Acute thalamic connectivity precedes chronic post-concussive symptoms in mild traumatic brain injury

Abstract

Chronic post-concussive symptoms are common after mild traumatic brain injury (mTBI) and are difficult to predict or treat. Thalamic functional integrity is particularly vulnerable in mTBI and may be related to long-term outcomes but requires further investigation. We compared structural MRI and resting state functional MRI in 108 patients with a Glasgow Coma Scale (GCS) of 13-15 and normal CT, and 76 controls. We examined whether acute changes in thalamic functional connectivity were early markers for persistent symptoms and explored neurochemical associations of our findings using PET data. Of the mTBI cohort, 47% showed incomplete recovery 6 months post-injury. Despite the absence of structural changes, we found acute thalamic hyperconnectivity in mTBI, with specific vulnerabilities of individual thalamic nuclei. Acute fMRI markers differentiated those with chronic post-concussive symptoms, with time- and outcome-dependent relationships in a sub-cohort followed longitudinally. Moreover, emotional and cognitive symptoms were associated with changes in thalamic functional connectivity to known serotonergic and noradrenergic targets, respectively. Our findings suggest that chronic symptoms can have a basis in early thalamic pathophysiology. This may aid identification of patients at risk of chronic post-concussive symptoms following mTBI, provide a basis for development of new therapies and facilitate precision medicine application of these therapies.

Keywords: functional connectivity; mild traumatic brain injury; postconcussive symptoms; resting-state fMRI; thalamus.

Figure 1

Nuclei-specific vulnerability comparing mTBI and controls. Asterisk indicates statistical significance at FDR-corrected P ≤ 0.05, HC = controls. (A) Thalamocortical connectivity comparisons. (B) Within-thalamus connectivity adjacency matrix by t-value colour from statistical testing, where red-yellow colours indicate higher functional connectivity in mTBI compared to controls. (C) Average within-thalamus connectivity values, derived from B, showing higher functional connectivity in mTBI in the same three nuclei as in A.

Figure 2

Voxel-wise results of increased functional connectivity in mTBI compared to controls. All images show voxels surviving significance and cluster-level correction, using colour-bar scale at top. (A) Results from left and right thalamus respectively, where seed mask is presented in greyscale. (B) Left and right hemisphere nuclei-specific results, where seed-nucleus is indicated by the colour legend. Images without clusters shown indicate no voxels exceeded cluster-corrected significance. Top left: Results seeded from vAnterior nuclei; top right: results from vlDorsal nuclei, partially obscured by hyperconnected clusters.

Figure 3

Relating thalamic hyperconnectivity to post-concussive outcomes. (A, C and E) Comparison of average thalamocortical functional connectivity between outcome groups looking at the three nuclei of interest; left and right vAnterior and right vlDorsal. Asterisk indicates statistical significance at P ≤ 0.05. (B, D and F) Column shows voxel-wise thalamic functional connectivity results seeded from these same nuclei surviving significance and cluster-level correction, compared between corresponding outcome groups. These results show higher functional connectivity in those with PCS, and cognitive/emotional symptom clusters, at the local and global level of investigation.

Figure 4

Significant correlations between averaged PET maps and voxel-wise SPM-t maps from group comparisons. (A) PET maps reaching significant association in one or more comparison, each normalized within-map to show range of z-scores. Higher z-score indicates greater density of that transmitter receptor or transporter. (B–D) Cortical SPM t-maps derived from groups comparisons of functional connectivity seeded from each respective thalamic ROI, where red regions indicate greater connectivity in one group (mTBI, Cog+, Emo+) than the second group (Control, Cog−, Emo−). These t-maps are correlated with PET maps and significant associations presented below. *Marginally non-significant when using Schaefer200 parcellation but found to be significant when using alternative parcellations (Glasser360 and Schaefer100).

Figure 5

Longitudinal follow-up of thalamocortical functional connectivity in three nuclei of interest in relationship to PCS. (A) Mixed ANOVA between acute and 12-month time-points between groups, where P-values given are significant interaction effects between time-point (acute or 12-month) and group (PCS+ or PCS−). Shaded regions give the IQR of controls for each nucleus, with solid line indicating the controls’ mean. (B) Post hoc results within-subjects finding significant decreases in functional connectivity only in those with PCS. Lines join individual subjects’ data at different time-points. All P-values in A and B are uncorrected for multiple comparisons due to small sample size, however corrected values are presented in-text.