Comparison of DOMS-related activation by contraction and physical stimulation in M1 and S1.

<p>Multi studies of activations by both stimuli in a standardized Talairach brain shown as activation maps <b>(a–f)</b> and as increases in hemodynamic response function <b>(g–j)</b>. Clusters were calculated by GLM contrasts between painful and non-painful stimulation conditions (t≥5). <u>Legend</u>: Light blue: activation by painless contraction; dark blue: activation by painless physical stimulation; magenta: common activation by both painless stimuli; dark green: activation by painful contraction; light green: activation by painful physical stimulation; orange: common activation by both painful stimuli. <b>(a)</b> coronal section showing orientation of sagittal sections b and c and transverse sections d, e and f. <b>(b, c)</b> Sagittal sections of the parasagittal cortical areas of both hemispheres illustrating the area somatotopically related to the respective thigh (M1 and S1). Painful stimulation –contraction as well as physical stimulation- activate areas expanding into the cingulate cortex. <b>(d, e, f)</b> Painless physical stimulation is centred in postcentral gyrus S1. Both contraction and physical stimulation activate precentral M1. Activation in response to painful stimulation expands over large areas of M1 and S1 with physical stimulation resulting in more widespread activation than voluntary contraction. (g–j) timeline of the BOLD-signal (average over 5 stimulus periods) in the respective clusters marked with circles in map (d). Red, painful condition, blue, non-painful condition, black bar, stimulus condition in event-related block design; error bars represent S.E.M. (g) contraction of the left thigh (control) and contraction of the right painful thigh both lead to an increase in BOLD signal in the right hemisphere in areas of the pre- and postcentral gyrus (blue timeline: control; red timeline: painful contraction of right-sided quadriceps); (h) painful contraction of the right thigh (red timeline) reveals a large increase in BOLD signal in somatotopically related areas of the left pre- and postcentral gyrus (red), similarly, the control contraction leads to coactivation in the left hemisphere (blue timeline); (i) BOLD signal in response to left-sided and right-sided physical stimulation (blue timeline and red timeline); (j) right-sided painful physical stimulation (red timeline), but not left-sided physical stimulation (blue timeline), leads to an increase in BOLD signal in the left-sided somatotopically related areas. Note: panels d-f were magnified by 40% in comparison to a–c.</p

Comparison of DOMS-related activation by contraction and physical stimulation in the cingulate cortex.

<p>Multi studies of activation following both means of stimulation in a standardized Talairach brain. Clusters were calculated by GLM contrasts between painful and non-painful stimulation conditions (t≥4.5). Dark green: activation by painful contraction; light green: activation by painful physical stimulation; orange: common activation by both painful stimuli. <b>a, b.</b> coronal and transverse section showing orientation of sagittal sections in c and d. <b>c.</b> Painful physical stimulation activates more widespread areas of the right posterior ACC. <b>d.</b> In the CMA contraction and physical stimulation activate similar areas, albeit physical stimulation-activated areas are more anterior. <b>e, f.</b> timeline of the BOLD-signal (average over 5 stimulus periods) for painful contraction (e) and physical stimulation (f) shown as red timelines in the same cluster of the CMA (circled cluster in b and d) compared to the respective painless contraction/stimulation (blue timeline). Painless contraction, but not physical stimulation, leads to coactivation of the contralateral cortical area.</p

ROI-based evaluation results for the comparison of BR and BF.

<p>Visualizations of F-values (<i>A</i>) and t-values from the post-hoc paired t-test (<i>B</i>). As in the previous figure, ROIs for intersections of areas with eccentricity intervals are arranged in a pattern corresponding to flat maps of the visual cortex (LH: left hemisphere, RH: right hemisphere, CF: calcarine fissure). In panel (<i>A</i>) the numbers of voxels showing significant effects-of-interest that were included in evaluations are documented as white numbers.</p

Stimulus conditions and experimental paradigm.

<p><b>a.</b> Muscle pain was evoked in a muscle group suffering DOMS during an fMRI measurement by two paradigms: voluntary contraction of the painful muscle (paradigm 1) and painful physical stimulation of the sore muscles with a 1.75 kg heavy marble rolling pin (paradigm 2). <b>b.</b> The scanning procedure included 5 repetitions of the same stimulus combination (5x EPI). A Scout epoque - used to determine the position of the subject's head within the scanner- is followed by the acquisition of the high-resolution anatomical MPRAGE data set. A short EPI sequence is required to accustom the subject to the unfamiliar noise of the following EPI scans. The numbers in the block design (x-axis) are equivalent to scanning frames and one frame corresponds to 3 s acquisition time. The conditions were as follows: 1: resting condition (baseline); 2: contralateral painless quadriceps contraction or painless physical stimulation; 3: ipsilateral painful quadriceps contraction or painful physical stimulation.</p

BOLD responses, individual flat map and maximum probability map for group analysis.

<p>(A) BOLD time series for the three conditions BF (red), BR (green) and BFR (blue), estimated for the individual visual areas (V1–V4 and MT+) and eccentricity intervals (E1–E5) within V1 to V4, averaged across all subjects (error bars: standard error of the mean). (B, C) Exemplary results on the individual flat map for a representative subject. The t-contrasts BFR/BR (B) and BFR/BF (C) are shown projected onto the flat maps of the subject’s left and right hemisphere (negative t-values: blue scale, positive t-values: red-to-yellow scale). Visual areas are separated by black lines and eccentricity intervals by green lines. (D) Maximum-probability flat maps (MPMs) of intersections of visual areas and eccentricity intervals for the subject group in normalized coordinates for the left and the right hemisphere. Areas are shown in different colors for better delineation (LH: left hemisphere, RH: right hemisphere).</p

Brain regions with increased activity during DOMS: comparison between painful voluntary contraction and physical stimulation with a rolling pin.

<p>p-values <0.000005 are indicated as “*” (uncorrected); S1: primary somatosensory cortex, M1: primary motor cortex; S/IPL: superior/inferior parietal lobule; STG: superior temporal gyrus; SSA: somatosensory association cortex; SMA: supplementary motor area; ACC: anterior cingulate cortex; PCC: posterior cingulate cortex; CMA: cingulate motor area; BA: Brodmann Areas or closest BA in vicinity; “Pain”, T-values are indicated for Pain = painful condition and Con = control condition and contrast; x, y, z: Talairach coordinates.</p

Three-dimensional projection of DOMS-related activation clusters onto the cortical surface.

<p>The result of the multi study analysis is projected onto the surface reconstruction of a single brain after Tailarach transformation in response comparing <b>(a)</b> contraction and <b>(b)</b> physical stimulation<b>.</b> Dotted lines represent the central sulcus; SMA: supplementary motor area, M1: primary motor area, S1: primary sensory area; P Lobule: paracentral lobule; Color code: blue-green clusters: higher changes in BOLD-signal during <b>(a)</b> non-painful contraction or <b>(b)</b> non-painful physical stimulation of the left-sided thigh, red-yellow: higher changes in BOLD-signal during <b>(a)</b> painful contraction or <b>(b)</b> painful physical stimulation of the right-sided painful thigh; strong activation was located bilaterally in the cingulate motor area.</p

ROI-based evaluation results for conditions BFR and BR.

<p>F-test and t-test results are visualized for the 41 ROIs per hemisphere. Panels (A) and (C) show the results of the factor condition for the F-test for BFR/BR, and (B) and (D) show them for BFR/BF. ROIs for intersections of visual areas and eccentricity intervals (E1–E5) are arranged schematically in a pattern corresponding to flat maps of the visual cortex (LH: left hemisphere, RH: right hemisphere, CF: calcarine fissure) (A,B), or are shown as their masks projected on the flat map for the subject group (C, D). Significance level was set to 5%, Bonferroni corrected (p<0.05/40 = 0.00125). Significant ROIs are colored in a red-to-yellow scale, non-significant ROIs are shown with grey levels. The numbers within the ROIs in (A) and (C) denote the number of voxels that showed significant effects of stimulation (total volumes can be obtained by multiplying these with the voxel volume, V = 3×3×3 mm³). Note the different scale limits for F-values. Within intersection ROIs that showed significant effects of stimulation, a post-hoc paired t-test was performed. In panels (E) and (F), the t-values for BFR–BR and BFR–BF are visualized. The comparison BFR–BR (E) shows exclusively negative t-values for ROIs in areas V3/V4 at higher eccentricities. In BFR–BF (F) only positive t-values were found, mainly for ROIs in V1/V2 at lower eccentricities.</p

Comparison of DOMS-related activation by contraction and physical stimulation in the cerebellum.

<p>Multi studies of activation following both means of stimulation in a standardized Talairach brain. Clusters were calculated by GLM contrasts between painful and non-painful stimulation conditions (t≥5). Dark green: activation by painful contraction; light green: activation by painful physical stimulation; orange: common activation by both painful stimuli. <b>a, b, d.</b> coronal and sagittal section showing orientation of transverse sections in c. <b>c.</b> In the cerebellum, contraction activates widespread areas. <b>d, e.</b> timeline of the BOLD-signal (average over 5 stimulus periods) for painful contraction (d) and painful stimulation (e) in the same cluster of the anterior cerebellum (circled cluster in c) shown as red timelines. Painless contraction/ painless physical stimulation shown as blue timeline.</p

Comparison of DOMS-related activation by contraction and physical stimulation in the insular cortex and ventral posteromedial thalamic nucleus (VPM).

<p>Multi studies of activation following both means of stimulation in a standardized Talairach brain. Clusters were calculated by GLM contrasts between painful and non-painful stimulation conditions (t≥5). Dark green: activation by painful contraction; light green: activation by painful physical stimulation; orange: intersection. <b>a, b.</b> coronal and sagittal section illustrating orientation of transversal sections in c and d. <b>a, b, c, d.</b> Physical stimulation resulted in much larger areas of activation bilaterally in the AIC (a, c) and the left VPM (d), while activation in the MIC and PIC largely overlapped with areas activated during the contraction-related task (b, c). <b>e, f.</b> timeline of the BOLD-signal (average over 5 stimulus periods) for painful contraction (red) versus physical stimulation (f) in the same area of the left MIC (circled cluster in c). Painless contraction, but not painless physical stimulation) leads to coactivation during painless contraction (blue) as seen in <b>Fig. 3</b>; <b>g, h.</b> timeline of the BOLD-signal (average over 5 stimulus periods) for painful contraction versus painful physical stimulation (red timelines) (f) in the same area of the left VPM (circled cluster in d). Again, painless contraction, but not physical stimulation leads to coactivation (blue timelines).</p