Regional variation in neurovascular coupling and why we still lack a Rosetta Stone

Functional magnetic resonance imaging (fMRI) is the dominant tool in cognitive neuroscience although its relation to underlying neural activity, particularly in the human brain, remains largely unknown. A major research goal, therefore, has been to uncover a ‘Rosetta Stone’ providing direct translation between the blood oxygen level-dependent (BOLD) signal, the local field potential and single-neuron activity. Here, I evaluate the proposal that BOLD signal changes equate to changes in gamma-band activity, which in turn may partially relate to the spiking activity of neurons. While there is some support for this idea in sensory cortices, findings in deeper brain structures like the hippocampus instead suggest both regional and frequency-wise differences. Relatedly, I consider four important factors in linking fMRI to neural activity: interpretation of correlations between these signals, regional variability in local vasculature, distributed neural coding schemes and varying fMRI signal quality. Novel analytic fMRI techniques, such as multivariate pattern analysis (MVPA), employ the distributed patterns of voxels across a brain region to make inferences about information content rather than whether a small number of voxels go up or down relative to baseline in response to a stimulus. Although unlikely to provide a Rosetta Stone, MVPA, therefore, may represent one possible means forward for better linking BOLD signal changes to the information coded by underlying neural activity.This article is part of the theme issue ‘Key relationships between non-invasive functional neuroimaging and the underlying neuronal activity’.     

Physiological basis and image processing in functional magnetic resonance imaging: Neuronal and motor activity in brain

Functional magnetic resonance imaging (fMRI) is recently developing as imaging modality used for mapping hemodynamics of neuronal and motor event related tissue blood oxygen level dependence (BOLD) in terms of brain activation. Image processing is performed by segmentation and registration methods. Segmentation algorithms provide brain surface-based analysis, automated anatomical labeling of cortical fields in magnetic resonance data sets based on oxygen metabolic state. Registration algorithms provide geometric features using two or more imaging modalities to assure clinically useful neuronal and motor information of brain activation. This review article summarizes the physiological basis of fMRI signal, its origin, contrast enhancement, physical factors, anatomical labeling by segmentation, registration approaches with examples of visual and motor activity in brain. Latest developments are reviewed for clinical applications of fMRI along with other different neurophysiological and imaging modalities.     

The neural basis of the blood-oxygen-level-dependent functional magnetic resonance imaging signal

Magnetic resonance imaging (MRI) has rapidly become an important tool in clinical medicine and biological research. Its functional variant (functional magnetic resonance imaging; fMRI) is currently the most widely used method for brain mapping and studying the neural basis of human cognition. While the method is widespread, there is insufficient knowledge of the physiological basis of the fMRI signal to interpret the data confidently with respect to neural activity. This paper reviews the basic principles of MRI and fMRI, and subsequently discusses in some detail the relationship between the blood-oxygen-level-dependent (BOLD) fMRI signal and the neural activity elicited during sensory stimulation. To examine this relationship, we conducted the first simultaneous intracortical recordings of neural signals and BOLD responses. Depending on the temporal characteristics of the stimulus, a moderate to strong correlation was found between the neural activity measured with microelectrodes and the BOLD signal averaged over a small area around the microelectrode tips. However, the BOLD signal had significantly higher variability than the neural activity, indicating that human fMRI combined with traditional statistical methods underestimates the reliability of the neuronal activity. To understand the relative contribution of several types of neuronal signals to the haemodynamic response, we compared local field potentials (LFPs), single- and multi-unit activity (MUA) with high spatio-temporal fMRI responses recorded simultaneously in monkey visual cortex. At recording sites characterized by transient responses, only the LFP signal was significantly correlated with the haemodynamic response. Furthermore, the LFPs had the largest magnitude signal and linear systems analysis showed that the LFPs were better than the MUAs at predicting the fMRI responses. These findings, together with an analysis of the neural signals, indicate that the BOLD signal primarily measures the input and processing of neuronal information within a region and not the output signal transmitted to other brain regions.     

Coupling of total hemoglobin concentration,oxygenation, and neural activity in rat somatosensory cortex

Recent advances in brain imaging techniques, including functional magnetic resonance imaging (fMRI), offer great promise for noninvasive mapping of brain function. However, the indirect nature of the imaging signals to the underlying neural activity limits the interpretation of the resulting maps. The present report represents the first systematic study with sufficient statistical power to quantitatively characterize the relationship between changes in blood oxygen content and the neural spiking and synaptic activity. Using two-dimensional optical measurements of hemodynamic signals, simultaneous recordings of neural activity, and an event-related stimulus paradigm, we demonstrate that (1) there is a strongly nonlinear relationship between electrophysiological measures of neuronal activity and the hemodynamic response, (2) the hemodynamic response continues to grow beyond the saturation of electrical activity, and (3) the initial increase in deoxyhemoglobin that precedes an increase in blood volume is counterbalanced by an equal initial decrease in oxyhemoglobin.     

Abnormal Neural Responses to Emotional Stimuli but Not Go/NoGo and Stroop Tasks in Adults with a History of Childhood Nocturnal Enuresis

Background

Nocturnal enuresis (NE) is a common disorder in school-aged children. Previous studies have reported that children with NE exhibit structural, functional and neurochemical abnormalities in the brain, suggesting that children with NE may have cognitive problems. Additionally, children with NE have been shown to process emotions differently from control children. In fact, most cases of NE resolve with age. However, adults who had experienced NE during childhood may still have potential cognitive or emotion problems, and this possibility has not been thoroughly investigated.

Methodology/Principal Findings

In this work, we used functional magnetic resonance imaging (fMRI) to evaluate brain functional changes in adults with a history of NE. Two groups, consisting of 21 adults with NE and 21 healthy controls, were scanned using fMRI. We did not observe a significant abnormality in activation during the Go/NoGo and Stroop tasks in adults with a history of NE compared with the control group. However, compared to healthy subjects, young adults with a history of NE mainly showed increased activation in the bilateral temporoparietal junctions, bilateral dorsolateral prefrontal cortex, and bilateral anterior cingulate cortex while looking at negative vs. neutral pictures.

Conclusions/Significance

Our results demonstrate that adults with a history of childhood NE have no obvious deficit in response inhibition or cognitive control but showed abnormal neural responses to emotional stimuli.     

Self-regulation of local brain activity using real-time functional magnetic resonance imaging (fMRI)

Functional magnetic resonance imaging (fMRI) measures the blood oxygen level-dependent (BOLD) signal related to neuronal activity. So far, this technique has been limited by time-consuming data analysis impeding on-line analysis. In particular, no brain-computer interface (BCI) was available which provided on-line feedback to learn physiological self-regulation of the BOLD signal. Recently, studies have shown that fMRI feedback is feasible and facilitates voluntary control of brain activity. Here we review these studies to make the fMRI feedback methodology accessible to a broader scientific community such as researchers concerned with functional brain imaging and the neurobiology of learning. Methodological and conceptual limitations were substantially reduced by artefact control, sensitivity improvements, real-time algorithms, and adapted experimental designs. Physiological self-regulation of the local BOLD response is a new paradigm for cognitive neuroscience to study brain plasticity and the functional relevance of regulated brain areas by modification of behaviour. Voluntary control of abnormal activity in circumscribed brain areas may even be applied as psychophysiological treatment.     

Simultaneous BOLD fMRI and fiber-optic calcium recording in rat neocortex

Functional magnetic resonance imaging (fMRI) based on blood oxygen level-dependent (BOLD) contrast is widely used for probing brain activity, but its relationship to underlying neural activity remains elusive. Here, we combined fMRI with fiber-optic recordings of fluorescent calcium indicator signals to investigate this relationship in rat somatosensory cortex. Electrical forepaw stimulation (1-10 Hz) evoked fast calcium signals of neuronal origin that showed frequency-dependent adaptation. Additionally, slower calcium signals occurred in astrocyte networks, as verified by astrocyte-specific staining and two-photon microscopy. Without apparent glia activation, we could predict BOLD responses well from simultaneously recorded fiber-optic signals, assuming an impulse response function and taking into account neuronal adaptation. In cases with glia activation, we uncovered additional prolonged BOLD signal components. Our findings highlight the complexity of fMRI BOLD signals, involving both neuronal and glial activity. Combined fMRI and fiber-optic recordings should help to clarify cellular mechanisms underlying BOLD signals.     

What does fMRI tell us about neuronal activity?

In recent years, cognitive neuroscientists have taken great advantage of functional magnetic resonance imaging (fMRI) as a non-invasive method of measuring neuronal activity in the human brain. But what exactly does fMRI tell us? We know that its signals arise from changes in local haemodynamics that, in turn, result from alterations in neuronal activity, but exactly how neuronal activity, haemodynamics and fMRI signals are related is unclear. It has been assumed that the fMRI signal is proportional to the local average neuronal activity, but many factors can influence the relationship between the two. A clearer understanding of how neuronal activity influences the fMRI signal is needed if we are correctly to interpret functional imaging data.     

Linear and nonlinear relationships between neuronal activity, oxygen metabolism, and hemodynamic responses

We investigated the relationship between neuronal activity, oxygen metabolism, and hemodynamic responses in rat somatosensory cortex with simultaneous optical intrinsic signal imaging and spectroscopy, laser Doppler flowmetry, and local field potential recordings. Changes in cerebral oxygen consumption increased linearly with synaptic activity but with a threshold effect consistent with the existence of a tissue oxygen buffer. Modeling analysis demonstrated that the coupling between neuronal activity and hemodynamic response magnitude may appear linear over a narrow range but incorporates nonlinear effects that are better described by a threshold or power law relationship. These results indicate that caution is required in the interpretation of perfusion-based indicators of brain activity, such as functional magnetic resonance imaging (fMRI), and may help to refine quantitative models of neurovascular coupling.     

Biophysical basis of brain activity: implications for neuroimaging

In vivo 13C magnetic resonance spectroscopy (MRS) studies of the brain have quantitatively assessed rates of glutamate-glutamine cycle (Veye) and glucose oxidation (CMRGle(ox)) by detecting 13C label turnover from glucose to glutamate and glutamine. Contrary to expectations from in vitro and ex vivo studies, the in vivo 13C-MRS results demonstrate that glutamate recycling is a major metabolic pathway, inseparable from its actions of neurotransmission. Furthermore, both in the awake human and in the anesthetized rat brain, Veye and CMRGle(ox) are stoichiometrically related, where more than two thirds of the energy from glucose oxidation supports events associated with glutamate neurotransmission. The high energy consumption of the brain measured at rest and its quantitative relation to neurotransmission reflects a sizeable activity level for the resting brain. The high activity of the non-stimulated brain, as measured by cerebral metabolic rate of oxygen use (CMRO2), establishes a new neurophysiological basis of cerebral function that leads to reinterpreting functional imaging data because the large baseline signal is commonly discarded in cognitive neuroscience paradigms. Changes in energy consumption (delta CMRO2%) can also be obtained from magnetic resonance imaging (MRI) experiments, using the blood oxygen level-dependent (BOLD) image contrast, provided that all the separate parameters contributing to the functional MRI (fMRI) signal are measured. The BOLD-derived delta CMRO2% when compared with alterations in neuronal spiking rate (delta v%) during sensory stimulation in the rat reveals a stoichiometric relationship, in good agreement with 13C-MRS results. Hence fMRI when calibrated so as to provide delta CMRO2% can provide high spatial resolution evaluation of neuronal activity. Our studies of quantitative measurements of changes in neuroenergetics and neurotransmission reveal that a stimulus does not provoke an arbitrary amount of activity in a localized region, rather a total level of activity is required where the increment is inversely related to the level of activity in the non-stimulated condition. These biophysical experiments have established relationships between energy consumption and neuronal activity that provide novel insights into the nature of brain function and the interpretation of fMRI data.     

Rude mechanicals in brain haemodynamics: non-neural actors that influence blood flow

Fluctuations in blood oxygenation and flow are widely used to infer brain activity during resting-state functional magnetic resonance imaging (fMRI). However, there are strong systemic and vascular contributions to resting-state signals that are unrelated to ongoing neural activity. Importantly, these non-neural contributions to haemodynamic signals (or ‘rude mechanicals’) can be as large as or larger than the neurally evoked components. Here, we review the two broad classes of drivers of these signals. One is systemic and is tied to fluctuations in external drivers such as heart rate and breathing, and the robust autoregulatory mechanisms that try to maintain a constant milieu in the brain. The other class comprises local, active fluctuations that appear to be intrinsic to vascular tissue and are likely similar to active local fluctuations seen in vasculature all over the body. In this review, we describe these non-neural fluctuations and some of the tools developed to correct for them when interpreting fMRI recordings. However, we also emphasize the links between these vascular fluctuations and brain physiology and point to ways in which fMRI measurements can be used to exploit such links to gain valuable information about neurovascular health and about internal brain states.This article is part of the theme issue ‘Key relationships between non-invasive functional neuroimaging and the underlying neuronal activity’.     

Insights into new techniques for high resolution functional MRI

Non-invasive functional magnetic resonance imaging (fMRI) has opened a unique window into human and animal brain function, with a spatial resolution of a few millimeters and a temporal resolution of a few seconds. To further improve the current technical limitations of fMRI, various post-processing and data acquisition schemes were developed. Improved fMRI methods include variations of a conventional fMRI technique, mapping a single physiological parameter such as cerebral blood flow or cerebral blood volume, and direct mapping of neural activity. Advances in fMRI techniques allow scientists to map submillimeter columnar and laminar functional structures and to detect tens of millisecond neural activity in certain specific tasks.     

fMRI Validation of fNIRS Measurements During a Naturalistic Task

We present a method to compare brain activity recorded with near-infrared spectroscopy (fNIRS) in a dance video game task to that recorded in a reduced version of the task using fMRI (functional magnetic resonance imaging). Recently, it has been shown that fNIRS can accurately record functional brain activities equivalent to those concurrently recorded with functional magnetic resonance imaging for classic psychophysical tasks and simple finger tapping paradigms. However, an often quoted benefit of fNIRS is that the technique allows for studying neural mechanisms of complex, naturalistic behaviors that are not possible using the constrained environment of fMRI. Our goal was to extend the findings of previous studies that have shown high correlation between concurrently recorded fNIRS and fMRI signals to compare neural recordings obtained in fMRI procedures to those separately obtained in naturalistic fNIRS experiments. Specifically, we developed a modified version of the dance video game Dance Dance Revolution (DDR) to be compatible with both fMRI and fNIRS imaging procedures. In this methodology we explain the modifications to the software and hardware for compatibility with each technique as well as the scanning and calibration procedures used to obtain representative results. The results of the study show a task-related increase in oxyhemoglobin in both modalities and demonstrate that it is possible to replicate the findings of fMRI using fNIRS in a naturalistic task. This technique represents a methodology to compare fMRI imaging paradigms which utilize a reduced-world environment to fNIRS in closer approximation to naturalistic, full-body activities and behaviors. Further development of this technique may apply to neurodegenerative diseases, such as Parkinson’s disease, late states of dementia, or those with magnetic susceptibility which are contraindicated for fMRI scanning.     

Optogenetic Functional MRI

The investigation of the functional connectivity of precise neural circuits across the entire intact brain can be achieved through optogenetic functional magnetic resonance imaging (ofMRI), which is a novel technique that combines the relatively high spatial resolution of high-field fMRI with the precision of optogenetic stimulation. Fiber optics that enable delivery of specific wavelengths of light deep into the brain in vivo are implanted into regions of interest in order to specifically stimulate targeted cell types that have been genetically induced to express light-sensitive trans-membrane conductance channels, called opsins. fMRI is used to provide a non-invasive method of determining the brain''s global dynamic response to optogenetic stimulation of specific neural circuits through measurement of the blood-oxygen-level-dependent (BOLD) signal, which provides an indirect measurement of neuronal activity. This protocol describes the construction of fiber optic implants, the implantation surgeries, the imaging with photostimulation and the data analysis required to successfully perform ofMRI. In summary, the precise stimulation and whole-brain monitoring ability of ofMRI are crucial factors in making ofMRI a powerful tool for the study of the connectomics of the brain in both healthy and diseased states.     

Functional imaging of memory processes in humans: positron emission tomography and functional magnetic resonance imaging

Human memory is not a unitary function; it consists of multiple memory systems, with different characteristics and specialisations that are implemented in the brain. The cognitive neuroscience of human memory tries to comprehend how we encode, store, and retrieve memory items within and across those systems. The emergence of functional neuroimaging techniques offered the unprecedented opportunity to directly observe the brain regions engaged in memory functions. Brain imaging techniques can roughly be divided into those measuring the electric or magnetic fields generated by neuronal activity (EEG, magnetencephalography [MEG]) and those measuring the haemodynamic or metabolic sequelae of neuronal activity (positron emission tomography [PET], functional magnetic resonance imaging [fMRI]). Out of these techniques, the following two will be discussed in detail: fMRI and PET. Although functional neuroimaging is able to acquire images of the brain engaged in consolidating or retrieving memories, these processes are not clearly visible in the data. Statistical techniques are needed to reduce the complexity of the data and to extract the processes of interest. This article outlines the experimental and analytical procedures of neuroimaging studies with PET and fMRI. We will use a PET-study on episodic memory in human volunteers to illustrate design, analysis, and interpretation of functional imaging studies on memory.     

Deep Brain Stimulation with Simultaneous fMRI in Rodents

In order to visualize the global and downstream neuronal responses to deep brain stimulation (DBS) at various targets, we have developed a protocol for using blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) to image rodents with simultaneous DBS. DBS fMRI presents a number of technical challenges, including accuracy of electrode implantation, MR artifacts created by the electrode, choice of anesthesia and paralytic to minimize any neuronal effects while simultaneously eliminating animal motion, and maintenance of physiological parameters, deviation from which can confound the BOLD signal. Our laboratory has developed a set of procedures that are capable of overcoming most of these possible issues. For electrical stimulation, a homemade tungsten bipolar microelectrode is used, inserted stereotactically at the stimulation site in the anesthetized subject. In preparation for imaging, rodents are fixed on a plastic headpiece and transferred to the magnet bore. For sedation and paralysis during scanning, a cocktail of dexmedetomidine and pancuronium is continuously infused, along with a minimal dose of isoflurane; this preparation minimizes the BOLD ceiling effect of volatile anesthetics. In this example experiment, stimulation of the subthalamic nucleus (STN) produces BOLD responses which are observed primarily in ipsilateral cortical regions, centered in motor cortex. Simultaneous DBS and fMRI allows the unambiguous modulation of neural circuits dependent on stimulation location and stimulation parameters, and permits observation of neuronal modulations free of regional bias. This technique may be used to explore the downstream effects of modulating neural circuitry at nearly any brain region, with implications for both experimental and clinical DBS.     

Identifying Neural Drivers with Functional MRI: An Electrophysiological Validation

Whether functional magnetic resonance imaging (fMRI) allows the identification of neural drivers remains an open question of particular importance to refine physiological and neuropsychological models of the brain, and/or to understand neurophysiopathology. Here, in a rat model of absence epilepsy showing spontaneous spike-and-wave discharges originating from the first somatosensory cortex (S1BF), we performed simultaneous electroencephalographic (EEG) and fMRI measurements, and subsequent intracerebral EEG (iEEG) recordings in regions strongly activated in fMRI (S1BF, thalamus, and striatum). fMRI connectivity was determined from fMRI time series directly and from hidden state variables using a measure of Granger causality and Dynamic Causal Modelling that relates synaptic activity to fMRI. fMRI connectivity was compared to directed functional coupling estimated from iEEG using asymmetry in generalised synchronisation metrics. The neural driver of spike-and-wave discharges was estimated in S1BF from iEEG, and from fMRI only when hemodynamic effects were explicitly removed. Functional connectivity analysis applied directly on fMRI signals failed because hemodynamics varied between regions, rendering temporal precedence irrelevant. This paper provides the first experimental substantiation of the theoretical possibility to improve interregional coupling estimation from hidden neural states of fMRI. As such, it has important implications for future studies on brain connectivity using functional neuroimaging.     

Separating vascular and neuronal effects of age on fMRI BOLD signals

Accurate identification of brain function is necessary to understand the neurobiology of cognitive ageing, and thereby promote well-being across the lifespan. A common tool used to investigate neurocognitive ageing is functional magnetic resonance imaging (fMRI). However, although fMRI data are often interpreted in terms of neuronal activity, the blood oxygenation level-dependent (BOLD) signal measured by fMRI includes contributions of both vascular and neuronal factors, which change differentially with age. While some studies investigate vascular ageing factors, the results of these studies are not well known within the field of neurocognitive ageing and therefore vascular confounds in neurocognitive fMRI studies are common. Despite over 10 000 BOLD-fMRI papers on ageing, fewer than 20 have applied techniques to correct for vascular effects. However, neurovascular ageing is not only a confound in fMRI, but an important feature in its own right, to be assessed alongside measures of neuronal ageing. We review current approaches to dissociate neuronal and vascular components of BOLD-fMRI of regional activity and functional connectivity. We highlight emerging evidence that vascular mechanisms in the brain do not simply control blood flow to support the metabolic needs of neurons, but form complex neurovascular interactions that influence neuronal function in health and disease.This article is part of the theme issue ‘Key relationships between non-invasive functional neuroimaging and the underlying neuronal activity’.     

High-resolution fMRI maps of cortical activation in nonhuman primates: correlation with intrinsic signal optical images

One of the most widely used functional brain mapping tools is blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI). This method has contributed to new understandings of the functional roles of different areas in the human brain. However, its ability to map cerebral cortex at high spatial (submillimeter) resolution is still unknown. Other methods such as single- and multiunit electrophysiology and intrinsic signal optical imaging have revealed submillimeter resolution of sensory topography and cortical columnar activations. However, they are limited either by spatial scale (electrophysiology characterizes only local groups of neurons) or by the inability to monitor deep structures in the brain (i.e., cortical regions buried in sulci or subcortical structures). A method that could monitor all regions of the brain at high spatial resolution would be ideal. This capacity would open the doors to investigating, for example, how networks of cerebral cortical columns relate to or produce behavior. In this article we demonstrate that, without benefit of contrast agents, at a magnetic field strength of 9.4 tesla, BOLD fMRI can reveal millimeter-sized topographic maps of digit representation in the somatosensory cortex of the anesthetized squirrel monkey. Furthermore, by mapping the "funneling illusion," it is possible to detect even submillimeter shifts in activation in the cortex. Our data suggest that at high magnetic field strength, the positive BOLD signal can be used to reveal high spatial resolution maps of brain activity, a finding that weakens previous notions about the ultimate spatial specificity of the positive BOLD signal.