Background & Aims

Patients with chronic pain report cognitive deficits,1 and have abnormalities in cognitive brain networks.2 Pain and cognitive demand compete for limited brain resources, with higher pain impacting cognitive task performance, and high cognitive load reducing pain intensity.3 Acute experimental pain during a cognitive task has an additive effect on brain activity in regions associated with cognitive load.4 The claustrum modulates cognitive networks, and is active during experimental pain. Connectivity between the right claustrum and medial dorsolateral prefrontal cortex (medDLPFC) is associated with cognitive tasks. Migraine patients have pathological activity of the claustrum and a lateral DLPFC (latDLPFC).5 However, the structural substrate of these connections has yet to be identified. Here, we aim to determine whether there are direct structural between the RCL and latDLPFC and medDLPFC, and whether the strength of these connections differ.

Methods

Ultra-high field (7T) diffusion weighted imaging (DWI) data from 174 participants (68 males, 106 females; mean age ± SD: 29.6 ± 3.1) were used from the Washington University and University of Minnesota (WU-Minn) S1200 Release from the Human Connectome Project (HCP).6 Preprocessed DWI data were downloaded from the HCP7,8, which underwent the generic HCP MR diffusion preprocessing pipeline (v3.19.0). Probabilistic tractography between RCL, latDLPFC and medDLPFC were run using FSL’s Probtrackx2 with 10,000 streamlines estimated per ROI voxel.9,10 The insula, thalamus, other DLPFC region (ie. medDLPFC excluded when analyzing RCL-latDLPFC connection), along with a mid-sagittal plane acted as exclusion regions in the analysis. To compare the differences in connectivity strengths between circuits, a non-parametric related-samples Wilcoxon signed-rank test was run, with significance set a p < 0.05.

Results

Direct comparisons between the RCL-latDLPFC and the RCL-medDLPFC found significant difference between the two circuits (W = 12607, p-FDR < 0.001), with a stronger connection observed in the RCL-medDLPFC. Tractogram analyses of the paths show that white matter connections between the RCL and either the latDLPFC and the medDLPFC, take two paths: (1) traveling from RCL posteriorly and superiorly along the middle longitudinal fasciculus to the arcuate fasciculus before joining the superior longitudinal fasciculus and on to the medDLPFC/latDLPFC; or (2) traveling from RCL directly superior along the superior thalamic radiation before connecting to the superior longitudinal fasciculus and then to the medDLPFC/latDLPFC. RCL-latDLPFC favors path 2, but the circuits appear to overlap superior to the insula before the RCL-latDLPFC circuit branches along the superior longitudinal fasciculus to latDLPFC.

Conclusions

These findings show a unique RCL-latDLPFC connection in healthy controls that may drive aberrant cognitive activity within migraine patients. The RCL appears to have a stronger structural connectivity with medDLPFC than latDLPFC, indicating a preferential RCL-DLPFC that may function in cognitive tasks in healthy individuals. Further, the RCL-latDLPFC and RCL-medDLPFC appear to have distinct structural connectivity white matter paths. These results provide evidence for the structural correlates of a potential RCL-latDLPFC functional circuit driving cognitive impairments in chronic pain.

References

1Baker, K. S., Gibson, S., Georgiou-Karistianis, N., Roth, R. M. & Giummarra, M. J. Everyday Executive Functioning in Chronic Pain: Specific Deficits in Working Memory and Emotion Control, Predicted by Mood, Medications, and Pain Interference. Clin J Pain 32, 673-680 (2016). https://doi.org/10.1097/ajp.0000000000000313
2Baliki, M. N., Geha, P. Y., Apkarian, A. V. & Chialvo, D. R. Beyond feeling: chronic pain hurts the brain, disrupting the default-mode network dynamics. J Neurosci 28, 1398-1403 (2008). https://doi.org/10.1523/jneurosci.4123-07.2008
3Buhle, J. & Wager, T. D. Performance-dependent inhibition of pain by an executive working memory task. Pain 149, 19-26 (2010). https://doi.org/10.1016/j.pain.2009.10.027
4Seminowicz, D. A. & Davis, K. D. Interactions of pain intensity and cognitive load: the brain stays on task. Cereb Cortex 17, 1412-1422 (2007). https://doi.org/10.1093/cercor/bhl052
5Stewart, B. W. et al. Pathological claustrum activity drives aberrant cognitive network processing in human chronic pain. bioRxiv (2023). https://doi.org/10.1101/2023.11.01.564054
6Van Essen, D. C. et al. The WU-Minn Human Connectome Project: An overview. NeuroImage 80, 62-79 (2013). https://doi.org/https://doi.org/10.1016/j.neuroimage.2013.05.041
7Glasser, M. F. et al. The minimal preprocessing pipelines for the Human Connectome Project. NeuroImage 80, 105-124 (2013). https://doi.org/https://doi.org/10.1016/j.neuroimage.2013.04.127
8Jenkinson, M., Bannister, P., Brady, M. & Smith, S. Improved optimization for the robust and accurate linear registration and motion correction of brain images. NeuroImage 17, 825-841 (2002). https://doi.org/S1053811902911328 [pii]
9Behrens, T. E. et al. Characterization and propagation of uncertainty in diffusion-weighted MR imaging. Magnetic resonance in medicine 50, 1077-1088 (2003). https://doi.org/10.1002/mrm.10609

Presenting Author

Matthew Cormie

Poster Authors

Matthew Cormie

MSc

University of Toronto

Lead Author

Brent Stewart

University of Maryland

Lead Author

David Seminowicz PhD

University of Western Ontario

Lead Author

Topics

  • Pain Imaging