Name: High-resolution Functional Magnetic Resonance Imaging Methods for Human Midbrain (Video) | JoVE Journal
Uploaded: 2012-05-10T13:00:00.000+00:00
Duration: 10 min 6 s
Description: Learn high-resolution fMRI techniques for mapping visual processing in human midbrain structures using 3T scanners. This method enables detailed topographic analysis of the superior colliculus with enhanced signal quality.

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This material is based upon work supported by the National Science Foundation under Grant BCS 1063774.

1. Polar-angle Topography Stimulus and Psychophysics
To obtain a polar-angle retinotopic map in the SC, we use a 90° wedge of moving dots as the stimulus (eccentricity 2-9° of visual angle, mean dot-speed 4° / sec) (Fig. 1). It is known that activity in the SC is enhanced by applying covert attention5, hence we use an attention task in our paradigm to increase available signal. On each 2 s trial, subjects are instructed to covertly attend to the entire wedge and perform a speed discrimination task while maintaining fixation. The wedge is divided into 2 × 3 virtual sectors with dots in one of the sectors, randomly chosen on each trial, moving slower or faster than all other dots. After each trial, the wedge is rotated 30° around fixation so that the stimulus rotates fully with a 24 sec period. Each run consists of 9.5 rotations of the stimulus (228 sec), and experimental sessions include 16-18 runs.
To maintain subject's performance on this task throughout the duration of each run, the difficulty of the task is adjusted using two randomly interleaved two-up-one-down staircases. After every two consecutive correct trials the speed difference is reduced by 8%, and for every incorrect trial, the difference is increased by 8%.
Prior to scanning, all subjects practice the visual task outside the scanner until they achieve a stable level of performance; this requires 3-4 20 minute duration practice sessions. Typical discrimination thresholds are in the range of 1°-1.5° / sec.
2. Subject Preparation
<ol>
 <li>Subjects heads are secured with pads to minimize head motion before they are positioned inside the scanner bore. At these high spatial resolutions, fMRI is particularly sensitive to motion artifacts, so head stabilization is critical.</li>
 <li>Subjects are given an MRI-compatible button pad in one hand and instructed about which button to press to indicate their judgments about dot speed.</li>
</ol>
3. Localizing and Prescribing the SC
<ol>
 <li>Human SC is a small but distinct structure, ~9 mm in diameter, located on the roof of the midbrain. When using a small number of fMRI slices, multiple localizer imaging series are required for its precise localization. We run these series along sagittal, axial, and coronal planes.</li>
 <li>We then use these localizer images to precisely prescribe the SC with 8-10 contiguous slices, 1.2 mm thick, field-of-view (FOV), 170 mm in an oblique, quasi-axial plane.</li>
 <li>Next, high-resolution T1-weighted structural images are obtained using a three-dimensional (3D) RF-spoiled GRASS (SPGR) sequence (15° flip angle, 1.2 mm voxels) once prior to collecting the functional data and once after. These images are used as a reference to align the fMRI data to a high-resolution structural reference volume obtained in a separate session that we describe later.</li>
</ol>
4. Functional MRI Parameters
All imaging was performed on a GE Signa HD12 3T MRI scanner using the GE-supplied 8-channel, head coil. Excitation was a 6.4 ms windowed-sinc pulse applied using the scanner body coil.
To obtain 1.2 mm sampling in human SC, we use a three-shot spiral-trajectory acquisition6,7. Three shots are needed for several reasons. In particular, single-shot acquisition for our scanner and FOV requires &gt; 77 msec, too long to be practical. The multiple shots are combined together after correction by subtracting the initial value and linear trend of the phase. TE is incremented by 2 ms on the first frame to estimate a field map from the first two volumes acquired, and this map is used for linear correction. Reconstructed images had an SNR of ~20. Temporal power spectra in SC voxels typically showed little of the structure associated with physiological noise; the use of a 3-shot acquisition had a strong filtering effect on the comparatively high-frequency effects of cardiac pulse and respiration. Other noise-reduction techniques are problematic in this high-resolution context. For example, retrospective correction methods such as RETROICOR6 are not applicable to multi-shot data, and cardiac gating introduces noise and artifact associated with disturbance of T1 equilibrium.
Echo time, TE = 40 msec, is longer than typically used in cortex (30 msec) because we measured a correspondingly longer T2* in SC tissue (~60 msec) than observed in cortical gray matter (~45 msec).
Acquisition bandwidth is limited to 62.5 kHz to reduce peak gradient current that causes unwanted heating on our scanner. We choose TR = 1 sec, so with three shots a volume is acquired every 3 sec.
5. Structural MRI and 3D Modeling
In a single separate session for each subject, we obtain a high-resolution (0.7 mm sampling) reference volume using a T1-weighted sequence that gives good tissue contrast (3D SPGR, 15° flip angle, inversion prepared with TI = 450 msec, 2 excitations, ~28 minute duration, 0.7 mm voxels).
In this reference volume, we segment the tissue of the midbrain, brainstem, and portions of the thalamus (Fig. 2A) using a combination of automatic and manual techniques provided by the ITK-SNAP application2. In particular, we use an automatic segmentation tool in which the user seeds multiple points within each brainstem; the software then automatically expands the segmentation around the seed points constrained within a region defined by contrast and intensity criteria. This automatic segmentation is then adjusted, if necessary, using manual, "paint-like" voxel tools.
The cerebrospinal fluid-tissue interface of the SC is interpolated from the segmentation using isodensity surface tessellation, and this initial surface is refined to reduce aliasing artifacts (Fig. 2, B and D) using a variational deformable-surface algorithm3. This surface provides vertices and outward normal vectors to be used as a reference for the laminar calculations (described below) as well as a means to visualize functional data.
6. Image Analysis
To analyze the fMRI data, we use the mrVista software package (available for download at <a href="http://white.stanford.edu/mrvista.php" target="_blank">http://white.stanford.edu/mrvista.php)</a> as well as tools developed on the mrVista framework in our lab. In the next few steps we use standard mrVista package tools:
<ol>
 <li>Initialize the session in mrVista, choosing the option to spatially normalize the intensity of the averaged data to reduce the effects of coil inhomogeneity. The normalization uses a homomorphic method, that is, dividing by a low-pass filtered version of the temporally averaged volume image intensities with an additive robust correction for estimated noise. The first half cycle of images (12 sec) is discarded to avoid transient MR equilibrium and hemodynamic effects.</li>
 <li>Correct within-run motion. Motion is estimated from the time series of volumes. However, because of the relatively low signal-to-noise ratio (SNR) of the images, we first perform a 5-sample boxcar smoothing upon the time series. Each volume is then registered to the average of the last 5 samples. Note that smoothing is only used to estimate the motion, and the actual data is not smoothed.</li>
 <li>Form temporal averages of each run's motion-corrected image data, and use these averages to correct the between-run motion using the last run as reference.</li>
 <li>Perform a slice-timing correction. We use sequential slice acquisition, so errors due to performing timing correction after the motion correction will be small (~125 msec).</li>
 <li>Average the multiple runs recorded within each session to improve SNR.</li>
 <li>Align the structural data from the fMRI session to the reference structural volume using a robust intensity-based registration algorithm8. Load the alignment and segmentation into mrVista.</li>
 <li>Transform the functional time series data to the segmented reference volume. In the following steps we use tools developed in our lab to perform further analysis.</li>
 <li>Compute a distance map by calculating the distance between each SC tissue voxels and its nearest vertex on the SC surface. These distances are used to measure laminar position within the reference volume.</li>
 <li>Perform a laminar segmentation process to enable depth averaging of time-series data to improve the SNR. Small (1.6 mm diameter) disks of tissue are associated with each vertex of the surface model along the entire superficial SC surface, and each disk is then extended both inward and outward from the SC tissue using the local surface normals to form an individual laminar neighborhood4.</li>
 <li>For each point on the SC surface, we use these laminar associations to average the time series over a specified depth range. Since, visually responsive neurons are primarily present in the superficial layers of the SC, for the visual stimulation experiment we used a depth range of 0-1.8 mm.</li>
</ol>
7. Topographic Mapping Analysis
For analyzing the topographic representation of the data, Coherence analysis is performed on the depth-averaged time series by fitting a sinusoid at the stimulus repetition frequency (i.e., 1/24 Hz for the 24 sec stimulus described above) for each voxel. From this fit, we derive surface maps of response amplitude, coherence, and phase. This analysis is performed in the frequency domain, and is a common technique to quantify retinotopic maps in visual cortex9,10.
The phase of the sinusoidal fit measures the position of the stimulus. Zero-phase corresponds to the upper vertical meridian (Fig. 3). The stimulus then rotates clockwise, so a π/2 phase corresponds to when the stimulus has rotated to the horizontal meridian in the right visual field. After π radians of phase, the stimulus crosses into the left visual field, and so forth.
We also obtained boundaries of the entire superficial extent of the SC using manual inspection of the high-resolution T1-weighted volume anatomy. These boundaries are marked in Fig. 3 by red dashed lines.
fMRI does not directly measure neural activity, but rather a blood-flow response that is tightly but sluggishly coupled to neural activity. This adds a hemodynamic delay to the phase response. The delay is estimated by taking all voxels above our coherence threshold from each SC region-of-interest, and centering their means around π in the complex plane. In our SC data, these delays are quite small, of the order of 2-4 sec. We remove this delay by rotating the colormap counter-clockwise by 45 degrees (corresponding to 3 sec) (Fig. 3).
8. Representative Results
Phase data overlaid on a 3D surface of the SC (Fig. 3) shows that the response to visual stimulation is represented contralaterally in the SC, i.e., the left visual field is represented on the right SC and vice-a-versa.
There is also a retinotopic organization of the activity. The right upper visual field is represented medially on the left colliculus (blue-magenta), and the lower field is represented laterally (red-yellow). Similarly, the left upper visual field is represented medially on the right colliculus (blue-cyan) and lower is represented laterally (green-yellow).
This topography is consistent with the results of non-human primate studies of SC responses: 1) to visual stimulation using single-unit electrophysiology, and 2) the mapping of microstimulation induced saccadic eye movements11,12.
<img alt="Brain MRI cross-section diagrams; sagittal and axial views for anatomical analysis." src="/files/ftp_upload/3746/3746fig1.jpg" data-altupdatedat="1787630408000" data-alt="Figure 1"> 
Figure 1. A) Slice prescription viewed on mid-sagittal image. B) Temporal mean (from 1-run) of functional images obtained from central slice marked in red in A).
<img alt="Particle aggregation process, rotation sequence diagram, demonstrating clustering behavior analysis." src="/files/ftp_upload/3746/3746fig2.jpg" data-altupdatedat="1787630408000" data-alt="Figure 2"> 
Figure 2. Polar-angle topography stimulus. A 90° wedge of moving black-and-white dots on a gray background rotated slowly around fixation. The wedge was divided into an array of 6 virtual sectors (gray lines added to emphasize sectors) to allow the subject to perform a speed discrimination task in a randomly chosen sector.
<img alt="Brain scan, MRI diagram; highlighted regions show neurological pathways and brain activities mapping." src="/files/ftp_upload/3746/3746fig3.jpg" data-altupdatedat="1787630408000" data-alt="Figure 3"> 
Figure 3. Segmentation and surface modeling. A) The midbrain, brainstem, and portions of the thalamus were segmented from high-resolution MRI anatomy volumes. B) A surface was created at the edge of segmented region. C) Sinusoidal-fit phase data viewed on an inplane slice (coherence &gt; 0.25). D) A rotated and enlarged view of the brainstem surface model was used to visualize phase data on the SC.
<img alt="Brain activity mapping, phase-encoded retinotopy, color-coded fMRI results, cortical visual areas." src="/files/ftp_upload/3746/3746fig4.jpg" data-altupdatedat="1787630408000" data-alt="Figure 4"> 
Figure 4. Polar-angle maps. fMRI phase maps in two subjects that encode visual polar angle. Coherence thresholds for each map are provided on the bottom right. The color wheel relates the overlaid phases of the stimulus in polar angle to their visual field positions.

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No conflicts of interest declared.

Our acquisition and data-analysis techniques enable the measurement of neural activity in subcortical human brain structures at high resolution (1.2 mm voxels). The 3-shot spiral acquisition reduces the physiological noise that is particularly detrimental to fMRI measurements around the midbrain. In addition, our laminar segmentation of the tissue allows us to perform depth averaging of the data that helps improve the SNR. We have used these methods to show precise polar-angle topographic maps of visual stimulation and c...

high-resolution functional magnetic resonance imaging methods for human midbrain

High-resolution Functional Magnetic Resonance Imaging Methods for Human Midbrain

Functional MRI (fMRI) is a widely used tool for non-invasively measuring correlates of human brain activity. However, its use has mostly been focused upon measuring activity on the surface of cerebral cortex rather than in subcortical regions such as midbrain and brainstem. Subcortical fMRI must overcome two challenges: spatial resolution and physiological noise. Here we describe an optimized set of techniques developed to perform high-resolution fMRI in human SC, a structure on the dorsal surface of the midbrain; the methods can also be used to image other brainstem and subcortical structures.
High-resolution (1.2 mm voxels) fMRI of the SC requires a non-conventional approach. The desired spatial sampling is obtained using a multi-shot (interleaved) spiral acquisition1. Since, T2* of SC tissue is longer than in cortex, a correspondingly longer echo time (TE ~ 40 msec) is used to maximize functional contrast. To cover the full extent of the SC, 8-10 slices are obtained. For each session a structural anatomy with the same slice prescription as the fMRI is also obtained, which is used to align the functional data to a high-resolution reference volume.
In a separate session, for each subject, we create a high-resolution (0.7 mm sampling) reference volume using a T1-weighted sequence that gives good tissue contrast. In the reference volume, the midbrain region is segmented using the ITK-SNAP software application2. This segmentation is used to create a 3D surface representation of the midbrain that is both smooth and accurate3. The surface vertices and normals are used to create a map of depth from the midbrain surface within the tissue4.
Functional data is transformed into the coordinate system of the segmented reference volume. Depth associations of the voxels enable the averaging of fMRI time series data within specified depth ranges to improve signal quality. Data is rendered on the 3D surface for visualization.
In our lab we use this technique for measuring topographic maps of visual stimulation and covert and overt visual attention within the SC1. As an example, we demonstrate the topographic representation of polar angle to visual stimulation in SC.

This article describes techniques to perform high-resolution functional magnetic resonance imaging with 1.2 mm sampling in human midbrain and subcortical structures using a 3T scanner. Use of these techniques to resolve topographic maps of visual stimulation in the human superior colliculus (SC) is given as an example.

Functional MRI (fMRI) is a widely used tool for non-invasively measuring correlates of human brain activity. However, its use has mostly been focused upon ...

The overall goal of this procedure is to measure high resolution FMRI signals in the human midbrain and brainstem. This is accomplished by first presenting the appropriate visual stimulus to the research subject. Then an optimal set of FMRI.Procedures and parameters are used to collect data and the data is analyzed using a combination of standard and surface based analysis techniques. The final step is to overlay the data on A 3D surface representation for visualization. Ultimately, high resolution FMRI is used to show a topographic representation of polar angle to visual stimulation in human superior colus.The main advantage of this technique over existing methods for subcortical structures is that we are able to achieve a high resolution while overcoming the low signal to noise ratio associated with high resolution FMRI. We are able to do this by using specialized image analysis and acquisition techniques. Although this method was designed specifically to image function in human superior colus, it can also be applied to other subcortical regions such as the lateral ululate nucleus, inferior colus, or subthalamic nucleus.To obtain a polar angle, retina atopic map in the superior Colus first set up a functional paradigm using a 90 degree wedge of moving dots as the stimulus. The stimulus is divided into two by three virtual sectors with dots in one of the sectors randomly chosen on each trial to move slower or faster than all other dots. Here is a sample trial with the center left sector dots moving faster than dots in other sectors.After each trial, the wedge rotates around the fixation in 30 degree increments so that the stimulus completes a full cycle with a 24 second period. Each run consists of nine and a half rotations of the stimulus and experimental sessions should include 16 to 18 runs prior to scanning. Have each subject practice the visual task for each two second trial.Instruct the subject to covertly, attend to the wedge and perform a speed discrimination task While maintaining fixation. Using a button press, the subject should indicate if dots in one of the sectors are moving faster or slower than other sectors prior to scanning standard MRI Safety procedures should be followed. Position the subject on the scanner table and place the RF coil over the head.Then be sure to secure the subject's head with foam pads to minimize head motion. Explain that FMRI is particularly sensitive to motion artifacts, especially at the high spatial resolutions used in this study. Also place an MRI COMPATIBLE button pad in one hand and give instructions regarding which button to press during the task.The stimulus is projected onto a display screen viewed using a mirror mounted on the coil. The human superior colus is a small but distinct structure about nine millimeters in diameter located on the dorsal surface of the midbrain and multiple localizer imaging series are required for its precise localization. Run the localizers along sagittal axial and coronal planes.Now use these localizer images to precisely prescribe the superior colus with eight to 10 contiguous slices. Then obtain high resolution T one weighted structural images using a three-dimensional SPGR sequence. These images will be used to align the FMRI data to a high resolution structural reference volume that should be obtained in a separate session.Next set up for functional imaging using a three shot spiral trajectory acquisition to obtain an in plain pixel size of 1.2 millimeters. Set the echo time to 40 milliseconds, which is longer than typically used in cortex, corresponding to a longer measured value of T two star set. TR to one second so that a volume is acquired every three seconds.When ready, begin the scan while running the functional paradigm. Once functional imaging is complete, obtain another high resolution T one structural image series in a separate session. For each subject, obtain a high resolution reference volume using a T one weighted sequence that will provide good tissue contrast.This sequence will be about 28 minutes long. Once imaging is completed, use a combination of automatic and manual techniques provided in the ITK SNAP software to segment portions of the brainstem and thalamus in the high resolution volume. The cerebrospinal fluid tissue interface of the superior colliculus is interpolated from the segmentation using ISO density tessellation and then refined to produce a smooth, accurate surface representation.This surface provides vertices and normals that are used for laminar calculations as well as a means to visualize functional data. The analysis described utilizes the Mr.Vista software package as well as tools developed on the Mr.Vista framework. Begin by initializing a session and choosing the option to spatially normalize the intensity of the average data to reduce the effects of coil in homogeneity and discard the first half cycle of images.To avoid transient MR equilibrium and hemodynamic effects. Then open the Mr.Vista software. Next, perform subject motion and slice timing corrections.Then average the multiple runs recorded within each session. To improve SNR, align the structural data for the FMRI session to the reference volume. Load the alignment and segmentation into Mr.Vista.Then transform the functional time series data to the segmented reference volume. The following steps, use tools developed on the Mr.Vista framework. Compute a distance map by calculating the distance between each SC tissue voxel and its nearest vertex on the SE surface.These distances are used to measure laminar position within the reference volume. Next, perform a laminar segmentation process to enable depth averaging of time series data to improve the SNR. For each point on the SC surface, use these laminar associations to average the time series over a specified depth range to analyze the topographic representation of the data.Perform coherence analysis on the depth average time series by fitting a sinusoid at the stimulus repetition frequency for each voxel from this fit derive surface maps of response, amplitude, coherence, and phase. The phase of the sinusoidal fit will measure the position of the stimulus. Here we see phase data overlaid on a 3D surface of the SC zero phase corresponds to the upper vertical meridian.The stimulus then rotates clockwise, so a pie over two phase corresponds to when the stimulus has rotated to the horizontal meridian in the right visual field. After PI radian of phase, the stimulus crosses into the left visual field and so forth. The response to visual stimulation is represented Contral laly in the SC IE, the left visual field is represented on the right SC and vice versa.Boundaries of the entire superficial extent of the SC are marked by red dashed lines. There is a topographic organization of the activity. The right upper visual field is represented medially on the left colus and the lower field is represented laterally.Similarly, the left upper visual field is represented medially on the right, colliculus and lower is represented laterally. After watching this video, you should have a good understanding of how to perform high resolution FMRI in human midbrain and brainstem in particular, you should be able to understand how to present a visual stimulus. Collect high resolution FMRI data, perform standard and surface based analysis, and finally render the data on a 3D surface to obtain Tino topic maps on the surface of superior colliculus.

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Research

JoVE Journal

Neuroscience

A technique is described for broadly opening the blood-brain barrier in the mouse using microbubbles and ultrasound. Using this technique, manganese can be administered to the mouse brain. Because manganese is an MRI contrast agent that accumulates in depolarized neurons, this approach enables imaging of neuronal activity.

Functional Neuroimaging Using Ultrasonic Blood-brain Barrier Disruption and Manganese-enhanced MRI

Source: Shafi, M. M., et al. A Multimodal Imaging- and Stimulation-based Method of Evaluating Connectivity-related Brain Excitability in Patients with Epilepsy. J. Vis. Exp. (2016)The video demonstrates the procedure for using transcranial magnetic stimulation (TMS) and electroencephalography (EEG) to assess neuronal excitability in patients with epilepsy. It details the steps for aligning the patient’s head with a pre-recorded brain scan, positioning the TMS coil over a functionally connected...

Assessing Brain Hyperexcitability with Transcranial Magnetic Stimulation and Electroencephalography

This protocol describes a standard method for simultaneous functional magnetic resonance imaging and deep brain stimulation in the rodent. The combined use of these experimental tools allows for the exploration of global downstream activity in response to electrical stimulation at virtually any brain target.

Deep Brain Stimulation with Simultaneous fMRI in Rodents

The goal of this manuscript is to study the hippocampus and hippocampal subfields using MRI. The manuscript describes a protocol for segmenting the hippocampus and five hippocampal substructures: cornu ammonis (CA) 1, CA2/CA3, CA4/dentate gyrus, strata radiatum/lacunosum/moleculare, and subiculum.

High-resolution In Vivo Manual Segmentation Protocol for Human Hippocampal Subfields Using 3T Magnetic Resonance Imaging

Here we present a protocol to determine the minimum number images that needed to be registered and averaged to resolve subcortical structures and test whether the individual layers of the LGN could be resolved in the absence of physiological noise.

High-resolution Structural Magnetic Resonance Imaging of the Human Subcortex In Vivo and Postmortem

This protocol describes the steps and data analysis required to successfully perform optogenetic functional magnetic resonance imaging (ofMRI). ofMRI is a novel technique that combines high-field fMRI readout with optogenetic stimulation, allowing for cell type-specific mapping of functional neural circuits and their dynamics across the whole living brain.

Optogenetic Functional MRI

This protocol describes the quantification of volumetric cerebral hemodynamic variations in the mouse brain using functional ultrasound (fUS). Procedures for 3D functional activation map following sensory stimulation as well as resting-state functional connectivity are provided as illustrative examples, in anesthetized and awake mice.

Whole-Brain 3D Activation and Functional Connectivity Mapping in Mice using Transcranial Functional Ultrasound Imaging

This protocol shows how to acquire neuromelanin-sensitive magnetic resonance imaging data of the substantia nigra.

Standardized Data Acquisition for Neuromelanin-Sensitive Magnetic Resonance Imaging of the Substantia Nigra

This paper presents an integrative approach to investigating the functional network for spatial navigation in the human brain. This approach incorporates a large-scale neuroimaging meta-analytic database, resting-state functional magnetic resonance imaging, and network modeling and graph-theoretical techniques.

Modeling the Functional Network for Spatial Navigation in the Human Brain

We have developed techniques for mapping the visual cortex function utilizing more of the visual field than is commonly used. This approach has the potential to enhance the evaluation of vision disorders and eye diseases.

Functional Magnetic Resonance Imaging (fMRI) of the Visual Cortex with Wide-View Retinotopic Stimulation

Learn high-resolution fMRI techniques for mapping visual processing in human midbrain structures using 3T scanners. This method enables detailed topographic analysis of the superior colliculus with enhanced signal quality.

High-resolution Functional Magnetic Resonance Imaging Methods for Human Midbrain

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