Lessons from fMRI about mapping cortical columns

Abstract

Recently developed fMRI can map small functional structures noninvasively and repeatedly without any depth limitation. However, there has been a persistent concern as to whether the high-resolution fMRI signals actually mark the sites of increased neural activity. To examine this outstanding issue, the authors used iso-orientation columns of isoflurane-anesthetized cats as a biological model and confirmed the neural correlation of fMRI iso-orientation maps by comparing them with intrinsic optical imaging maps. The results suggest that highest fMRI signals indeed indicate the sites of increased neuronal activity. Now fMRI can be used to determine plastic and/or developmental change of functional columnar structure possibly on a layer-to-layer basis. In this review, the authors focus mainly on what technical aspects should be considered when mapping functional cortical columns, including imaging techniques and experimental design.

Fig. 1

A schematic of vascular responses induced by neural activity. Blood containing oxyhemoglobin (red circles) and/or deoxyhemoglobin (blue circles) travel from arteries, arterioles, capillaries, venuoles, finally to veins. Oxygen delivered via oxyhemoglobins diffuses into (extravascular) tissue, and is used as metabolic substrates. At pre-stimulus baseline conditions, blood oxygen saturation is close to 100% in arteries, while it is ~60% in veins (even though it varies dependent on subject’s physiological condition). When neural activities increase, they will trigger an increase in blood velocity (indicated by the size of arrows) and dilation of vessels directly or indirectly. Since the CBF increase induced by an increase in neural activity overcompensates an increase in oxygen consumption rate, venous blood is less oxygenated during stimulation (i.e., more oxyhemoglobin and less deoxyhemoglobin contents). Partially deoxygenated blood will drain from capillaries to large veins.

Fig. 2

Schematics of slice selections and apparent patterns of columns. Columns orthogonal to the surface of the cortex run across the entire cortex. 2-dimenstional MR imaging slice(s) can be chosen with a well-defined thickness at an arbitrary angle. Thus, appearance of columns in 2-D images is dependent on the slice selection relative to the column direction. When the imaging slice is orthogonal to the column direction, fMRI patterns are same as dorsal view of columns (red circles). If the imaging slice is oblique to the column direction, column patterns elongate depending on the oblique angle and slice thickness (green ovals). If the imaging slice is parallel to the column direction, bar-like patterns appear dependent on slice thickness (yellow bars).

Fig. 3

A sketch of cat brain and 2-D slice view of various imaging slices. In the dorsal view of the cat brain (A), gray area indicates visual area 17 and 18, where orientation columns are expected to be present. To select imaging slices for columnar mapping, a 3-dimensional venographic image was acquired. From the 3-D image, a 2-D section can be selected for fMRI studies. In the coronal view (B), three different imaging slices indicated by 1-mm thick slabs can be chosen to cover visual area 17 or 18, transverse (c), oblique (d), and sagittal (e). Corresponding images are shown in C, D, and E. Dark lines or spots indicate venous blood vessels. Most intracortical vessels run nominal to the surface of the cortex. When vessels appear as small dark dots, then the imaging plane is selected roughly orthogonal to the vessel direction. LS (dashed line), lateral sulcus; ML (dashed and dotted line), midline; mg, marginal gyrus; D, dorsal; V, ventral; M, medial; L, lateral; A, anterior; P, posterior.

Fig. 4

Stimulation paradigms used for mapping orientation columns. (A) Block-design. Orientation-selective stimulation period follows pre-stimulus control period. Red double-arrow in black-and-white gratings indicates a direction of motions. The same stimulus may be repeated or two orthogonal stimuli may be interleaved. (B) Continuous stimulation paradigm. Orientation-selective stimuli are presented without any control period. In this specific example, 8 different orientations are presented sequentially. Since no control period is used here, total response induced by one orientation cannot be determined, and the difference of signals induced by different stimuli will be observed.

Fig. 5

Perfusion (CBF)-weighted fMRI map corresponding to 0° stimulation and time course of active pixels (Duong et al. 2002). An imaging slice was selected in a transverse plane, and arterial spin labeled images were acquired with temporal resolution of 6.0 s. Functional map was generated by using cross-correlation analysis between raw time course and a box-car reference function based on block-design stimulation paradigm. Functional map (color) was overlaid on an anatomic image. Color bar, cross-correlation value between 0.3 and 0.8; scale bar, 1 mm; gray bars, stimulation periods.

Fig. 6

CBV-weighted fMRI. CBV-weighted fMRI was obtained in a sagittal plane after intravascular injection of superparamagnetic iron oxide nanoparticles. Negative signal change indicates an increase in CBV during stimulation. Single-condition maps corresponding to 45° and 135° stimulation (A and B, respectively) are shown as well as their differential map (C). Dorsal contour indicates the edge of the brain, while the ventral contour is the splenial sulcus. To easily visualize patches responding to 45°, green plus signs were obtained from the 45° single-condition map and then overlaid on 135° single-condition map (B) and the differential map (C). Clearly, functional territories responding to two orthogonal stimuli are complementary. Spatial profiles in a posterior-anterior direction indicated by a line were obtained (D). Clearly, negative signal changes indicating increases in CBV were observed from baseline (dashed horizontal line). The subtraction of 135 from 45° profiles enhances differential responses induced by two orthogonal stimuli; negative peaks represent the regions preferred to 45° stimulation, while positive peaks represent 135° stimulation. Interval between positive (or negative) peaks is related to inter-column distance.

Fig. 7

Orientation-selective modulations during 800-s continuous stimulation. Eight 10-s long orientation-selective stimuli starting 0° and increasing 22.5° were repeated 10 times. CBV- (blue) and dHb-weighted (red) fMRI signals (A) and OIS responses (B) were obtained from 0°-specific columns. In optical imaging (B), reflected response of 570-nm wavelength light is weighted by CBV, while that of 610-nm wavelength is weighted by dHb. A decrease in CBV- and dHb-weighted signal indicates an increase in CBV and dHb, respectively. In both fMRI and OIS data, orientation-selective stimulation induces a decrease in CBV-weighted signals (i.e., an increase in CBV). BOLD response increases during orientation-selective stimulation, while 610-nm OIS response decreases. The time to peak of CBV and BOLD response slightly differs due to their different response characteristics.

Fig. 8

Comparison between CBV-weighted fMRI and optical images (Fukuda et al., 2006a). An fMRI slice was selected in the middle of the cortex through the gyrus in the right hemisphere (indicated as a dashed slab), while optical imaging obtained from the upper cortical layers including the surface of the cortex. Thus, to co-register both modality images, pial vessel patterns just above the fMRI slice (indicated as a solid slab in A) were compared with optical image (B vs. C). Functional maps were obtained from continuous stimulation and Fourier analysis. In the functional maps, dark patches represent the region preferentially responding to the orientation stimulus shown in the right corner, while white patches represent orthogonal orientation stimulation. Plus signs were marked based on fMRI patches and overlaid on optical maps. Clearly, fMRI and optical images agree very well.

Fig. 9

CBV-weighted vs. BOLD fMRI. CBV-weighted fMRI followed conventional BOLD fMRI. Both maps were determined from continuous stimulation data and Fourier analysis. Higher signal change responding to 0° stimulation appears as black, while that responding to 90° appears white. Gray indicates either 45° or 135° response area. Green contours indicating 0° columns were marked based on CBV-weighted fMRI and overlaid on fMRI maps. Even though some regions mismatch between CBV-weighted and BOLD fMRI, there is generally good agreement between the two modalities.

Fig. 10

CBV-weighted fMRI map in the medial region (Fukuda et al., 2006a). CBV-weighted fMRI was obtained on a sagittal imaging slice in the medial bank of cortical area 17 (A) with continuous stimulation paradigm. Vessel-weighted sagittal image (B) shows orientations of intracortical veins relative to the imaging slice; dark lines indicates vessels run within the imaging slice (as indicated between lines 1–2 and 3–4), while dark spots indicates vessels run through the imaging slice (lines 2–3). Spatially distinct activation patterns appear as irregular patches and bands. Patchy patterns appear in the region between dashed lines 2 and 3, where the imaging plane is parallel to the cortical surface. Band-shaped patterns appear in regions where the imaging plane is perpendicular to the cortical surface (between dashed lines 1 and 2, and between lines 3 and 4).