Review articleIlluminating the BOLD signal: combined fMRI–fNIRS studies
Introduction
Investigating functional principles of the human brain requires a multimodal approach. Psychophysical findings are complemented by electrophysiological and imaging data, disclosing the succession and localization of neuronal processes in the brain. The most widely used imaging technique [functional magnetic resonance imaging (fMRI)] relies on an indirect signal, the “blood oxygenation level-dependent” (BOLD) contrast [1], which is caused by an increase in oxygen delivery, strongly exceeding the metabolic demand [2].
While it is agreed on that neuronal processing, metabolic and vascular responses are highly correlated in space and time, the details of the translation between an ensemble of neurons firing and the ensuing increase in focal cerebral blood flow remain controversial. The lack of a detailed understanding of the underlying physiology did not hinder an overwhelming success of fMRI; on the other hand, the more complex the paradigms investigated the more mandatory is a thorough understanding of the imaging signal.
In the present article we focus on physiological principles and the dynamics of the vascular response. We address the interdependencies between different parameters, which constitute the vascular response, by discussing the temporal evolution of changes in blood flow, blood volume and blood oxygenation. Functional near-infrared spectroscopy (fNIRS) has the potential to elucidate some key issues concerning the basis of the vascular response, since it measures the physiological quantities total and deoxygenated hemoglobin concentration — which are the major constituents of BOLD signal changes — and it can be simultaneously applied with fMRI.
Since the first combined study in 1996 [3], a number of researchers have elaborated on the hemodynamic response, mainly focusing on the issue mentioned above: finding the direct physiological correlate of the BOLD-signal changes (see “Focus of study” column in Table 1 listing all combined studies summarized here). Here we will discuss the rather inhomogenous findings on this issue in the frame of the most refined model of the vascular response, the “balloon model.” This model formulates the relationship between an increase in CMRO2 and cerebral blood flow on the one side, and the resulting changes in cerebral blood volume (CBV) and deoxyhemoglobin concentration [deoxy-Hb] on the other [23]. Since such a biophysical model is relevant for the interpretation of the data from a combined approach and has so far only been applied in a few cases (see “Hemodynamic model” column in Table 1), it will be introduced at the beginning of the methodological part of this review. The determination of the hemodynamic observables (BOLD, CBF, [deoxy-Hb], oxyhemoglobin concentration [oxy-Hb] and total hemoglobin concentration [tot-Hb]) is subject of the following sections. We show that novel NIRS technology with a better quantification and specificity has so far not been implemented in combined studies, giving hope to increase the homogeneity of observations in future experiments.
The second application-related part of this review highlights some questions on the transient features of the hemodynamic response such as an early deoxygenation (“dip”), the poststimulus overshoot in deoxyhemoglobin (undershoot in BOLD) or the latencies of the hemodynamic observables during the rise time (see Fig. 1). It has been shown very recently that these transients are sensitive to assumptions on the vascular response dynamics and, thus, have to be critically regarded when conclusions on neuronal activity are drawn [24]. While the concept of a neurovascular coupling is well established for the steady state, these transients are a matter of ongoing research and we here show how their physiological origin can be unmasked by a combined approach.
Section snippets
A biophysical model for the hemodynamic response
A biophysical model detailing different aspects of the hemodynamic response is the balloon model [23]. It allows to calculate normalized changes in the hemodynamic observables such as the [deoxy-Hb] or CBV. In its initial form [23], it was based on the simplifying assumption of a venous balloon, an oxygen extractor (see Fig. 2) and a trapezoidal change in CBF. Sophistication of the model by a number of extensions now allows for a more complete modeling, including the option of modeling neuronal
BOLD
The term functional MRI comprises different MRI modalities for the measurement of temporal changes in blood flow, blood volume and oxygenation. The largest number of studies devoted to the understanding of human brain function, however, has applied BOLD signal. Cognitive neuroscience has adopted this signal to an extent that the terms activation and deactivation of the human cortex are now broadly used to denote changes in T2 and T2* caused by the hemodynamic response. Hence, it is not
Data fusion of fNIRS and fMRI
Apart from the methodological aspects discussed so far, differences in spatial sensitivity of fNIRS and fMRI are of particular concern when both methods are combined. Given the difference in spatial resolution of about one order of magnitude (centimeter resolution of fNIRS vs. millimeter resolution of fMRI), either the BOLD signal has to be integrated over a larger subregion or the resolution of fNIRS has to be improved to perform a more direct data analysis between the methods.
Fig. 3 shows a
Physiological questions addressed by fNIRS–fMRI
In the past 10 years, 19 articles have been published comparing fMRI and fNIRS results, in part based on simultaneously acquired data (see Table 1). Since the first article in 1996 [3], most of the articles deal with the generation of the BOLD signal. Generally, the temporal correlation of the BOLD signal with changes in deoxyhemoglobin is considered the common denominator of the two methodologies. Unfortunately however, very few publications address transient features of the hemodynamic
Conclusion
Combined fMRI–fNIRS studies own the strength to shed light on the generation of the BOLD signal in humans. While recent studies have mostly focused on the correlation of the BOLD signal to the changes in the hemoglobin concentrations, new studies are needed to explore the transients of the BOLD signal. These transients allow (i) to study the interplay of the vascular dynamics in flow, volume and oxygen extraction and (ii) to evaluate the driver of the BOLD signal due to the differential
Acknowledgments
The work was funded by the Bundesministerium für Bildung und Forschung (BMBF) and the Europäischer Fond für regionale Entwicklung (EFRE).
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