Pathological claustrum activity drives aberrant cognitive network processing in human chronic pain

Abstract

Aberrant cognitive network activity and cognitive deficits are established features of chronic pain. However, the nature of cognitive network alterations associated with chronic pain and their underlying mechanisms require elucidation. Here, we report that the claustrum, a subcortical nucleus implicated in cognitive network modulation, is activated by acute painful stimulation and pain-predictive cues in healthy participants. Moreover, we discover pathological activity of the claustrum and a region near the posterior inferior frontal sulcus of the right dorsolateral prefrontal cortex (piDLPFC) in migraine patients during acute pain and cognitive task performance. Dynamic causal modeling suggests a directional influence of the claustrum on activity in this piDLPFC region, and diffusion weighted imaging verifies their structural connectivity. These findings advance understanding of claustrum function during acute pain and provide evidence of a possible circuit mechanism driving cognitive impairments in chronic pain.

Keywords: BOLD fMRI; DCM; DWI; clinical research; cognition; cognitive control; cortical networks; effective connectivity; executive function; headache.

Figure 1.. Claustrum BOLD signal increases in response to experimental heat pain

(A) MNI template displaying LCL (blue) and RCL (red). (B) Experimental timeline for each trial in dataset 1 pain scans. (C) Average FIR time series of LCL BOLD percent signal change showed a significant increase at t = 32.5 s (pain onset: t = 3.011, p-FDR = 0.023) in dataset 1 healthy participants (n = 34). (D) Average FIR time series of RCL BOLD percent signal change showed significantly greater signal during pain than warm time points (t = 2.882, p-FDR = 0.004). See also Figure S1. Error bars in all figures show standard error of the mean across subjects unless otherwise noted. * represents a p value of < 0.05, ** < 0.01, and *** < 0.001. Caduceus symbol signifies dataset 1 results. Unfilled bars/plot points signify healthy participant results. Abbreviations: ALFF, amplitude of low-frequency fluctuations; BOLD, blood oxygenation level dependent, DCM, dynamic causal modeling; DWI, diffusion weighted imaging; FIR, finite impulse response; GLM, general linear model; HCP, human connectome project; HRF, hemodynamic response function; LaINS, left anterior insula; LCL, left claustrum; LinsFl, left insular flank (see text); LV, latent variable; MNI, Montreal Neurological Institute; MSIT, multi-source interference task, piDLPFC, posterior inferior right dorsolateral prefrontal cortex (see text); psDLPFC, posterior superior right dorsolateral prefrontal cortex (see text); RaINS, right anterior insula; RCL, right claustrum; RInsFl, right insular flank (see text); ROI, region of interest; TR, repetition time; and WM, white matter.

Figure 2.. Claustrum BOLD signal is distinguishable from neighboring regions

(A) Left and middle: average anatomical scan from 56 dataset 1 subjects including LCL (blue), LInsFl (light blue), LaINS (green), RCL (red), RInsFl (pink), and RaINS (orange) ROIs. Right: Same z stack as left and middle with ROIs overlaid on a dataset 1 healthy participant’s preprocessed functional resting-state image. (B and C) Average FIR time series of dataset 1 healthy participant thermal stimulation trials displayed greater increases at pain onset and pain offset (black arrows) in (B) LInsFl vs. LCL and (C) RInsFl vs. RCL BOLD percent signal change. No statistical tests were performed on (B) and (C). (D) Average parameter estimation (regression slope) detected significantly different activation at pain onset between LCL and LaINS (t = 4.086, p-FDR < 0.001), LCL and LInsFl (t = 3.266, p-FDR = 0.002), RCL and RaINS (t = 5.816, p-FDR < 0.001), and RCL and RInsFl (RCL vs. RInsFl: t = 5.039, p-FDR < 0.001). (E) Significantly different activation at pain offset was observed between LCL and LaINS (t = 2.133, p-FDR = 0.037), LCL and LInsFl (t = 3.551, p-FDR = 0.001), RCL and RaINS (t = 2.773, p-FDR = 0.0096), and RCL and RInsFl (t = 4.095, p-FDR < 0.001). See also Figures S2, S3, and S6, and Tables S3–S5. Assessment of region effects via unpaired t tests was limited to comparisons of LCL vs. LaINS, LCL vs. LInsFl, RCL vs. RaINS, and RCL vs. RInsFl.

Figure 3.. Claustrum BOLD signal increases in response to a pain-predictive cue

(A) Timeline of thermal stimulation for each trial in dataset 2 (n = 39 healthy participants). (B) LCL displayed significant activation in response to the cue preceding thermal stimulation (t = 3.172, p-FDR = 0.030) but not to the onset of any thermal stimulation conditions following the cue (intense onset: t = 1.034, p-FDR = 0.615; moderate onset: t = 0.460, p-FDR = 0.811; slight onset: t = 0.699, p-FDR = 0.699; warm onset: t = 0.153, p-FDR = 0.879). (C) RCL did not display significant activation in response to the cue (t = 2.341, p-FDR = 0.123) or the onset of any thermal stimulation conditions (intense onset: t = 1.416, p-FDR = 0.550; moderate onset: t = 0.707, p-FDR = 0.699; slight onset: t = 1.176, p-FDR = 0.615; warm onset: t = 0.319, p-FDR = 0.835). (D) Significantly different activation in response to the auditory cue was observed between LCL and LInsFl (t = 2.713, p-FDR = 0.033), but not between LCL and LaINS (t = 0.009, p-FDR = 0.993), RCL and RaINS (t = 0.059, p-FDR = 0.993), or RCL and RInsFl (t = 1.161, p-FDR = 0.499). (E) In response to the onset of intense pain, significantly different activation was observed between LCL and LaINS (t = 2.564, p-FDR = 0.049), but not between LCL and LInsFl (t = 1.817, p-FDR = 0.098), RCL and RaINS (t = 1.587, p-FDR = 0.117), or RCL and RInsFl (t = 1.816, p-FDR = 0.098). (F) In response to the offset of intense pain, significantly different activation was observed between LCL and LaINS (t = 3.745, p-FDR = 0.001), LCL and LInsFl (t = 2.553, p-FDR = 0.017), RCL and RaINS (t = 3.637, p-FDR = 0.001), but not between RCL and RInsFl (t = 1.938, p-FDR = 0.056). Assessment of condition effects in (B) and (C) via unpaired t tests was limited to comparisons of cue with thermal stimulation onset conditions. Assessment of region effects via unpaired t tests in (D)–(F) was limited to comparisons of LCL vs. LaINS, LCL vs. LInsFl, RCL vs. RaINS, and RCL vs. RInsFl. Speaker symbol signifies dataset 2 results.

Figure 4.. Migraine patients engage a pain-responsive prefrontal cortex region during pain-free cognitive task processing

(A) Top left: the multivariate pattern accounting for the most variance (LV1) in brain activity (increases-red, decreases-blue) associated with increasing cognitive load in dataset 1 healthy controls (n = 35, LV1: p < 0.001). Slices from z = 30, 40, 50, and 60. Top right: LV1 of brain activity associated with cognitive task conditions in dataset 1 migraine patients (n = 112, LV1: p < 0.001). Slices from z = 30, 40, 50, and 60. Bottom left: voxels exhibiting significant signal increases in LV1 of healthy controls (blue), LV1 of migraine patients (red), and their overlap (purple). Slices from z = 54, 59, and 64. Bottom right: clusters (>50 voxels) depicting significantly different cognitive task-associated signal changes between patients and controls (patients vs. controls LV1: p < 0.048). Slices from z = 31, 46, and 57. All significant clusters exhibited greater signal in patients than controls. (B) Left: piDLPFC (gold) depicted alongside healthy controls’ cognitive task LV1 signal increases (blue). Middle: psDLPFC (purple) similarly overlaid. Right: shapes and locations of piDLPFC and psDLPFC. (C) Left: cognitive task-induced piDLPFC activation was only observed in patients during difficult onset (t = 10.129, p-FDR < 0.001) and difficult block (t = 5.178, p-FDR < 0.001) conditions. Two-way ANOVA found significant main effects of group (F (1, 580) = 20.38, p < 0.001), condition (F (3, 580) = 18.84, p < 0.001), and their interaction (F (3, 580) = 10.20, p < 0.001), and post-hoc comparisons detected significantly greater activation in patients than controls during the difficult onset condition (t = 7.003, p < 0.001). Right: significant psDLPFC activation was detected in cognitive task conditions in healthy controls (easy onset: t = 2.835, p-FDR = 0.008; difficult onset: t = 11.328, p-FDR < 0.001; difficult block: t = 9.327, p-FDR < 0.001) and migraine patients (easy onset: t = 3.956, p-FDR < 0.001; difficult onset: t = 14.767, p-FDR < 0.001; difficult block: t = 11.980, p-FDR < 0.001). No main effect of group was detected (F (1, 580) = 0.939, p = 0.333). (D) Left: average FIR time series of psDLPFC BOLD percent signal change during thermal stimulation in healthy controls (n = 34) and migraine patients (n = 105). Middle: average FIR time series of piDLPFC BOLD percent signal change during thermal stimulation in both groups. No statistical tests were performed on these time series. Right: significant piDLPFC activation was observed in both groups at pain onset (controls: t = 2.265, p-FDR = 0.048; patients: t = 6.481, p-FDR < 0.001) and during pain block (controls: t = 3.557, p-FDR = 0.003; patients: t = 2.358, p-FDR = 0.041). Two-way ANOVA found significant main effects of group (F (1, 548) = 11.38, p < 0.001), and condition (F (3, 548) = 8.985, p < 0.001), but not their interaction (F (3, 548) = 2.396, p = 0.067), and post-hoc comparisons detected significantly greater activation in patients than controls during the warm onset (t = 3.08, p = 0.009) and pain onset (t = 2.973, p = 0.012) conditions. (E–G) (E) psDLPFC and piDLPFC activation aligned with LCL but diverged from bilateral anterior insula in dataset 2 in response to the auditory cue (LCL: t = 3.172, p-FDR = 0.008; psDLPFC: t = 2.811, p-FDR = 0.013; piDLPFC: t = 3.151, p-FDR = 0.008; LaINS: t = 1.929, p-FDR = 0.077; RaINS: t = 1.437, p-FDR = 0.159), (F) the onset of intense pain (LCL: t = 1.034, p-FDR = 0.470; psDLPFC: t = 0.896, p-FDR = 0.470; piDLPFC: t = 0.216, p-FDR = 0.830; LaINS: t = 3.409, p-FDR = 0.008; RaINS: t = 2.649, p-FDR = 0.029), and (G) the offset of intense pain (LCL: t = 0.678, p-FDR = 0.627; psDLPFC: t = 1.025, p-FDR = 0.519; piDLPFC: t = 0.483, p-FDR = 0.632; LaINS: t = 3.926, p-FDR < 0.001; RaINS: t = 5.003, p-FDR < 0.001). Unfilled bars/plot points signify healthy participant results. Filled bars/plot points signify migraine patient results.

Figure 5.. Pathological claustrum activity coincides with aberrant cognitive network region activity in migraine patients

(A and B) (A) No LCL activation differences between dataset 1 groups were observed during the difficult cognitive task or (B) pain. (C and D) (C) Significant activation differences between groups were observed in RCL at difficult cognitive task onset (two-way ANOVA main effect of group: F (1, 290) = 4.474, p = 0.035; main effect of condition: F (1, 290) = 18.05, p < 0.001; interaction: F (1, 290) = 1.311, p = 0.253; post-hoc diff onset controls vs. patients: p = 0.043) and (D) pain onset (two-way ANOVA main effect of group: F (1, 274) = 3.891, p = 0.0496; main effect of condition: F (1, 274) = 8.279, p = 0.004; interaction: F (1, 274) = 4.666, p = 0.032; post-hoc pain onset controls vs. patients: p = 0.008). (E) Two-way ANOVA of ALFF detected significantly greater spontaneous claustrum activity at rest in migraine patients(n = 109) than controls (n =33) (main effect of group: F (1, 280) = 13.30, p < 0.001), and in RCL than LCL (main effect of hemisphere: F (1, 280) = 14.07, p < 0.001). Post-hoc comparisons found greater ALFF in patients than controls in RCL (p = 0.015) and LCL (p = 0.028). No significant interaction effect was observed (F (1, 280) = 0.022, p = 0.881). (F) Two-way ANOVA of RCL and piDLPFC activation at pain onset found significantly greater activation across regions in patients than controls (F (1, 274) = 8.503, p = 0.004). There was no significant main effect of region (F (1, 274) = 2.699, p = 0.102) or significant interaction (F (1, 274) = 0.044, p = 0.834). Heatmaps of RCL (bottom structure) and piDLPFC (top structure) similarly depicted greater activation at pain onset across regions in patients (right) than controls (left). (G) FIR time series illustrated coincident increases in RCL and piDLPFC BOLD percent signal change in dataset 1 patients at left: the onset of pain and right: the onset of the difficult cognitive task. Time series are consistent with changes at condition onsets due to hemodynamic delay. No statistical tests were performed on these time series. 3D-rendered brains display shape and location of RCL (red) and piDLPFC (gold). x axes in left and right panels are unique as they display regional responses in different scan types with distinct stimulus durations and presentation protocols. See also Figures S1–S5.

Figure 6.. Structural and effective connectivity are consistent with an excitatory RCL→piDLPFC projection altered in migraine patients

(A) Group tractograms of (left-top) RCL-piDLPFC and (left-bottom) RCL-psDLPFC structural connectivity thresholded at 50% (indicating WM fibers detected in at least 50% of individuals sampled) in healthy HCP participants (n = 174). Right: median structural connectivity strength (a.u.) of RCL-piDLPFC and RCL-psDLPFC circuits in healthy HCP participants with 95% CI. Both circuits showed significant structural connectivity (RCL-piDLPFC: W = 15,225, p-FDR < 0.001; RCL-psDLPFC: W = 15,225, p-FDR < 0.001), and RCL-psDLPFC showed significantly greater connectivity strength than RCL-piDLPFC (W = 12,607, p-FDR < 0.001). (B) Fully connected DCM models with bidirectional RCL←→piDLPFC excitatory projections and self-inhibitory connections were modeled for dataset 1 pain and cognitive task scans separately. Experimental stimuli (green arrow) were modeled to affect RCL. In subsequent panels, blue lines represent connections detected on average across healthy participants. Red lines depict effects of chronic pain and therefore represent significant group differences. Large font numbers represent second level coupling parameters (positive = excitatory), and small font numbers in parentheses represent posterior probabilities quantifying the strength of evidence for each coupling parameter (0.00–1.00). (C) At acute pain onset, DCM found evidence in healthy controls for inhibitory self-connections in RCL (coupling strength: −0.126, posterior probability: 0.86) and piDLPFC (−0.211, 1.00), as well as bidirectional excitatory projections (RCL→piDLPFC: 0.144, 0.96; piDLPFC→RCL: 0.098, 1.00). No effects of chronic pain were detected. (D) At difficult cognitive task onset, DCM only found evidence in healthy controls of inhibitory self-connections (RCL: −0.186, 1.00; piDLPFC: −0.157, 0.99). Evidence was found for increased bidirectional effective connectivity due to chronic pain (RCL→piDLPFC: 0.218, 0.93; piDLPFC→RCL: 0.042, 0.82). See also Figure S7.