44 research outputs found
Cortical lamina-dependent blood volume changes in human brain at 7T
Cortical layer-dependent high (sub-millimeter) resolution functional magnetic resonance imaging (fMRI) in human or animal brain can be used to address questions regarding the functioning of cortical circuits, such as the effect of different afferent and efferent connectivities on activity in specific cortical layers. The sensitivity of gradient echo (GE) blood oxygenation level-dependent (BOLD) responses to large draining veins reduces its local specificity and can render the interpretation of the underlying laminar neural activity impossible. The application of the more spatially specific cerebral blood volume (CBV)-based fMRI in humans has been hindered by the low sensitivity of the noninvasive modalities available. Here, a vascular space occupancy (VASO) variant, adapted for use at high field, is further optimized to capture layer-dependent activity changes in human motor cortex at sub-millimeter resolution. Acquired activation maps and cortical profiles show that the VASO signal peaks in gray matter at 0.8–1.6 mm depth, and deeper compared to the superficial and vein-dominated GE-BOLD responses. Validation of the VASO signal change versus well-established iron-oxide contrast agent based fMRI methods in animals showed the same cortical profiles of CBV change, after normalization for lamina-dependent baseline CBV. In order to evaluate its potential of revealing small lamina-dependent signal differences due to modulations of the input-output characteristics, layer-dependent VASO responses were investigated in the ipsilateral hemisphere during unilateral finger tapping. Positive activation in ipsilateral primary motor cortex and negative activation in ipsilateral primary sensory cortex were observed. This feature is only visible in high-resolution fMRI where opposing sides of a sulcus can be investigated independently because of a lack of partial volume effects. Based on the results presented here, we conclude that VASO offers good reproducibility, high sensitivity and lower sensitivity than GE-BOLD to changes in larger vessels, making it a valuable tool for layer-dependent fMRI studies in humans
Contralateral dissociation between neural activity and cerebral blood volume during recurrent acute focal neocortical seizures
OBJECTIVE: Whether epileptic events disrupt normal neurovascular coupling mechanisms locally or remotely is unclear. We sought to investigate neurovascular coupling in an acute model of focal neocortical epilepsy, both within the seizure onset zone and in contralateral homotopic cortex. METHODS: Neurovascular coupling in both ipsilateral and contralateral vibrissal cortices of the urethane-anesthetized rat were examined during recurrent 4-aminopyridine (4-AP, 15 mm, 1 μl) induced focal seizures. Local field potential (LFP) and multiunit spiking activity (MUA) were recorded via two bilaterally implanted 16-channel microelectrodes. Concurrent two-dimensional optical imaging spectroscopy was used to produce spatiotemporal maps of cerebral blood volume (CBV). RESULTS: Recurrent acute seizures in right vibrissal cortex (RVC) produced robust ipsilateral increases in LFP and MUA activity, most prominently in layer 5, that were nonlinearly correlated to local increases in CBV. In contrast, contralateral left vibrissal cortex (LVC) exhibited relatively smaller nonlaminar specific increases in neural activity coupled with a decrease in CBV, suggestive of dissociation between neural and hemodynamic responses. SIGNIFICANCE: These findings provide insights into the impact of epileptic events on the neurovascular unit, and have important implications both for the interpretation of perfusion-based imaging signals in the disorder and understanding the widespread effects of epilepsy. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here
Comparison of stimulus-evoked cerebral hemodynamics in the awake mouse and under a novel anesthetic regime
Neural activity is closely followed by a localised change in cerebral blood flow, a process termed neurovascular coupling. These hemodynamic changes form the basis of contrast in functional magnetic resonance imaging (fMRI) and are used as a correlate for neural activity. Anesthesia is widely employed in animal fMRI and neurovascular studies, however anesthetics are known to profoundly affect neural and vascular physiology, particularly in mice. Therefore, we investigated the efficacy of a novel ‘modular’ anesthesia that combined injectable (fentanyl-fluanisone/midazolam) and volatile (isoflurane) anesthetics in mice. To characterize sensory-evoked cortical hemodynamic responses, we used optical imaging spectroscopy to produce functional maps of changes in tissue oxygenation and blood volume in response to mechanical whisker stimulation. Following fine-tuning of the anesthetic regime, stimulation elicited large and robust hemodynamic responses in the somatosensory cortex, characterized by fast arterial activation, increases in total and oxygenated hemoglobin, and decreases in deoxygenated hemoglobin. Overall, the magnitude and speed of evoked hemodynamic responses under anesthesia resembled those in the awake state, indicating that the novel anesthetic combination significantly minimizes the impact of anesthesia. Our findings have broad implications for both neurovascular research and longitudinal fMRI studies that increasingly require the use of genetically engineered mice
Pathophysiological Interference with Neurovascular Coupling – When Imaging Based on Hemoglobin Might Go Blind
Assessing neuronal activity by non-invasive functional brain imaging techniques which are based on the hemodynamic response depends totally on the physiological cascade of metabolism and blood flow. At present, functional brain imaging with near infrared spectroscopy (NIRS) or BOLD-fMRI is widely used in cognitive neuroscience in healthy subjects where neurovascular coupling and cerebrovascular reactivity can be assumed to be intact. Local activation studies as well as studies investigating functional connectivity between brain regions of the resting brain provide a rapidly increasing body of knowledge on brain function in humans and animals. Furthermore, functional NIRS and MRI techniques are increasingly being used in patients with severe brain diseases and this use might gain more and more importance for establishing their use in the clinical routine. However, more and more experimental evidence shows that changes in baseline physiological parameters, pharmacological interventions, or disease-related vascular changes may significantly alter the normal response of blood flow and blood oxygenation and thus may lead to misinterpretation of neuronal activity. In this article we present examples of recent experimental findings on pathophysiological changes of neurovascular coupling parameters in animals and discuss their potential implications for functional imaging based on hemodynamic signals such as fNIRS or BOLD-fMRI. To enable correct interpretation of neuronal activity by vascular signals, future research needs to deepen our understanding of the basic mechanisms of neurovascular coupling and the specific characteristics of disturbed neurovascular coupling in the diseased brain
Physiological and pathological brain activation in the anesthetized rat produces hemodynamic-dependent cortical temperature increases that can confound the BOLD fMRI signal
Anesthetized rodent models are ubiquitous in pre-clinical neuroimaging studies. However, because the associated cerebral morphology and experimental methodology results in a profound negative brain-core temperature differential, cerebral temperature changes during functional activation are likely to be principally driven by local inflow of fresh, core-temperature, blood. This presents a confound to the interpretation of blood-oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) data acquired from such models, since this signal is also critically temperature-dependent. Nevertheless, previous investigation on the subject is surprisingly sparse. Here, we address this issue through use of a novel multi-modal methodology in the urethane anesthetized rat. We reveal that sensory stimulation, hypercapnia and recurrent acute seizures induce significant increases in cortical temperature that are preferentially correlated to changes in total hemoglobin concentration (Hbt), relative to cerebral blood flow and oxidative metabolism. Furthermore, using a phantom-based evaluation of the effect of such temperature changes on the BOLD fMRI signal, we demonstrate a robust inverse relationship between both variables. These findings suggest that temperature increases, due to functional hyperemia, should be accounted for to ensure accurate interpretation of BOLD fMRI signals in pre-clinical neuroimaging studies
Seizure epicenter depth and translaminar field potential synchrony underlie complex variations in tissue oxygenation during ictal initiation
Whether functional hyperemia during epileptic activity is adequate to meet the heightened metabolic demand of such events is controversial. Whereas some studies have demonstrated hyperoxia during ictal onsets, other work has reported transient hypoxic episodes that are spatially dependent on local surface microvasculature. Crucially, how laminar differences in ictal evolution can affect subsequent cerebrovascular responses has not been thus far investigated, and is likely significant in view of possible laminar-dependent neurovascular mechanisms and angioarchitecture. We addressed this open question using a novel multi-modal methodology enabling concurrent measurement of cortical tissue oxygenation, blood flow and hemoglobin concentration, alongside laminar recordings of neural activity, in a urethane anesthetized rat model of recurrent seizures induced by 4-aminopyridine. We reveal there to be a close relationship between seizure epicenter depth, translaminar LFP synchrony and tissue oxygenation during the early stages of recurrent seizures, whereby deep layer seizures are associated with decreased cross laminar synchrony and prolonged periods of hypoxia, and middle layer seizures are accompanied by increased cross-laminar synchrony and hyperoxia. Through comparison with functional activation by somatosensory stimulation and graded hypercapnia, we show that these seizure-related cerebrovascular responses occur in the presence of conserved neural-hemodynamic and blood flow-volume coupling. Our data provide new insights into the laminar dependency of seizure-related neurovascular responses, which may reconcile inconsistent observations of seizure-related hypoxia in the literature, and highlight a potential layer-dependent vulnerability that may contribute to the harmful effects of clinical recurrent seizures. The relevance of our findings to perfusion-related functional neuroimaging techniques in epilepsy are also discussed
Investigating the biomechanics and biochemistry underlying MRI measures of neuronal function
This thesis investigates the biophysical mechanisms underlying functional magnetic resonance imaging (fMRI) measures of brain activity. Diffusion-weighted fMRI (DWfMRI) has been suggested as an alternative to the established Blood Oxygenation Level Dependent (BOLD) method. It is speculated to be sensitive to transient microstructural changes within active brain tissue, which could provide a more direct measure of neuronal activity than techniques relying on attendant haemodynamic changes. DWfMRI has yet to become widely accepted however, as the mechanism driving the observed signal is not well understood. Here, experimental and theoretical investigations of the fMRI signal are presented.
As part of this work, a functional MRI study was undertaken to compare BOLD and DWfMRI responses to stimulated brain activity in human volunteers. The effect of different experimental protocols were explored, with an emphasis on stimulus design. Analysis methods and their potential impact on interpretation of the response are explored.
Neuronal activation is accompanied by heamodynamic changes detectable with Optical Imaging Spectroscopy. Additionally, there is a growing base of evidence showing microstructural changes in excited neuronal tissue. This tortuosity change might be observable through the use of Spatial Frequency Domain Imaging (SFDI). These properties can be observed in the animal model and compared with fMRI to aid interpretation. The following work presents the development of in-vivo optical imaging techniques for the measurement of tissue optical property changes during brain activity. This includes theoretical explorations of the analysis pipeline, and of the potential limitations of these techniques and their sensitivity.
A Monte Carlo simulation of light transport through tissue was written to provide calibration data for the optical imaging methods. The simulation was used to explore the impact of tissue parameters on the optical results and inform interpretation. The simulation was extended to explore tissue absorption in the context of biophotomodulation
Depth-Dependent Physiological Modulators of the BOLD Response in the Human Motor Cortex
This dissertation proposes a set of methods for improving spatial localization of cerebral metabolic changes using functional magnetic resonance imaging (fMRI).
Blood oxygen level dependent (BOLD) fMRI estabilished itself as the most frequently used technique for mapping brain activity in humans. It is non-invasive and allows to obtain information about brain oxygenation changes in a few minutes. It was discovered in 1990 and, since then, it contributed enormously to the developments in neuroscientific research.
Nevertheless, the BOLD contrast suffers from inherent limitations. This comes from the fact that the observed response is the result of a complex interplay between cerebral blood flow (CBF), cerebral blood volume (CBV) and cerebral metabolic rate of oxygen consumption (CMRO2) and has a strong dependency on baseline blood volume and oxygenation. Therefore, the observed response is mislocalized from the site where the metabolic activity takes place and it is subject to high variability across experiments due to normal brain physiology.
Since the peak of BOLD changes can be as much as 4 mm apart from the site of metabolic changes, the problem of spatial mislocalization is particularly constraining at submillimeter resolution.
Three methods are proposed in this work in order to overcome this limitation and make data more comparable.
The first method involves a modification of an estabilished model for calibration of BOLD responses (the dilution model), in order to render it applicable at higher resolutions.
The second method proposes a model-free scaling of the BOLD response, based on spatial normalization by a purely vascular response pattern.
The third method takes into account the hypothesis that the cortical vasculature could act as a low-pass filter for BOLD fluctuations as the blood is carried downstream, and investigates differences in frequency composition of cortical laminae.
All methods are described and tested on a depth-dependent scale in the human motor cortex