Continuous Descending Modulation of the Spinal Cord Revealed by Functional MRI.

Spontaneous variations in spinal cord activity may arise from regulation of any of a number of functions including sensory, motor, and autonomic control. Here, we use functional MRI (fMRI) of healthy participants to identify properties of blood oxygenation-level dependent (BOLD) variations in the spinal cord in response to knowledge that either a noxious stimulus is impending, or that no stimulus is to be expected. Expectation of a noxious stimulus, or no stimulus, is shown to have a significant effect on wide-spread BOLD signal variations in the spinal cord over the entire time period of the fMRI acquisition. Coordination of BOLD responses between/within spinal cord and brainstem regions are also influenced by this knowledge. We provide evidence that such signal variations are the result of continuous descending modulation of spinal cord function. BOLD signal variations in response to noxious stimulation of the hand are also shown, as in previous studies. The observation of both continuous and reactive BOLD responses to emotional/cognitive factors and noxious peripheral stimulation may have important implications, not only for our understanding of endogenous pain modulation, but also in showing that spinal cord activity is under continuous regulatory control

affective_sfmri.zip

<div>Healthy participants were imaged at 3 tesla (Siemens Magnetom Trio) using a T2-weighted single-shot </div><div>fast spin-echo sequence (HASTE) for BOLD contrast and high image quality in the brainstem and spinal cord.</div><div>Images were acquired in contiguous sagittal planes spanning from below the T1/T2 intervertebral disc to above</div><div>the thalamus.</div><div>Participants were familiarized with the study paradigm in advance, and temperatures were calibrated to produce</div><div>a pain rating of 50 on a 100 point scale (corresponding to "moderate pain").  Variations in pain ratings occured across</div><div>repeated runs but the temperature was not varied after the initial calibration.</div><div>Multiple runs were acquired in each participant in a randomly interleaved manner.  For "stim" runs the participant was informed 1 minute after the start of the run that a stimulus would be applied. The stimulus was applied </div><div>starting 1 minute 50 seconds after the start of the run, and consisted of 10 brief contacts of heated thermode against the skin overlying the thenar eminence on the right hand (C6 dermatome).  Contacts lasted 1.5 seconds and onsets were every 3 seconds, for a total of 30 seconds of stimulation. After the stimulus scanning was continued for 2 minutes 10 seconds.  The total duration of each run was 4 minutes 30 seconds.</div><div>For "nostim" runs participants were informed 1 minute after the start of the run that a stimulus woudl not be applied.</div><div>The run continued for the total duration of 4 minutes and 30 seconds.</div><div>A rest period of 2 minutes was allowed between repeated runs to allow receptors on the skin to recover and to</div><div>acquire pain ratings from the participant.</div><div>The total TR for each volume is 6.75 seconds (TR is specified per slice for HASTE sequences, and the actual slice TR was 750 msec, not the 720 msec specified in the image headers), and a total of 40 volumes were acquired for each run. </div><div>A total of 5 runs were acquired for each study type (stim or nostim) in each participant and these data are to </div><div>be combined into one data set for each study type. One exception is participant 17 with 4 runs acquired in the</div><div>nostim condition.</div><div>Participant information and pain ratings for each run are provided in the Excel files.</div

Average time-courses of spinal cord voxels which are significantly correlated with seed regions in (A) (left) the right-dorsal region of C6, and (B) (right) the left-dorsal region of C6.

<p>The voxels are as depicted in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0167317#pone.0167317.g002" target="_blank">Fig 2</a>. Signal intensity patterns obtained during stimulation conditions are shown in blue, and the no-stimulation condition is shown in red. Time-course data were converted to z-scores with mean values of zero. Error bars indicate the standard-error-of-the-mean across fMRI runs. Red and blue asterisks (*) indicate values which are significantly different than the mean value of zero, at p < 10⁻⁴, for no-stimulation and stimulation runs, respectively. Black asterisks indicate intensity values which are significantly different between the two study conditions, at p < 10⁻⁴. Times are indicated corresponding to when participants were informed of the study type, the start of the stimulation period (for studies with heat stimulation), and the time at which the rating scale was displayed in all studies.</p

A structural equation modeling (SEM) analysis was used to investigate input signaling to the spinal cord dorsal horn (DH) in the 6^th cervical segment, from the nucleus raphe magnus (NRM), nucleus gigantocellularis (NGc), and the dorsal reticular nucleus (DRt).

<p>Results are shown for the sub-regions (right panel) which provided the best fit to the BOLD signal intensity variations in the spinal cord DH, when a stimulus was expected and applied, and when a stimulus was not expected and not applied (i.e. no-stimulation). The time-series responses in the identified regions are shown (left panels) for each study condition, as well as the SEM fit to the spinal cord time-series responses (red lines). Plotted values are the average over the region across runs/participants and error bars indicate the standard error of the mean (SE) across participants. The SEM weighting factors that were determined, and used for the fit, are indicated below each time-series plot (± SE). Periods are highlighted when the participants were informed of the study type, and when the stimulus was applied, or was not applied.</p

Connectivity between voxels and selected seed regions.

<p>Anatomical locations of regions with time-courses that are significantly correlated with seed regions in the right/left and dorsal/ventral regions of C6, are shown in colour overlaid on gray-scale anatomical images. Each frame represents a 1 mm thick transverse slice, and slices are shown every 4 mm along the cord (horizontally in the figure) to depict the rostral-caudal range along the spinal cord, and a section of the medulla. The seed regions are identified by the highly correlated (dark red) voxels within the regions. Positions along the cord/brainstem are indicated relative to the seed region center, in millimeters.</p

Dynamic variations in the correlation between time-series responses are shown for the regions identified by the SEM analysis as having the strongest relationships (i.e. the best fit).

<p>Time intervals spanning 41 seconds were selected throughout the fMRI paradigm, and the correlation was computed to investigate how the relationships evolved. Correlations between the cord DH time series and the NRM (red), NGc (green), and DRt (blue), are shown for the no-stimulation condition (brighter tones), and with a stimulus applied (darker tones). Positive correlations are most notable prior to the stimulation period, and are primarily in the NRM, whereas negative correlations predominate during and after the stimulation period, and are primarily in the DRt. Significant correlations are inferred at |R| ≥ 0.74 (indicated by horizontal lines).</p