Background & Aims
Pain experience is strongly influenced by prior experience[1]. One example of this is offset analgesia, a phenomenon in which pain intensity from a noxious-range stimulus is rated much lower following the experience of a more intense stimulus compared with a constant noxious stimulus[2, 3]. Offset analgesia is thought to be centrally-mediated[4]; however, its neural correlates remain minimally studied. In volunteers, 3T fMRI studies have implicated descending pain modulatory structures[5-7]. In a separate line of work, studies of noxious stimulus increases confirmed that onset hyperalgesia can also be measured, whereby subjective pain intensity from a noxious-range stimulus is much higher following the experience of a less intense stimulus [8]. There have been no studies examining the neural correlates of onset hyperalgesia and no studies of offset analgesia using 7T fMRI. The current 7T study sought to identify brain structures associated with offset analgesia and onset hyperalgesia.
Methods
Subjects: N=21 healthy adults(11F), average age=31. Stimuli: An fMRI-compatible thermode on the inner left calf. Following heat-pain thresholding, subjects underwent imaging during a pain task while continuously rating pain perception with a finger-span device. The task had 4 conditions(offset, offset control, onset, onset control, 3 repetitions each). MRI data: Siemens 7T at the SFVAHS: 0.7 mm iso T1s [9] with a B0 map for distortion correction. The functional EPI had TR=0.65s, IPAT=2, MB factor=5, 2 mm voxels with 1140 vols. Analysis: We used afni_proc.py[10]. T1s were nonlinearly registered to MNI space[11,12]. Functional data was cleaned of noise[13-15] and smoothed at 5mm. The HRF was modeled using TENT functions in 3dDeconvolve from stimulus start(50 sec, 26 TENTs). Linear mixed effects were modeled with 3dLMEr with condition(stimulus, control) and TENT function order with subject as a random factor[16]. Corrected, voxel-level results were thresholded at p=0.001[17].
Results
In-scanner subjective pain ratings showed the expected modulation related to offset analgesia and onset hyperalgesia heat stimuli. Specifically, paired t-test showed significantly lower average pain during the offset stimulus compared to the respective control condition (offset: 18.5±4.2; control: 37.9±4.9; t(20)=-4.59, p=0.0001). Likewise, we observed significantly higher average pain during the onset stimulus compared to the respective control condition (onset: 79.5±4.7; control: 70±5.8; t(20)=2.81, p=0.005). With fMRI, several regions showed a “flipped” activation pattern. Specifically, striatal and cingulate/SMA activation increased during offset while decreasing during onset contrasts. Conversely, medial prefrontal activation decreased during offset while increasing during onset contrasts. Furthermore, increased activation within dorsolateral prefrontal and anterior thalamus were observed during offset and onset contrasts, respectively.
Conclusions
We observed significant subjective and neural changes during both offset analgesia and onset hyperalgesia. Our findings in offset analgesia align with previous imaging studies. Notably, the distinct and overlapping neural activation patterns observed during onset hyperalgesia offer novel insights into the mechanisms underlying this phenomenon, possibly through attentional and/or reward-related modulation. Considering that offset analgesia and onset hyperalgesia likely collectively reflect temporal contrast enhancement[18], pinpointing the overlapping and distinct neural substrates for these phenomena will offer unique insights into how pain perception is either attenuated or intensified based on prior pain experiences and/or expectations.
References
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Presenting Author
Salvatore Torrisi
Poster Authors
Salvatore Torrisi
PhD
University of California, San Francisco
Lead Author
Sergio Garcia Guerra
NCIRE
Lead Author
Tiffany Toor BS
Emotion and Pain Laboratory, San Francisco Veterans Affairs Health Care Center
Lead Author
Emily Murphy MA
Emotion and Pain Laboratory, San Francisco Veterans Affairs Health Care Center
Lead Author
Alan N. Simmons PhD
San Diego Veterans Affairs Healthcare Center, San Diego, CA
Lead Author
Irina Strigo
Emotion and Pain Laboratory, San Francisco Veterans Affairs Health Care Center
Lead Author
Benedict Alter
University of Pittsburgh
Lead Author
Topics
- Pain Imaging