Prospective Longitudinal Analysis of Amygdala Volumes and Association with Mood and Memory Outcomes in Brain Tumor Patients

Abstract

<h3>Purpose/Objective(s)</h3> The amygdala, a deep gray matter structure comprised of several nuclei with different functional connectivity, plays a key role in emotional processing and memory. We analyzed volume change of the amygdala and respective nuclei after brain RT using quantitative brain MRI, and association with mood and memory outcomes. <h3>Materials/Methods</h3> On a prospective trial, primary brain tumor patients (n=63) receiving fractionated RT underwent volumetric brain MRI and mood and memory testing (Beck Depression Inventory [BDI]; Beck Anxiety Inventory [BAI]; Brief Visuospatial Memory Test [BVMT] Total/Delayed Recall; Hopkins Verbal Learning Test [HVLT] Total/Delayed Recall) at baseline, 3, 6, and 12 months post RT. Amygdala and 8 nuclei (lateral [L], basal [B], central [C], medial [M], cortical [CO], accessory basal [AB], corticoamygdaloid transition [CA], paralaminar [PL]) were autosegmented bilaterally with validated methods. Tumor/surgical cavity/edema were censored. Nuclei with "higher order" cortical connectivity (CA, B, AB) were grouped. Linear mixed effects models assessed longitudinal change in amygdala volumes and association with dose, controlling for time and subject-specific effects. Amygdala volume change from baseline to 3 and 6 months was dichotomized by the median (low vs high atrophy). Wilcoxon rank sum tests assessed association between volume change and cognitive scores. <h3>Results</h3> We found atrophy over time in combined (p=0.001), right (p=0.001), and left (p<0.05) amygdala. Atrophy was noted bilaterally in CA (left p=0.023, right p=0.003), B (left p=0.024, right p=0.006) and AB nuclei (left p=0.016, right p=0.005), which are higher order nuclei. Higher RT dose was associated with atrophy in combined (p=0.037), left (0.011) and right (0.002) amygdala volumes. Left higher order nuclei atrophy was inversely associated with change in BDI scores from baseline to 6 months (p=0.025). Similarly, right higher order nuclei atrophy was inversely associated with change in BDI scores from baseline to 3 months (p=0.04). BAI scores at 6 months were higher in the low atrophy group for combined amygdala volume (p=0.038). Right higher order nuclei volume change from baseline to 3 months was associated with BVMT total (p=0.009) and delayed (p=0.007) recall at 6 months, and change in BVMT total (p=0.041) from baseline to 6 months; higher scores were found in patients with less volume loss. There were no significant associations on HVLT. <h3>Conclusion</h3> The amygdala and its subregions exhibit dose-dependent volume loss after brain RT. Certain subregions, particularly higher order nuclei with more cortical connectivity, are more susceptible. Atrophy within higher order nuclei appears associated with depression and anxiety symptoms, and decline in visuospatial but not verbal memory. Future cognitive-sparing efforts should consider this amygdala subregion.