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1.
PLoS One ; 19(2): e0297435, 2024.
Article in English | MEDLINE | ID: mdl-38381733

ABSTRACT

Advancements in brain imaging techniques have significantly expanded the size and complexity of real-time neuroimaging and behavioral data. However, identifying patterns, trends and synchronies within these datasets presents a significant computational challenge. Here, we demonstrate an approach that can translate time-varying neuroimaging data into unique audiovisualizations consisting of audible representations of dynamic data merged with simplified, color-coded movies of spatial components and behavioral recordings. Multiple variables can be encoded as different musical instruments, letting the observer differentiate and track multiple dynamic parameters in parallel. This representation enables intuitive assimilation of these datasets for behavioral correlates and spatiotemporal features such as patterns, rhythms and motifs that could be difficult to detect through conventional data interrogation methods. These audiovisual representations provide a novel perception of the organization and patterns of real-time activity in the brain, and offer an intuitive and compelling method for complex data visualization for a wider range of applications.


Subject(s)
Brain , Neuroimaging , Brain/diagnostic imaging
2.
Cell Rep ; 37(1): 109794, 2021 10 05.
Article in English | MEDLINE | ID: mdl-34610299

ABSTRACT

Cortical spreading depolarizations (CSDs) are increasingly suspected to play an exacerbating role in a range of acute brain injuries, including stroke, possibly through their interactions with cortical blood flow. We use simultaneous wide-field imaging of neural activity and hemodynamics in Thy1-GCaMP6f mice to explore the neurovascular dynamics of CSDs during and following Rose Bengal-mediated photothrombosis. CSDs are observed in all mice as slow-moving waves of GCaMP fluorescence extending far beyond the photothrombotic area. Initial CSDs are accompanied by profound vasoconstriction and leave residual oligemia and ischemia in their wake. Later, CSDs evoke variable responses, from constriction to biphasic to vasodilation. However, CSD-evoked vasoconstriction is found to be more likely during rapid, high-amplitude CSDs in regions with stronger oligemia and ischemia, which, in turn, worsens after each repeated CSD. This feedback loop may explain the variable but potentially devastating effects of CSDs in the context of acute brain injury.


Subject(s)
Brain Injuries/pathology , Cortical Spreading Depression/physiology , Hemodynamics , Acute Disease , Animals , Brain Injuries/metabolism , Calcium-Binding Proteins/genetics , Cerebral Cortex/blood supply , Cerebral Cortex/physiopathology , Female , Mice , Mice, Inbred C57BL , Mice, Transgenic , Neurons/metabolism , Rose Bengal/toxicity , Thrombosis/chemically induced , Thrombosis/pathology , Thy-1 Antigens/genetics , Vasoconstriction , Voltage-Sensitive Dye Imaging/methods
3.
Cell Rep ; 31(2): 107500, 2020 04 14.
Article in English | MEDLINE | ID: mdl-32294436

ABSTRACT

Diffusely infiltrating gliomas are known to cause alterations in cortical function, vascular disruption, and seizures. These neurological complications present major clinical challenges, yet their underlying mechanisms and causal relationships to disease progression are poorly characterized. Here, we follow glioma progression in awake Thy1-GCaMP6f mice using in vivo wide-field optical mapping to monitor alterations in both neuronal activity and functional hemodynamics. The bilateral synchrony of spontaneous neuronal activity gradually decreases in glioma-infiltrated cortical regions, while neurovascular coupling becomes progressively disrupted compared to uninvolved cortex. Over time, mice develop diverse patterns of high amplitude discharges and eventually generalized seizures that appear to originate at the tumors' infiltrative margins. Interictal and seizure events exhibit positive neurovascular coupling in uninfiltrated cortex; however, glioma-infiltrated regions exhibit disrupted hemodynamic responses driving seizure-evoked hypoxia. These results reveal a landscape of complex physiological interactions occurring during glioma progression and present new opportunities for exploring novel biomarkers and therapeutic targets.


Subject(s)
Glioma/physiopathology , Neurovascular Coupling/physiology , Animals , Brain/physiopathology , Cerebral Cortex/metabolism , Disease Progression , Hemodynamics/physiology , Male , Mice , Mice, Inbred C57BL , Nerve Net/physiopathology , Neurons/metabolism , Seizures/physiopathology
4.
6.
Proc Natl Acad Sci U S A ; 113(52): E8463-E8471, 2016 12 27.
Article in English | MEDLINE | ID: mdl-27974609

ABSTRACT

Brain hemodynamics serve as a proxy for neural activity in a range of noninvasive neuroimaging techniques including functional magnetic resonance imaging (fMRI). In resting-state fMRI, hemodynamic fluctuations have been found to exhibit patterns of bilateral synchrony, with correlated regions inferred to have functional connectivity. However, the relationship between resting-state hemodynamics and underlying neural activity has not been well established, making the neural underpinnings of functional connectivity networks unclear. In this study, neural activity and hemodynamics were recorded simultaneously over the bilateral cortex of awake and anesthetized Thy1-GCaMP mice using wide-field optical mapping. Neural activity was visualized via selective expression of the calcium-sensitive fluorophore GCaMP in layer 2/3 and 5 excitatory neurons. Characteristic patterns of resting-state hemodynamics were accompanied by more rapidly changing bilateral patterns of resting-state neural activity. Spatiotemporal hemodynamics could be modeled by convolving this neural activity with hemodynamic response functions derived through both deconvolution and gamma-variate fitting. Simultaneous imaging and electrophysiology confirmed that Thy1-GCaMP signals are well-predicted by multiunit activity. Neurovascular coupling between resting-state neural activity and hemodynamics was robust and fast in awake animals, whereas coupling in urethane-anesthetized animals was slower, and in some cases included lower-frequency (<0.04 Hz) hemodynamic fluctuations that were not well-predicted by local Thy1-GCaMP recordings. These results support that resting-state hemodynamics in the awake and anesthetized brain are coupled to underlying patterns of excitatory neural activity. The patterns of bilaterally-symmetric spontaneous neural activity revealed by wide-field Thy1-GCaMP imaging may depict the neural foundation of functional connectivity networks detected in resting-state fMRI.


Subject(s)
Cortical Synchronization , Hemodynamics , Neurons/physiology , Animals , Brain/physiology , Electrophysiological Phenomena , Fluorescent Dyes/chemistry , Green Fluorescent Proteins/chemistry , Magnetic Resonance Imaging , Mice , Models, Neurological , Nerve Net , Optical Imaging , Time Factors
7.
Article in English | MEDLINE | ID: mdl-27574312

ABSTRACT

Although modern techniques such as two-photon microscopy can now provide cellular-level three-dimensional imaging of the intact living brain, the speed and fields of view of these techniques remain limited. Conversely, two-dimensional wide-field optical mapping (WFOM), a simpler technique that uses a camera to observe large areas of the exposed cortex under visible light, can detect changes in both neural activity and haemodynamics at very high speeds. Although WFOM may not provide single-neuron or capillary-level resolution, it is an attractive and accessible approach to imaging large areas of the brain in awake, behaving mammals at speeds fast enough to observe widespread neural firing events, as well as their dynamic coupling to haemodynamics. Although such wide-field optical imaging techniques have a long history, the advent of genetically encoded fluorophores that can report neural activity with high sensitivity, as well as modern technologies such as light emitting diodes and sensitive and high-speed digital cameras have driven renewed interest in WFOM. To facilitate the wider adoption and standardization of WFOM approaches for neuroscience and neurovascular coupling research, we provide here an overview of the basic principles of WFOM, considerations for implementation of wide-field fluorescence imaging of neural activity, spectroscopic analysis and interpretation of results.This article is part of the themed issue 'Interpreting BOLD: a dialogue between cognitive and cellular neuroscience'.


Subject(s)
Brain Mapping/methods , Brain/physiology , Neurons/physiology , Optical Imaging/methods , Animals , Brain/blood supply , Brain/diagnostic imaging , Brain Mapping/instrumentation , Hemodynamics , Humans , Mice , Optical Imaging/instrumentation , Rats
8.
J Neurosci ; 36(25): 6704-17, 2016 06 22.
Article in English | MEDLINE | ID: mdl-27335402

ABSTRACT

UNLABELLED: In the adult brain, increases in neural activity lead to increases in local blood flow. However, many prior measurements of functional hemodynamics in the neonatal brain, including functional magnetic resonance imaging (fMRI) in human infants, have noted altered and even inverted hemodynamic responses to stimuli. Here, we demonstrate that localized neural activity in early postnatal mice does not evoke blood flow increases as in the adult brain, and elucidate the neural and metabolic correlates of these altered functional hemodynamics as a function of developmental age. Using wide-field GCaMP imaging, the development of neural responses to somatosensory stimulus is visualized over the entire bilaterally exposed cortex. Neural responses are observed to progress from tightly localized, unilateral maps to bilateral responses as interhemispheric connectivity becomes established. Simultaneous hemodynamic imaging confirms that spatiotemporally coupled functional hyperemia is not present during these early stages of postnatal brain development, and develops gradually as cortical connectivity is established. Exploring the consequences of this lack of functional hyperemia, measurements of oxidative metabolism via flavoprotein fluorescence suggest that neural activity depletes local oxygen to below baseline levels at early developmental stages. Analysis of hemoglobin oxygenation dynamics at the same age confirms oxygen depletion for both stimulus-evoked and resting-state neural activity. This state of unmet metabolic demand during neural network development poses new questions about the mechanisms of neurovascular development and its role in both normal and abnormal brain development. These results also provide important insights for the interpretation of fMRI studies of the developing brain. SIGNIFICANCE STATEMENT: This work demonstrates that the postnatal development of neuronal connectivity is accompanied by development of the mechanisms that regulate local blood flow in response to neural activity. Novel in vivo imaging reveals that, in the developing mouse brain, strong and localized GCaMP neural responses to stimulus fail to evoke local blood flow increases, leading to a state in which oxygen levels become locally depleted. These results demonstrate that the development of cortical connectivity occurs in an environment of altered energy availability that itself may play a role in shaping normal brain development. These findings have important implications for understanding the pathophysiology of abnormal developmental trajectories, and for the interpretation of functional magnetic resonance imaging data acquired in the developing brain.


Subject(s)
Afferent Pathways/physiology , Brain Mapping , Brain/growth & development , Brain/metabolism , Cerebrovascular Circulation/physiology , Nerve Net/metabolism , Neurovascular Coupling/physiology , Age Factors , Animals , Animals, Newborn , Brain/diagnostic imaging , Female , Hemodynamics , Hemoglobins/metabolism , Luminescent Proteins/genetics , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Oxyhemoglobins/metabolism , Physical Stimulation
9.
J Am Heart Assoc ; 3(3): e000787, 2014 Jun 12.
Article in English | MEDLINE | ID: mdl-24926076

ABSTRACT

BACKGROUND: The functional modulation of blood flow in the brain is critical for brain health and is the basis of contrast in functional magnetic resonance imaging. There is evident coupling between increases in neuronal activity and increases in local blood flow; however, many aspects of this neurovascular coupling remain unexplained by current models. Based on the rapid dilation of distant pial arteries during cortical functional hyperemia, we hypothesized that endothelial signaling may play a key role in the long-range propagation of vasodilation during functional hyperemia in the brain. Although well characterized in the peripheral vasculature, endothelial involvement in functional neurovascular coupling has not been demonstrated. METHODS AND RESULTS: We combined in vivo exposed-cortex multispectral optical intrinsic signal imaging (MS-OISI) with a novel in vivo implementation of the light-dye technique to record the cortical hemodynamic response to somatosensory stimulus in rats before and after spatially selective endothelial disruption. We demonstrate that discrete interruption of endothelial signaling halts propagation of stimulus-evoked vasodilation in pial arteries, and that wide-field endothelial disruption in pial arteries significantly attenuates the hemodynamic response to stimulus, particularly the early, rapid increase and peak in hyperemia. CONCLUSIONS: Involvement of endothelial pathways in functional neurovascular coupling provides new explanations for the spatial and temporal features of the hemodynamic response to stimulus and could explain previous results that were interpreted as evidence for astrocyte-mediated control of functional hyperemia. Our results unify many aspects of blood flow regulation in the brain and body and prompt new investigation of direct links between systemic cardiovascular disease and neural deficits.


Subject(s)
Cerebrovascular Circulation/physiology , Endothelium, Vascular/physiology , Animals , Cerebral Cortex/blood supply , Functional Neuroimaging , Hemodynamics/physiology , Magnetic Resonance Imaging , Muscle, Smooth, Vascular/physiology , Rats , Vasodilation/physiology
10.
J Neurotrauma ; 28(11): 2277-85, 2011 Nov.
Article in English | MEDLINE | ID: mdl-21381883

ABSTRACT

Increased intracranial pressure (ICP) caused by edema following severe traumatic brain injury (TBI) or stroke contributes to high rates of mortality and morbidity. The search continues for more effective treatments that target the edema that contributes to increased ICP. We previously described the effect of the fixed charge density (FCD) of brain on its swelling behavior according to the Donnan effect. Here we show that reduction of brain tissue FCD is an effective means of reducing brain tissue swelling and edema in rat and porcine cortical brain tissue in vitro. The effect of enzymes directed at digesting candidate contributors to cellular FCD such as chondroitin sulfate proteoglycans (CSPGs), heparin sulfate proteoglycans (HSPGs), and DNA was examined in slices of the adult rat cortex. All enzymes were capable of decreasing FCD in the tissue by ?20%, and reducing tissue swelling over a 24?h period following dissection from ?60% to ?30%. Chondroitinase ABC (ChABC) was most effective at reducing dead brain tissue swelling in response to changes in ionic osmotic environments. ChABC reduced swelling in live slices of tissue even within the first 2?h following dissection. It also significantly reduced the FCD, initial tissue swelling, and volume change in response to hypotonic bathing solution in porcine cortical brain tissue. The use of ChABC to reduce tissue FCD may be an effective method for reducing brain edema and controlling ICP following injury.


Subject(s)
Brain Edema/drug therapy , Brain Edema/enzymology , Chondroitin ABC Lyase/therapeutic use , Animals , Organ Culture Techniques , Rats , Rats, Sprague-Dawley , Swine
11.
Philos Trans A Math Phys Eng Sci ; 368(1912): 585-603, 2010 Feb 13.
Article in English | MEDLINE | ID: mdl-20047940

ABSTRACT

Cerebral oedema or brain tissue swelling is a significant complication following traumatic brain injury or stroke that can increase the intracranial pressure (ICP) and impair blood flow. Here, we have identified a potential driver of oedema: the negatively charged molecules fixed within cells. This fixed charge density (FCD), once exposed, could increase ICP through the Donnan effect. We have shown that metabolic processes and membrane integrity are required for concealing this FCD as slices of rat cortex swelled immediately (within 30 min) following dissection if treated with 2 deoxyglucose + cyanide (2DG+CN) or Triton X-100. Slices given ample oxygen and glucose, however, did not swell significantly. We also found that dead brain tissue swells and shrinks in response to changes in ionic strength of the bathing medium, which suggests that the Donnan effect is capable of pressurizing and swelling brain tissue. As predicted, a non-ionic osmolyte, 1,2 propanediol, elicited no volume change at 2000 x 10(-3) osmoles l(-1) (Osm). Swelling data were well described by triphasic mixture theory with the calculated reference state FCD similar to that measured with a 1,9 dimethylmethylene blue assay. Taken together, these data suggest that intracellular fixed charges may contribute to the driving forces responsible for brain swelling.


Subject(s)
Brain Edema/physiopathology , Brain/physiopathology , Intracranial Pressure , Models, Neurological , Animals , Computer Simulation , In Vitro Techniques , Organ Size , Osmotic Pressure , Rats , Rats, Sprague-Dawley , Static Electricity , Stress, Mechanical
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