Background & Aims

Neuropathic pain (NP) is a prevalent condition typically associated with heightened pain responsiveness suggestive of central sensitization, shown experimentally through enhanced temporal summation of pain (TSP). Determining predictors of treatment outcome towards personalised treatment strategies for NP are of interest. White matter properties have been under-explored for this purpose and may reflect more stable “trait-like” markers than functional neuroimaging metrics. Previously, pre-treatment functional connectivity within and between the default mode network (DMN) and descending pain modulation pathway (including the periaqueductal gray, PAG) have been associated with ketamine effectiveness for chronic pain [1, 2]. Here we used a fixel-based approach to evaluate if pre-treatment white matter microstructure integrity in the DMN or DMN-PAG pathway is associated with pain relief and reductions in TSP (reflecting attenuated central sensitization) following ketamine treatment for NP.

Methods

We retrospectively analyzed data from 70 people: 35 with NP (17 female, 18 male) who underwent ketamine treatment and 35 age/sex-matched healthy controls (HCs). Pain relief was calculated as a % change in pain intensity from pre- to 1-month post-treatment. Those with ?30% pain relief were considered responders.

Participants underwent 1) TSP testing using 10 thermal stimuli applied to the forearm at 0.33 Hz. The treatment effect on TSP was calculated as the pre- minus 1-month post-treatment TSP, and 2) 3T MRI (GE Medical Systems, Chicago) to acquire diffusion-weighted imaging data.

We used a fixel-based analysis [3] to evaluate white matter microstructure (fibre density, FD) within nodes of the DMN (medial prefrontal cortex and posterior cingulate cortex / precuneus) and DMN-PAG pathways. We assessed differences in FD between responders, non-responders and HCs, and in NP we determined relationships between structural integrity and pain relief and absolute change in TSP.

Results

Following ketamine treatment, 18 individuals were classified as responders (10 male, 8 female; mean ± SD pain intensity NRS pre-treatment: 7 ± 1; post-treatment: 3 ± 2; mean ± SD pain relief: 58 ± 23%) and 17 as non-responders (8 male, 9 female; pain intensity pre-treatment: 8 ± 1; post-treatment: 8 ± 1; pain relief: 2 ± 9%).

A total of 28 NP and 27 HCs were included in TSP analysis due to some exclusion factors. TSP was higher in the pre-treatment NP group compared to HCs (mean ± SEM TSP: pre-treatment: 16 ± 2; HC: 8 ± 2). Following ketamine, TSP in the NP group was reduced to 11 ± 2 (a change of -5 ± 2).

Pre-treatment white matter microstructure within the DMN and DMN-PAG pathways did not differentiate ketamine responders from non-responders or HCs. However, pre-treatment FD in a region of the anterior limb of the internal capsule correlated with pain relief. Moreover, pre-treatment FD in the DMN and DMN-PAG negatively correlated with changes in TSP.

Conclusions

Our main findings show an association between pre-treatment white matter microstructure integrity in a region of the anterior limb of internal capsule and ketamine analgesia. Furthermore, we found that white matter microstructure integrity in the DMN and DMN-PAG pathway was associated with the degree to which ketamine reduces central sensitization. Thus, fixel metrics of white matter microstructure holds promise to predict ketamine treatment outcomes for NP.

References

[1] Bosma, R.L., Cheng, J.C., Rogachov, A., Kim, J.A., Hemington, K.S., Osborne, N.R., Venkat Raghavan, L., Bhatia, A. and Davis, K.D., 2018. Brain dynamics and temporal summation of pain predicts neuropathic pain relief from ketamine infusion. Anesthesiology, 129(5), pp.1015-1024.

[2] Motoyama, Y., Oshiro, Y., Takao, Y., Sato, H., Obata, N., Izuta, S., Mizobuchi, S. and Kan, S., 2019. Resting-state brain functional connectivity in patients with chronic pain who responded to subanesthetic-dose ketamine. Scientific Reports, 9(1), p.12912.

[3] Dhollander, T., Clemente, A., Singh, M., Boonstra, F., Civier, O., Duque, J.D., Egorova, N., Enticott, P., Fuelscher, I., Gajamange, S. and Genc, S., 2021. Fixel-based analysis of diffusion MRI: methods, applications, challenges and opportunities. Neuroimage, 241, p.118417.

Presenting Author

Emily Mills

Poster Authors

Emily Mills, PhD

PhD

University Health Network, Toronto, ON, Canada

Lead Author

E-mail

Rachael Bosma

PhD

Women's College Hospital

Lead Author

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Anton Rogachov

PhD

Krembil Brain Institute and University of Toronto

Lead Author

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Joshua Cheng

PhD

University of Toronto and University Health Network, Toronto, ON, Canada

Lead Author

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Natalie Osborne

Northshore University HealthSystem

Lead Author

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Junseok Kim

PhD

University of Toronto and University Health Network, Toronto, ON, Canada

Lead Author

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Ariana Besik

MSc

University Health Network, Toronto, ON, Canada

Lead Author

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Anuj Bhatia

MD

Toronto Western Hospital

Lead Author

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Karen Davis

PhD

University of Toronto and University Health Network, Toronto, ON, Canada

Lead Author

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Topics

  • Pain Imaging