Single Session Imaging of Cerebellum at 7 Tesla: Obtaining Structure and Function of Multiple Motor Subsystems in Individual Subjects

<div><p>The recent increase in the use of high field MR systems is accompanied by a demand for acquisition techniques and coil systems that can take advantage of increased power and accuracy without being susceptible to increased noise. Physical location and anatomical complexity of targeted regions must be considered when attempting to image deeper structures with small nuclei and/or complex cytoarchitechtonics (i.e. small microvasculature and deep nuclei), such as the brainstem and the cerebellum (Cb). Once these obstacles are overcome, the concomitant increase in signal strength at higher field strength should allow for faster acquisition of MR images. Here we show that it is technically feasible to quickly and accurately detect blood oxygen level dependent (BOLD) signal changes and obtain anatomical images of Cb at high spatial resolutions in individual subjects at 7 Tesla in a single one-hour session. Images were obtained using two high-density multi-element surface coils (32 channels in total) placed beneath the head at the level of Cb, two channel transmission, and three-dimensional sensitivity encoded (3D, SENSE) acquisitions to investigate sensorimotor activations in Cb. Two classic sensorimotor tasks were used to detect Cb activations. BOLD signal changes during motor activity resulted in concentrated clusters of activity within the Cb lobules associated with each task, observed consistently and independently in each subject: Oculomotor vermis (VI/VII) and CrusI/II for pro- and anti-saccades; ipsilateral hemispheres IV-VI for finger tapping; and topographical separation of eye- and hand- activations in hemispheres VI and VIIb/VIII. Though fast temporal resolution was not attempted here, these functional patches of highly specific BOLD signal changes may reflect small-scale shunting of blood in the microvasculature of Cb. The observed improvements in acquisition time and signal detection are ideal for individualized investigations such as differentiation of functional zones prior to surgery.</p></div

Functional Delineation of Task-Related Activity, Separation of Eye and Finger Movements in Ventrolateral Cb.

<p>Example of the specificity of localized activity resulting from the two motor systems (in addition to the obvious distinctions visible in Figs <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0134933#pone.0134933.g002" target="_blank">2</a>–<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0134933#pone.0134933.g005" target="_blank">5</a>): differentiation of FT-related <i>h</i>VIII activity from PA-related <i>h</i>VIIb activity is displayed for each subject (zoomed-in area denoted by a dotted box); activations from separate tasks do not overlap. Separable activations are located more anteriorly in some subjects (S02, S05 and S06, axial slices) and the proximity and arrangement of the clusters also varies between subjects. Slice locations (in non-normalized MNI space) are displayed at the top of each panel and maximum T-values from within the zoomed areas are displayed at the bottom of the axial (rightmost) panels, color-coded by task—PA in red-orange and FT in blue-green. Refer to <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0134933#pone.0134933.g001" target="_blank">Fig 1a</a> for a guide to anatomical lobule definitions.</p

Concomitant Correlation of Task-Related Cb Cortex Activity and Anticorrelation of DCN Activity.

<p>The detail of the T2W scan allows visualization of DCN revealing increases (+) and decreases (-) in task-related functional activity in Cb cortex and within the dentate (respectively) of a single subject. Correlation of task-related activity (+) in the Cb cortex is concomitant with anticorrelation of activity (-) in the dentate and that cognitive depression (PA, green at -57) is located more caudal in the dentate than (the stronger) motor depression (FT, purple at -48). Slice locations (in non-normalized MNI space) are displayed at the top of each panel and maximum T-values from clusters within the circles are displayed at the bottom of the panels; coloring matching the respective color bar. Refer to <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0134933#pone.0134933.g001" target="_blank">Fig 1a</a> for a guide to anatomical lobule definitions. FN—fastigial nucleus, IN—interpositus nucleus, D—dentate nucleus.</p

Functional Accuracy of Thumb Tapping Activations in Cb, Ipsilateral IV-VI.

<p>Ipsilateral <i>h</i>IV<i>-</i>VI is activated during the FT task; crosshairs denote an active cluster in or adjacent to right <i>h</i>V (S04 –<i>h</i>VI-VII). Activations for both tasks are shown in all images, with PA activity denoted by red-yellow and FT activity by blue-green color bars. Note the large structural and functional (with regard to both location and strength) variability between subjects; maximum FT-clusters can be located anywhere between the IV-V border (S03, S05 and S06) to the V-VI border (S01, S02, S04). Slice locations (in non-normalized MNI space) are displayed at the top of each panel and T-values at the crosshairs are displayed at the bottom of the axial (rightmost) panels. Refer to <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0134933#pone.0134933.g001" target="_blank">Fig 1a</a> for a guide to anatomical lobule definitions.</p

Experimental Design.

<p><b>a)</b> Cb is divided into three main parts—vermis (medial Cb; will be denoted in the text with a “<i>v</i>”), paravermal (medio-lateral Cb) and hemispheres (lateral Cb; both of which will be denoted collectively in the text with an “<i>h</i>”)–which are then further divided into ten numbered lobules, arranged dorsoventrally I-X. Task-related activations were expected in five regions of interest: oculomotor vermis (<i>v</i>VI-VII) & <i>h</i>VIIb for the PA task, with possible cognition-related activation in lobules CrusI & CrusII (<i>h</i>VII), and in <i>h</i>V & <i>h</i>VIII for the FT task. These lobules are color-coded and overlaid on an average Cb from the SUIT toolbox [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0134933#pone.0134933.ref020" target="_blank">20</a>] and listed, in matching colors, on the right. <b>b)</b><i>top</i>–Two high-density surface coils with 16 elements each were used for signal reception (adapted from [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0134933#pone.0134933.ref021" target="_blank">21</a>]), <i>bottom</i>–the coils were placed beneath Cb using the inion of the skull as a landmark and accurate placement was confirmed with a scout scan. <b>c)</b> The stimulus sequence was identical for both eye- and finger-movement tasks: In the pro-/anti-saccade (PA) task subjects made eye movements to locations which were either identical to (pro-saccade) or opposite from (anti-saccade) the location of a white target that appeared after a red or a blue central cue; color and movement direction pairings were counterbalanced across subjects. In the finger tapping (FT) task subjects moved their thumb at 2 Hz whenever the dots were moving. In each task the active period lasted for 20s and alternated with 20s of fixation for one full run of eight minutes.</p

Functional Accuracy of Pro-Anti Activations in Cb, Oculomotor Vermis and Paravermis VI.

<p>Activity in OMV (medial posterior Cb, layers <i>v</i>VIc and <i>v</i>VII, central panel) and paravermis VI and CrusII/VIIa during the PA task is displayed on sagittal slices (vertical lines dissecting rightmost coronal view). Ventral OMV is active in all subjects besides S05 during this task while activity is also present in dorsal OMV for all subjects besides S03 and S04; slices are through Cb vermis and paravermis only. Slice locations (sagittal non-normalized MNI space, x-plane) are displayed at the top of each panel. Refer to <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0134933#pone.0134933.g001" target="_blank">Fig 1a</a> for a guide to anatomical lobule definitions.</p

Inter-Subject Variability of Normalized Cb Activations.

<p><b>a)</b><i>left—</i>Normalized PA-activity, crosshairs at left paravermis VI; <i>right—</i>normalized FT-activity, crosshairs at ipsilateral (right) V; data are from all subjects, each subject is color-coded. <b>b)</b> PA activity is localized to oculomotor vermis (VIc and VII), bilateral <i>h</i>VI, and (right) <i>h</i>CrusI/II for all subjects. <b>c)</b> FT-activity in ipsilateral <i>h</i>V/VI for all subjects and ventral activity only for S01, S02 and S05. Activations from both tasks are clustered within the expected lobules yet inter-subject activations rarely overlap. Activations are T-maps from SUIT normalized functional images with Cb mask overlaid on SUIT template Cb [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0134933#pone.0134933.ref020" target="_blank">20</a>]. Each subject is represented by a single color cluster-thresholded at <i>p</i> < .05 (AT).</p

Functional Accuracy of Pro-Anti Activations in Cb, Bilateral VI.

<p>Bilateral <i>h</i>VI is activated during PA; crosshairs denote an active cluster in left paravermis VI and distinct clusters can be seen aligned along lobule VI in the axial (rightmost) panels. Slice locations (in non-normalized MNI space) are displayed at the top of each panel and T-values at the crosshairs are displayed at the bottom of the axial panels. Refer to <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0134933#pone.0134933.g001" target="_blank">Fig 1a</a> for a guide to anatomical lobule definitions.</p

Spatial activation maps and time courses of the GE and SE HRF upon short visual stimulation.

<p>A) Percent signal change (PSC) map of the visual cortex V1 for the GE (top) and SE (bottom) HRF data with isotropic voxel sizes of 1 mm and 2 mm, respectively. As expected the SE contrast shows reduced sensitivity. B) Closer examination of the cortical surface and pial vasculature on the 0.5 mm T2*-weighted anatomical scan. The cortical surface (white) was manually delineated in 3D and from this surface the cortical depth profiles were computed: black; 0–1 mm, red; 1–2 mm, and green; 2–3 mm. The high-resolution T2*-weighted scan was also used to identify the larger pial draining veins, which were excluded from the GE BOLD analysis. C) GE HRFs across cortical depth (0–1, 1–2, and 2–3 mm) and the SE HRF for a representative subject (subject 4 as indicated in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0054560#pone-0054560-t001" target="_blank">Table 1</a>). As the GE and SE BOLD do not measure from the exact same vasculature there should be no exact spatial match in their activation patterns from the functional localizer. We therefore focused on the temporal evolution of the estimated HRFs, with the following parameters of interest: onset time, time-to-peak (TTP), full-width-at-half-maximum (FWHM), and maximum percent signal change (PSC). Onset times of the SE and GE HRF in deep gray matter (>1 mm cortical depth) are very comparable while the FWHM and TTP are increased for the GE HRF for all cortical depths indicating that the earlier part of deep gray matter GE HRF is weighted toward microvascular dynamics. Shaded areas denote the standard error of the mean (SEM). The black bar indicates the stimulus onset and duration (250 ms).</p

Box plot of the temporal HRF properties of the GE HRF across the cortical depth and SE HRF across all subjects.

<p>A) Onset time (s), B) TTP (s) C) FWHM (s), and D) PSC (%). Comparing the SE HRF with surface gray matter GE HRF (0–1 mm cortical depth) shows that all temporal properties are significantly increased (P<0.01, Wilcoxon signed–rank test). This indicates that the surface gray matter GE contrast probes a different part of the vascular system upon activation than the SE contrast. Surface gray matter in V1 contains mainly postcapillary veins (diameters ∼70 μm) and much less capillaries (diameters ∼5 μm) than deep gray matter regions <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0054560#pone.0054560-Duvernoy1" target="_blank">[20]</a>. Looking at the deep gray matter GE HRFs (>1 mm cortical depth) and the SE HRF we found that the TTP, FWHM and PSC were all significantly increased for the GE HRF. The onset times, however, did not differ significantly. These findings suggest that the earlier part of the deep gray matter GE HRF is in close correspondence to the SE HRF and hence is weighted towards the microvasculature. ^*** denotes significant difference between the two compartments (Wilcoxon signed–rank test for P<0.01, ** for P<0.05, * for P<0.1).</p