High-resolution functional magnetic resonance imaging mapping of noxious heat and tactile activations along the central sulcus in New World monkeys

Abstract

This study mapped the fine-scale functional representation of tactile and noxious heat stimuli in cortical areas around the central sulcus of anesthetized squirrel monkeys by using high-resolution blood oxygen level-dependent (BOLD) fMRI at 9.4T. Noxious heat (47.5°C) stimulation of digits evoked multiple spatially distinct and focal BOLD activations. Consistent activations were observed in areas 3a, 3b, 1, and 2, whereas less frequent activation was present in M1. Compared with tactile activations, thermal nociceptive activations covered more area and formed multiple foci within each functional area. In general, noxious heat activations in area 3b did not colocalize with tactile responses. The spatial relationships of heat and tactile activations in areas 3a and 1/2 varied across animals. Subsequent electrophysiological mapping confirmed that the evoked heat and tactile BOLD signals were somatotopically appropriate. The magnitude and temporal profiles of the BOLD signals to noxious heat stimuli differed across cortical areas. Comparatively late-peaking but stronger signals were observed in areas 3b and 2, whereas earlier-peaking but weaker signals were observed in areas 3a, 1, and M1. In sum, this study not only confirmed the involvement of somatosensory areas of 3a, 3b, and 1, but also identified the engagements of area 2 and M1 in the processing of heat nociceptive inputs. Differential BOLD response profiles of the individual cortical areas along the central sulcus suggest that these areas play different roles in the encoding of nociceptive inputs. Thermal nociceptive and tactile inputs may be processed by different clusters of neurons in different areas. To critically bridge animal and human pain studies, human fMRI was related to primate fMRI and electrophysiology of nociceptive processing, examining the functional role of the primary somatosensory cortex in heat nociception and demonstrating that subregion areas 3a, 3b, 1, 2, and M1 are responsive to noxious heat stimuli.

Figure 1. Placement of imaging slice and imaging coregistration

(A) One oblique image slice (red rectangle) was positioned to cover SI and M1 contralateral to stimulated fingers. (D) T2* weighted oblique structural image revealed central (CS) and lateral (LS) sulci (green lines) as well as other blood vessel features as indicated by blue arrows and red dots. (E) T2 weighted oblique structural image taken on different day revealing very similar blood vessel landmarks (arrows and dots). (F) Blood vessel map of the same region showing corresponding landmarks in D and E. Landmarks highlighted in D, E and F were used to coregister activations across image session and modality. (B & C) Brain schematic maps adapted from Kaas 2004 [22] illustrate the anterior to posterior organization of M1 to SI cortices in monkeys. (C) Zoomed-in view shows the detailed topographic organization of areas M1, 3a, 3b, 1 and 2 and their relative territory ratio. Note: the topographic organization and the territory span were determined electrophysiologically and anatomically.

Figure 2. Across-run nociceptive heat activations in two representative monkeys (M1 and M2)

(A–D, F–I): Individual run nociceptive activation maps. Thresholded at p≤10⁻⁴ except activation in D was thresholded at p ≤ 10⁻⁶ (peak at 10⁻⁹) based in the method described in Zhang et al 2010 [62]. (E & J): Frequency maps generated in these two animals. Color bars indicate the frequency of activation incidence. E range: 3 out of 5 to 5 out of 5 runs. J range: 3 out of 10 to 8 out of 10 runs.

Figure 3. Single digit tactile activations in two representative monkeys (M3 and M4)

(A–C, E–F): Single condition tactile activation maps to individual digit stimulation (D2, D3 or D4). (D & G): Composite activation maps of D2–D4 (pink, blue, and red patches) in M3, and of D2 (pink) and D4 (red) in M4. Black and white bars in A and E indicate 1 mm spatial scale bar.

Figure 4. Comparison of nociceptive heat and tactile activations within SI in four representative monkeys (M1, M2, M5 and M6)

(A, E, I, M, Q): Color-coded activation convergence maps from four animals illustrate the frequency of detected activations (in each run) to noxious heat stimulation within each imaging session (five total, M and Q were repeats from the same animal). (B, F, J, N): Composite digit tactile activation maps of the same animals. Letters indicate the stimulated digits associated with the activation. (C, G, K, O): Color-coded digit representation maps as determined electrophysiologically by microelectrode mapping. Dotted lines indicate the estimated inter-areal borders. (D, H, L, P, R): Composite maps of heat and tactile fMRI activation patterns and electrophysiological maps in each animal. P and R were repeats across imaging sessions of the same animal. Color coded scale bars indicate the number of activated runs out of total of scanned runs (far right). Receptive field properties of each penetration were color-coded for different digits. A: anterior; p: posterior; m: middle; l: lateral. Scale bars: 1mm.

Figure 5. Localization of noxious heat and tactile activations with electrophysiology and histology in two monkeys (M7 and M8)

FMRI activation maps to noxious heat (A & G) and tactile (B & H) stimulation were aligned with electrophysiological blood vessel maps (C & I), and fiber Myelin stains (E & K) for determining activation locations. Color bars next to A and G represent the color-coded activation frequency observed in these two animals. In E and K, different Myelin stain features were present in different areas. These features include dense stain in areas 3b and 1 digit region separated by lightly stained palm region and dense stain in M1 but light stain in posterior nearby area 3a. The staining pattern was used to determine inter-areal borders (r.f. [44]). Arrows indicate the light myelin stain feature of the hand-face border in area 3b. For localization purposes, the inter-areal border lines were coregistered with other maps (C–D, I–J).

Figure 6. Single trial BOLD signal timecourse during noxious heat stimulation of the fingers

Statistical activation map to 47.5 °C stimulation was thresholded at p≤10⁻⁴ for displaying spatially distinct multiple activation foci (A). Color scale bar indicates the p value ranges. Single trial timecourses were plotted from six selected regions of interest (indicated by small color coded boxes and stars). (C–G). Yellow bars along the X-axis indicate the repeated 24 sec heat stimulation while the white space between bars indicate the 30 sec inter-stimulus interval without stimulus. Y-axis is the percentage BOLD signal change. Electrophysiological map was aligned to structural MRI image for the determination of cortical area, and the estimated inter-areal borders (dotted black lines in B). Neuronal receptive field properties at each penetration site were color coded as D1-green; D2-light blue; D3-red; D4-yellow; and D5-dark blue. Scale bar: 1mm.

Figure 7. Temporal profiles of noxious heat evoked BOLD signal changes in subregions of SI and M1 in monkey 1

(A) Timecourses of BOLD signals in six-selected response clusters in areas 3a, 3b, 1, 2, M1, and one control region during 24 sec 47.5°C heat stimulation (red line). Error bars indicate the standard deviations of signal change. (B) Plot of signal magnitudes and temporal profiles across cortical areas. Y-axis: % signal change; X-axis: time in sec.

Figure 8. Comparison of average BOLD timecourses and two gamma fittings across animals in different cortical areas

(A). Plot of average timecourses of BOLD signal changes in each area. (B) Two gamma curve fits of raw average BOLD timecourses from all cases. (C) Plot of normalized BOLD signal changes across areas. Grey bars: stimulus presentation period.