Friday, June 3, 2016

Direct Neural Current Imaging in an Intact Cerebellum with Magnetic Resonance Imaging

In the 5th edition of Intermediate Physics for Medicine and Biology, Russ Hobbie and I added a paragraph to Chapter 18 (Magnetic Resonance Imaging) about using MRI to image neural activity.
Much recent research has focused on using MRI to image neural activity directly, rather than through changes in blood flow (Bandettini et al. 2005). Two methods have been proposed to do this. In one, the biomagnetic field produced by neural activity (Chap. 8) acts as the contrast agent, perturbing the magnetic resonance signal. Images with and without the biomagnetic field present provide information about the distribution of neural action currents. In an alternative method, the Lorentz force (Eq. 8.2) acting on the action currents in the presence of a magnetic field causes the nerve to move slightly. If a magnetic field gradient is also present, the nerve may move into a region having a different Larmor frequency. Again, images taken with and without the action currents present provide information about neural activity. Unfortunately, both the biomagnetic field and the displacement caused by the Lorentz force are tiny, and neither of these methods has yet proved useful for neural imaging. However, if these methods could be developed, they would provide information about brain activity similar to that from the magnetoencephalogram, but without requiring the solution of an ill-posed inverse problem that makes the MEG so difficult to interpret.
I am skeptical about most claims of measuring neural currents using MRI. However, a recent paper (Sundaram et al., NeuroImage,132:477-490, 2016) from the laboratory of Yoshio Okada has forced me to reconsider. Below I reproduce the introduction to this article (with references removed), which introduces the topic nicely.
Functional study of the human brain has become possible with advances in non-invasive neuroimaging methods. The most widely used technique is blood oxygenation level-dependent functional MRI (BOLD-fMRI). Although BOLD-fMRI is a powerful tool for human brain activity mapping, it does not measure neuronal signals directly. Rather, it images slow local hemodynamic changes correlated with neuronal activity through a complex neurovascular coupling. At present, only electroencephalography (EEG) and magnetoencephalography (MEG) detect signals directly related to neuronal currents with a millisecond resolution. However, they estimate neuronal current sources from electrical potentials on the scalp or from magnetic fields outside the head, respectively. Measurement of these signals outside the brain leads to relatively poor spatial resolution due to ambiguity in inverse source estimation.

Our understanding of human brain function would significantly accelerate if it were possible to noninvasively detect neuronal currents inside the brain with superior spatiotemporal resolution. This possibility has led researchers to look for a method to detect neuronal currents with MRI. Many MRI approaches have been explored in the literature. Of these, the mechanism most commonly used is based on local changes in MR phase caused by neuronal magnetic fields. Electrical currents in active neurons produce magnetic fields (ΔB) locally within the tissue. The component of this field (ΔBz) along the main field (Bo) of the MR scanner alters the precession frequency of local water protons. This leads to a phase shift ΔΦ of the MR signal. For a gradient-echo (GE) sequence,

ΔΦ = γΔBzTE

where γ is the gyromagnetic ratio for hydrogen (2π x 42.58 MHz/T for protons) and TE is the echo time. According to Biot-Savart's law, ΔBz(t) is proportional to the current density J(t) produced by a population of neurons in the local region of the tissue. Thus, measurements of the phase shift ΔΦ can be used to directly estimate neuronal currents in the brain.

Many attempts have been made to detect neuronal currents in human subjects in vivo, but the results so far are inconclusive. The literature contains several reports of positive results which conflict with reports of negative results. This difficulty is presumably due to confounding factors such as blood flow, respiration and motion. Theoretical models, phantoms and cell culture studies indicate that it should be possible to detect neuronal currents with MRI in the absence of physiological noise sources.

Although these studies indicate that MRI technology should have enough sensitivity to detect neural currents, two types of key evidence are still lacking for demonstrating how MRI can be useful for neural current imaging: (1) there are no data showing that the phase shift is timelocked to some measure of population activity and that the phase shift time course matches that of a concurrently recorded local field potential (LFP), and (2) there is still no report showing how the phase shift data can be used to estimate the neuronal current distribution in the brain tissue, even though this should be the goal for neural current imaging.

Our work demonstrates that it is possible to measure an MR phase shift time course matching that of the simultaneously recorded evoked LFP in an isolated, intact whole cerebellum of turtle, free of physiological noise sources. We show how these MR phase maps can be used to estimate the neuronal current distribution in the active region in the tissue. We show that this estimated current distribution matches the distribution predicted based on spatial LFP maps. We discuss how these results can provide an empirical anchor for future development of techniques for in vivo neural current imaging.
After presenting their methods and results, Sundaram et al. write:
We demonstrated that the ΔΦ can be detected reliably in individual cerebelli and that this phase shift is time-locked to the concurrently recorded LFP. The temporal waveform of the ΔΦ matched that of the LFP. Both the MR signal and LFP were produced by neuronal currents mediated by mGluRs. The measured values of ΔΦ in the individual time traces corresponded to local magnetic fields of 0.67–0.93 nT for TE = 26 ms. According to our forward solutions, these values correspond to a current dipole moment density q of 1–2 nA m/mm2,which agrees with the reported current density of 1–2 nA m/mm2 determined on the basis of MEG signals measured 2 cm above the cerebellum.

We also show that the MR phase data can be used to estimate the active neuronal tissue. This second step is important if MRI were to be used for imaging neuronal current distributions in the brain. We were able to use the minimum norm estimation technique developed in the field of MEG to estimate the current distribution in the cerebellum responsible for the measured phase shift. The peak values of ΔΦ in the phase map averaged across 7 animals were 0.15° and −0.10°, corresponding to peak ΔB values of +0.37 nT and −0.25 nT, respectively. The empirically obtained group-average ΔΦ of 0.12° and ΔB of 0.30 nT are close to the predicted values of 0.2° and 0.49 nT assuming q = 1 nA m/mm2. The slightly smaller group-average ΔΦ and ΔB may be due to variability in the spatial phase map and responses across animals.
They conclude
Our results for metabotropic receptor mediated evoked neuronal activity in an isolated whole turtle cerebellum demonstrate that MRI can be used to detect neuronal currents with a time resolution of 100 ms, approximately ten times greater than for BOLD-fMRI, and with a sensitivity sufficiently high for near single-voxel detection. We have shown that it is possible to detect the MR phase shift with a time course matching that of the concurrently measured local field potential in the tissue. Furthermore, we showed how these MR phase data can be used to accurately estimate the spatial distribution of the current dipole moment density in the tissue.
I have been interested in this topic for quite a while, publishing on the subject with Ranjith Wijesinghe of Ball State University (2009, 2012) and Peter Basser of the National Institutes of Health (2009, 2014). My graduate student Dan Xu (2012) examined the use of MRI to measure electrical activity in the heart, where the biomagnetic fields are largest. I remain skeptical that magnetic resonance imaging can record neural activity of the human brain in a way as accurate as functional MRI using BOLD. Yet, this is the first claim to have measured the magnetic field of neurons using MRI that I actually believe. It is a beautiful result and a landmark study. I hope that I am wrong and the method does have the potential for clinical functional imaging.

4 comments:

  1. I propose the following experimental setting for measuring in vivo neural current in the peripheral nerve (or spinal cord) of a living person:

    Anesthetize, paralyze and ventilate a subject whose extremity (or spinal column) is positioned in an MRI scanner. Stimulate a major peripheral nerve fiber proximally with a standard regional anesthesia nerve stimulator (used for peripheral nerve blocks). Because the subject is paralyzed, there will be no noise from muscle contractions otherwise elicited by the nerve stimulator. Use choice MR sequencing technique to attempt neural activity imaging of large nerve fiber which will be conducting action potentials at whatever firing rate is set by the stimulator.

    The direct, conventional MRI tissue image of the nerve trunk can be compared to the neural activity image obtained by differing MR sequencing techniques.

    Please permit me to join you in doing this experiment if you need a board certified anesthesiologist (who has purchased two editions of IPMB) to assist.

    Eric Franck, MD
    Portland, Oregon

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  2. Do you think any IRB in the country would approve this experiment?

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  3. First we show that you can stimulate safely in a scanner.

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  4. And to answer your question: yes I do.

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