IRON fMRI measurements of CBV and implications for BOLD signal

MGH/MIT/HMS Athinoula A Martinos Center for Biomedical Imaging, Charlestown, MA 02129, USA.
NeuroImage (Impact Factor: 6.36). 01/2012; 62(2):1000-8. DOI: 10.1016/j.neuroimage.2012.01.070
Source: PubMed


Changes in cerebral blood volume (CBV) and blood magnetization each induce changes in the transverse relaxation rate of MRI signal that are associated with changes in cerebral activity. BOLD signal, the preeminent method for non-invasive localization of task-induced brain function in human subjects, reflects a combination of changes in CBV and blood magnetization. Intravenous injection of paramagnetic contrast media, usually iron oxide particles surrounded by larger macromolecules, can overwhelm the BOLD response and sensitize signal to blood plasma volume, a method we have deemed "IRON" fMRI. The practical advantage of this technique is the ability to optimize blood magnetization at any echo time, enabling high detection power and the use of short echo times; for these reasons, IRON fMRI has become a valuable imaging tool in animal models. The temporal response of blood plasma volume is quite different from blood flow and BOLD signal; thus, CBV has been identified as a prominent source of transient features of the BOLD response. This article reviews the methodological advantages of the IRON method and how CBV measurements have informed our understanding of the BOLD response.

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    • "g . , iron oxide particles ) is required to monitor brain activity changes represented by signal intensity changes induced by local CBV alterations ( Mandeville , 2012 ) . Within this review we opted to describe BOLD based fMRI techniques and applications while methods using labeling methods or contrast injections - which are also applied in pharmacological research ( Borsook and Becerra , 2011 ; Jenkins , 2012 ) - were considered beyond the current scope . "
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    ABSTRACT: Functional magnetic resonance imaging (fMRI) is an excellent tool to study the effect of pharmacological modulations on brain function in a non-invasive and longitudinal manner. We introduce several blood oxygenation level dependent (BOLD) fMRI techniques, including resting state (rsfMRI), stimulus-evoked (st-fMRI), and pharmacological MRI (phMRI). Respectively, these techniques permit the assessment of functional connectivity during rest as well as brain activation triggered by sensory stimulation and/or a pharmacological challenge. The first part of this review describes the physiological basis of BOLD fMRI and the hemodynamic response on which the MRI contrast is based. Specific emphasis goes to possible effects of anesthesia and the animal's physiological conditions on neural activity and the hemodynamic response. The second part of this review describes applications of the aforementioned techniques in pharmacologically induced, as well as in traumatic and transgenic disease models and illustrates how multiple fMRI methods can be applied successfully to evaluate different aspects of a specific disorder. For example, fMRI techniques can be used to pinpoint the neural substrate of a disease beyond previously defined hypothesis-driven regions-of-interest. In addition, fMRI techniques allow one to dissect how specific modifications (e.g., treatment, lesion etc.) modulate the functioning of specific brain areas (st-fMRI, phMRI) and how functional connectivity (rsfMRI) between several brain regions is affected, both in acute and extended time frames. Furthermore, fMRI techniques can be used to assess/explore the efficacy of novel treatments in depth, both in fundamental research as well as in preclinical settings. In conclusion, by describing several exemplary studies, we aim to highlight the advantages of functional MRI in exploring the acute and long-term effects of pharmacological substances and/or pathology on brain functioning along with several methodological considerations.
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    • "The 6-OHDA lesion model provides a means to test the effects of mGlu stimulation on the control and on the dopamine denervated side simultaneously. After the last PET imaging studies we investigated the effects of mGlu 4 PAM and mGlu 5 NAM induced regional signal changes recorded as hemodynamic response using the IRON (Increased Relaxivity for Optimized Neuroimaging) technique for measurement of cerebral blood volume (CBV) (Chen et al., 2001; Mandeville, 2012). Regional signal changes were induced by a mGlu 4 ligand, DFMPP, (N-(4-chloro-3-methoxyphenyl)-2- picolinamide) which is a PAM and a mGlu 5 NAM, MTEP (3-((2- methyl-4-thiazolyl)ethynyl) pyridine). "
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    ABSTRACT: G-protein coupled dopamine and metabotropic glutamate receptors (mGlu) can modulate neurotransmission during Parkinson's disease (PD)-like neurodegeneration. PET imaging studies in a unilateral dopamine denervation model (6-OHDA) showed a significant inverse correlation of presynaptic mGlu4 and postsynaptic mGlu5 expression in the striatum and rapidly declining mGlu4 and enhanced mGlu5 expression in the hippocampus during progressive degeneration over time. Immunohistochemical studies verified the decreased mGlu4 expression in the hippocampus on the lesion side but did not show difference in mGlu5 expression between lesion and control side. Pharmacological MRI studies showed enhanced hemodynamic response in several brain areas on the lesion side compared to the control side after challenge with mGlu4 positive allosteric modulator or mGlu5 negative allosteric modulator. However, mGlu4 response was biphasic having short enhancement followed by negative response on both sides of brain. Studies in mGlu4 expressing cells demonstrated that glutamate induces cooperative increase in binding of mGlu4 ligands - especially at high glutamate levels consistent with in vivo concentration. This suggests that mGlu allosteric modulators as drug candidates will be highly sensitive to changes in glutamate concentration and hence metabolic state. These experiments demonstrate the importance of the longitudinal imaging studies to investigate temporal changes in receptor functions to obtain individual response for experimental drugs.
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    • "First, we only imaged ~250 μm below the surface of the cortex, meaning that the entire depth of cortex we imaged over would be lumped together into a single 'upper layer' in an fMRI experiment, in which the contribution from intracortical vessels in the upper levels will likely overwhelm any blood volume changes due to pial vessels. In addition, the vascular density on the surface of the brain is ~3× higher than inside the brain, and the pial vasculature is almost entirely composed of large vessels (Tsai et al., 2009), which could cause greatly reduced sensitivity to pial vessel dilation when using supermagnetic particle fMRI techniques, which are sensitive to vessel size (Mandeville, 2012; S.-G. Kim et al., 2013a; J.H. Kim et al., 2013b). "
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    ABSTRACT: Understanding the spatial dynamics of dilation in the cerebral vasculature is essential for deciphering the vascular basis of hemodynamic signals in the brain. We used two-photon microscopy to image neural activity and vascular dynamics in the somatosensory cortex of awake behaving mice during voluntary locomotion. Arterial dilations within the histologically-defined forelimb/hindlimb (FL/HL) representation were larger than arterial dilations in the somatosensory cortex immediately outside the FL/HL representation, demonstrating that the vascular response during natural behaviors was spatially localized. Surprisingly, we found that locomotion drove dilations in surface vessels that were nearly three times the amplitude of intracortical vessel dilations. The smaller dilations of the intracortical arterioles were not due to saturation of dilation. Anatomical imaging revealed that, unlike surface vessels, intracortical vessels were tightly enclosed by brain tissue. A mathematical model showed that mechanical restriction by the brain tissue surrounding intracortical vessels could account for the reduced amplitude of intracortical vessel dilation relative to surface vessels. Thus, under normal conditions, the mechanical properties of the brain may play an important role in sculpting the laminar differences of hemodynamic responses. Copyright © 2015. Published by Elsevier Inc.
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