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Functional magnetic resonance imaging with intermolecular multiple-quantum coherences

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Abstract

For the first time, we demonstrate here functional magnetic resonance imaging (fMRI) using intermolecular multiple-quantum coherences (iMQCs). iMQCs are normally not observed in liquid-state NMR because dipolar interactions between spins average to zero. If the magnetic isotropy of the sample is broken through the use of magnetic field gradients, dipolar couplings can reappear, and hence iMQCs can be observed. Conventional (BOLD) fMRI measures susceptibility variations averaged over each voxel. In the experiment performed here, the sensitivity of iMQCs to frequency variations over mesoscopic and well-defined distances is exploited. We show that iMQC contrast is qualitatively and quantitatively different from BOLD contrast in a visual stimulation task. While the number of activated pixels is smaller in iMQC contrast, the intensity change in some pixels exceeds that of BOLD contrast severalfold.

Introduction

The phenomenon of intermolecular multiple quantum coherences (iMQCs) was first described a few years ago [1], [2], [3], [4]. In NMR, we can directly observe only single-quantum single-spin coherences (this corresponds to magnetization). Two-dimensional NMR methods [5] make it possible to observe other coherences between states in a multi-spin system as well; these coherences are made to evolve ‘silently’ during a successively incremented time interval and are detected after transformation into magnetization. In order for this transformation to take place, a net coupling between the spins involved must exist. In the case of spins 1/2 (such as the hydrogen nucleus), we can distinguish two types of couplings: scalar couplings, which act through chemical bonds, and dipolar couplings, which are much stronger than scalar couplings and act through space. Scalar couplings are commonly used to effect the abovementioned transformation of multi-spin coherences into magnetization; hence 2-D NMR method can provide information about the connectivity between spins in a molecule. On the other hand, dipolar couplings are normally not observable in liquids. The dipolar coupling strength between two spins scales as Dij ∝ 3cos2θ−1 where θ is the angle between the interspin vector and the main magnetic field. This coupling averages to zero when integrated over all directions (the surface of a sphere). In the case of short-range dipolar interactions, the interspin vector samples all directions on an NMR time scale through molecular diffusion.

This is not true for long-range dipolar interactions, where θ is almost constant in time. However, in that case the distribution of spins is quasi-continuous, and the dipolar interactions average to zero in space as long as the liquid is magnetically isotropic. Magnetic field gradient pulses applied during the experiment can break this isotropy; hence long-range dipolar couplings can be reintroduced by the experimenter in a controlled fashion. In this manner, the structure of a sample can be probed on the distance scale on which the dipolar couplings act. Most importantly, this distance may be tuned through the choice of experimental parameters. The gradient pulse causing the reappearance of dipolar couplings (the so-called ‘correlation gradient’) can be thought to wind up a helix of magnetization along its axis; the dipolar interactions that are reintroduced in this manner act over a distance scale of approximately one half pitch of that helix. Hence the larger the area under the gradient pulse is, the shorter is the correlation distance. In practice, the correlation distance ranges from tens to hundreds of micrometers, which is of course far above the microscopic range that is provided by scalar couplings, yet below the size of an imaging voxel. The method described here is therefore among the few NMR methods that can provide structural information on a mesoscopic distance scale.

FMRI was first demonstrated a few years ago [6], [7], [8] and is today one of the most powerful neuroimaging techniques. FMRI can measure brain activity noninvasively, with a spatial resolution of millimeters and a temporal resolution of seconds. Most fMRI techniques are based on the ‘blood oxygen level dependent’ (BOLD) effect. The BOLD effect is thought to arise from localized changes in the concentration of the strongly paramagnetic deoxyhemoglobin molecules in the brain, which are coupled to alterations in neuronal activity. Blood flow increases within seconds near the site of activation and overcompensates for the increased metabolic demand, resulting in decreased deoxy- and increased (diamagnetic) oxy-hemoglobin contents. The ensuing changes in susceptibility gradients across capillaries and venous blood vessels result in an increase of the apparent transverse relaxation time (T2) of the spins [9]. Therefore, an image whose intensity is weighted by T2 will show neuronal activation, through the secondary effect of blood oxygenation, as an increase in signal intensity. The typical signal increase upon activation is on the order of a few percent; hence this method is relatively insensitive.

The application of iMQCs to fMRI is based on the rationale that multi-spin coherences themselves do have a different, and possibly higher, sensitivity to susceptibility gradients than single-spin coherences. They may also be more specific to the site of activation. For example, an intermolecular zero-quantum coherence (iZQC) evolves at the difference of the single-quantum frequencies of the two spins involved, hence the zero-quantum signal intensity is a function of the distribution of susceptibility gradients. The BOLD signal, on the other hand, is a function of the average strength of those gradients within a voxel. Hence iZQC contrast is fundamentally different from T2 contrast [this has been shown previously by our group [3]], but still a function of blood oxygenation. Furthermore, the choice of correlation distance provides an additional degree of freedom to optimize contrast, which conventional methods do not possess. Susceptibility gradients due to deoxyhemoglobin arise from blood vessels ranging from densely distributed capillaries to low density large veins. The latter are clearly undesirable in fMRI experiments since they will not have accurate correspondence with the actual sites of enhanced neuronal activity. iMQCs offer the possibility of altering the distance scale over which the dipolar-couplings lead to observable signal, and hence the sensitivity to blood vessels of different sizes. Here, we provide initial evidence that iMQCs (here actually intermolecular double quantum coherences that are, in our pulse sequence, made to depend on the frequency difference between the spins, like iZQCs) can indeed generate large contrast related to functional activation of the brain.

Section snippets

Hardware

Experiments were carried out with a whole-body 7 Tesla imaging system (Varian/Magnex) with a head gradient insert and a double-loop surface coil.

Pulse sequences

The pulse sequence used for iMQC contrast is shown in Fig. 1. It is a modification of previously used pulse sequences, with the goal to minimize signal fluctuations. This sequence was discussed in ref. [3] and selects for double-quantum coherences (iDQCs). Hence, after the first r.f. pulse a double quantum coherence between spins 1 and 2, such as (Ix1I

Authenticity of the iDQC signal

An important property of iMQCs is the overall scaling of the signal by a factor of (3 cos2θ −1) (this is similar to the scaling factor for dipolar couplings), where in this case θ is the angle between the main magnetic field and the correlation gradient direction. Accordingly, we expect that the signal is twice as large for the longitudinal (z) gradient direction as for the transverse (x or y) gradient direction, and that the phase difference between them is π. This is shown in Fig. 2. Shown

Discussion

This experiment constitutes the first demonstration of functional activation revealed by iMQCs. At this moment, we lack a physiological model to relate the observed activation to blood flow, blood oxygenation, blood volume, vascular structure, oxygen consumption, and other potentially relevant parameters quantitatively; this is also largely true for the BOLD mechanism. We find it particularly noteworthy that the foci of activation are partially, but not completely, congruent in the two methods.

Conclusion

We demonstrate here that the iMQC method yields signal changes in the brain that are coupled to alterations in neuronal activity. Future work will have to explore methods to increase the stability of the signal toward physiological and instrumental fluctuations, and the influence of the correlation distance on the observed contrast. The iMQC method may become an invaluable tool for the elucidation of brain structure and function.

Acknowledgements

Supported by NIH National Resources grant RR08079 (University of Minnesota), the Keck Foundation, and NIH GM 35253 and the McKnight Foundation (Princeton University).

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