels of PD, the density of streamlines between the ACb and precuneus increased (r = -0.67, p\u3c0.05) and those between the ACb and white matter projecting to the superior-frontal cortex (r = -0.86, p = 0.0006) decreased significantly. CONCLUSIONS: The correlations between neural structure and both the clinical Level of PD survey measure and the HONC suggest that the Level of PD and the HONC may reflect the microstructural integrity of white matter, as influenced by tobacco abuse. Given that the Level of PD is measuring a sequence of symptoms of neurophysiologic dependence that develops over time, the correlation between the Level of PD and neural structure suggests that these features might represent neuroplastic changes that develop over time to support the development of neurophysiologic dependence

Fear induced neuronal alterations in a genetic model of depression: An fMRI study on awake animals

Previous human imaging studies used facial stimuli to explore the potential association between depression and fear. This study aimed at investigating brain alterations in a rodent model of depression when innate fear was induced in the form of the predator odor trimethylthiazoline (TMT). Flinders sensitive line rats (FSL), a genetic animal model of depression, and their control counterpart Flinders resistant line (FRL), were used in this functional magnetic resonance imaging (fMRI) assessment. Compared to FRL, FSL rats exhibited greater BOLD activation in the cortical amygdala and hypoactivation in the prefrontal cortex in response to TMT, suggesting cortico-amygdalar dysfunction in the depressed strain. In addition, the hyperactivation in the insular cortex in FSL rats may be the basis for enhanced neuronal responses to fear and aversion in depression. These results are evidence for the value of translational models of depression in expanding understanding of the neural circuitries sub-serving common human co-morbidities like depression and fear

Keeping weight off: Mindfulness-Based Stress Reduction alters amygdala functional connectivity during weight loss maintenance in a randomized control trial

Obesity is associated with significant comorbidities and financial costs. While behavioral interventions produce clinically meaningful weight loss, weight loss maintenance is challenging. The objective was to improve understanding of the neural and psychological mechanisms modified by mindfulness that may predict clinical outcomes. Individuals who intentionally recently lost weight were randomized to Mindfulness-Based Stress Reduction (MBSR) or a control healthy living course. Anthropometric and psychological factors were measured at baseline, 8 weeks and 6 months. Functional connectivity (FC) analysis was performed at baseline and 8 weeks to examine FC changes between regions of interest selected a priori, and independent components identified by independent component analysis. The association of pre-post FC changes with 6-month weight and psychometric outcomes was then analyzed. Significant group x time interaction was found for FC between the amygdala and ventromedial prefrontal cortex, such that FC increased in the MBSR group and decreased in controls. Non-significant changes in weight were observed at 6 months, where the mindfulness group maintained their weight while the controls showed a weight increase of 3.4% in BMI. Change in FC at 8-weeks between ventromedial prefrontal cortex and several ROIs was associated with change in depression symptoms but not weight at 6 months. This pilot study provides preliminary evidence of neural mechanisms that may be involved in MBSR\u27s impact on weight loss maintenance that may be useful for designing future clinical trials and mechanistic studies

Cortical depth dependent functional responses in humans at 7T: improved specificity with 3D GRASE

Ultra high fields (7T and above) allow functional imaging with high contrast-to-noise ratios and improved spatial resolution. This, along with improved hardware and imaging techniques, allow investigating columnar and laminar functional responses. Using gradient-echo (GE) (T2* weighted) based sequences, layer specific responses have been recorded from human (and animal) primary visual areas. However, their increased sensitivity to large surface veins potentially clouds detecting and interpreting layer specific responses. Conversely, spin-echo (SE) (T2 weighted) sequences are less sensitive to large veins and have been used to map cortical columns in humans. T2 weighted 3D GRASE with inner volume selection provides high isotropic resolution over extended volumes, overcoming some of the many technical limitations of conventional 2D SE-EPI, whereby making layer specific investigations feasible. Further, the demonstration of columnar level specificity with 3D GRASE, despite contributions from both stimulated echoes and conventional T2 contrast, has made it an attractive alternative over 2D SE-EPI. Here, we assess the spatial specificity of cortical depth dependent 3D GRASE functional responses in human V1 and hMT by comparing it to GE responses. In doing so we demonstrate that 3D GRASE is less sensitive to contributions from large veins in superficial layers, while showing increased specificity (functional tuning) throughout the cortex compared to GE