Frontoamygdala hyperconnectivity predicts affective dysregulation in adolescent moderate-severe TBI

Abstract

In survivors of moderate to severe traumatic brain injury (msTBI), affective disruptions often remain underdetected and undertreated, in part due to poor understanding of the underlying neural mechanisms. We hypothesized that limbic circuits are integral to affective dysregulation in msTBI. To test this, we studied 19 adolescents with msTBI 17 months post-injury (TBI: M age 15.6, 5 females) as well as 44 matched healthy controls (HC: M age 16.4, 21 females). We leveraged two previously identified, large-scale resting-state (rsfMRI) networks of the amygdala to determine whether connectivity strength correlated with affective problems in the adolescents with msTBI. We found that distinct amygdala networks differentially predicted externalizing and internalizing behavioral problems in patients with msTBI. Specifically, patients with the highest medial amygdala connectivity were rated by parents as having greater externalizing behavioral problems measured on the BRIEF and CBCL, but not cognitive problems. The most correlated voxels in that network localize to the rostral anterior cingulate (rACC) and posterior cingulate (PCC) cortices, predicting 48% of the variance in externalizing problems. Alternatively, patients with the highest ventrolateral amygdala connectivity were rated by parents as having greater internalizing behavioral problems measured on the CBCL, but not cognitive problems. The most correlated voxels in that network localize to the ventromedial prefrontal cortex (vmPFC), predicting 57% of the variance in internalizing problems. Both findings were independent of potential confounds including ratings of TBI severity, time since injury, lesion burden based on acute imaging, demographic variables, and other non-amygdalar rsfMRI metrics (e.g., rACC to PCC connectivity), as well as macro- and microstructural measures of limbic circuitry (e.g., amygdala volume and uncinate fasciculus fractional anisotropy). Supporting the clinical significance of these findings, patients with msTBI had significantly greater externalizing problem ratings than healthy control participants and all the brain-behavior findings were specific to the msTBI group in that no similar correlations were found in the healthy control participants. Taken together, frontoamygdala pathways may underlie chronic dysregulation of behavior and mood in patients with msTBI. Future work will focus on neuromodulation techniques to directly affect frontoamygdala pathways with the aim to mitigate such dysregulation problems.

Keywords: affective dysregulation; amygdala; behavioral dysregulation; frontoamygdala; moderate to severe TBI; resting-state fMRI.

Figure 1

Previously published rsfMRI functional connectivity maps of the amygdala. Previously published one sample group mean significance maps color coded (A) for each of 3 amygdala seeds (N=89) displayed in standard views (B) and selected views for network differentiation (C). The maps are binarized at p < 10⁻⁵ and overlaid on a T1 MNI152 0.5 mm template brain in radiologic convention to demonstrate the distinct and shared connectivity across maps (38).

Figure 2

Medial amygdala hyperconnectivity predicted behavioral dysregulation but not working memory problems for patients in the TBI group. Scatter plots showing the correlation between medial amygdala (A) rFC values (x-axis) and the BRIEF Emotional control (B), CBCL Externalizing behavior (C), and BRIEF Working memory (D) scale ratings (y-axis) with statistics for the Pearson correlation overlaid.

Figure 3

Voxelwise correlation between BRIEF emotional control ratings and medial amygdala connectivity. Resultant clusters of voxels in the rostral anterior cingulate cortex (rACC) and posterior cingulate cortices (PCC) for the regression of BRIEF Emotional Control ratings on medial amygdala rFC (A, p-uncorrected < 0.01 with cluster-size p-FDR corrected < 0.05). Scatter plots (B) showing the correlation between rFC of the medial amygdala to peak voxels in the rACC and PCC clusters (x-axis) and the BRIEF scale (y-axis) with overlaid statistics for the GLM on the first row of plots derived from the voxelwise regression.

Figure 4

Ventrolateral amygdala hyperconnectivity predicted internalizing problems but not working memory problems for patients in the TBI group. Scatter plots showing the correlation between ventrolateral amygdala (A) rFC values (x-axis) and the CBCL Internalizing problems (B) and BRIEF Working memory (C) scale ratings (y-axis) with statistics for the Pearson correlation overlaid.

Figure 5

Voxelwise correlation between CBCL Internalizing Problem ratings and ventrolateral amygdala connectivity. Resultant clusters of voxels in the ventromedial prefrontal cortex (vmPFC) for the regression of Internalizing problem ratings from the CBCL on ventrolateral amygdala rFC (A, p-uncorrected < 0.01 with cluster-size p-FDR corrected < 0.05). Scatter plot (B) showing the correlation between rFC of the ventrolateral amygdala to peak voxel in the vmPFC cluster (x-axis) and Internalizing Problem ratings from the CBCL (y-axis) with overlaid statistics for the GLM (given these were derived from the voxelwise regression).