Nuclei-Specific Amygdala Enlargement Is Linked to Psychiatric Comorbidities in Drug-Resistant Focal Epilepsy

Abstract

Objective: Amygdala enlargement has been the subject of controversial studies regarding its significance in terms of pathogenicity both in epilepsy and in psychiatric comorbidities such as anxiety, depression, and post-traumatic stress disorder. However, no causal link has been established in either direction, and the role of distinct amygdala nuclei remains unknown. We investigated volumetric changes of the amygdala and its nine main nuclei and their associations with psychiatric comorbidities in patients with drug-resistant focal epilepsy.

Methods: Eighty-seven adult patients with drug-resistant focal epilepsy, available 7 T MRI, and completed standardized psychiatric assessments were included. Whole amygdala and nuclei volumes were quantified and compared to healthy controls. Correlations between the amygdala or nuclei volumes and psychiatric scores were analyzed, as well as the prevalence and severity of each comorbidity depending on the presence of enlargement.

Results: Amygdala enlargement was present in 41% of patients, with bilateral enlargement observed in 30% of these cases, while atrophy was noted in 2%. Bilateral enlargement correlated with higher posttraumatic stress disorder and depression scores. Central nucleus enlargement was associated with a greater prevalence of depression and more severe anxiety. Bilateral enlargement of distinct nuclei in the basolateral group was linked to more severe depression or posttraumatic stress disorder.

Interpretation: These findings suggest that bilateral amygdala enlargement, particularly in specific nuclei, may serve as a morphological marker of psychiatric comorbidities in epilepsy. Further research is needed to explore the specific roles of amygdala nuclei in psycho-epileptogenesis.

Keywords: amygdala; epilepsy; psychiatric comorbidities.

FIGURE 1

Flow‐chart of patients' inclusion.

FIGURE 2

Pipeline for automated, atlas‐based volumetric segmentation of the amygdala and its nuclei using 7 T MRI template. Automated volumetric segmentation of the amygdala and its nine nuclei was performed in all patients and healthy controls (n = 32), using a combination of two atlases: The 7TAMI atlas for the whole amygdala and the Tyszka and Pauli atlas for the amygdala nuclei. The segmentation was performed using 7 T MP2RAGE images on high‐resolution 7TAMI template. Pre‐processing included correcting for gradient distortion, B1+ inhomogeneity distortion and creating a denoised image, followed by non‐linear registration of the 7TAMI model to individual anatomy. Nine different nuclei were segmented for each amygdala: AAA, anterior amygdaloid area; ASTA, amygdalo‐striatal transition area; ATA, periamygdaloid cortex; BL, basolateral; BM, accessory basal; CEN, central nucleus; CMN, corticomedial; LA, lateral; PL, paralaminar. Volumes were normalized using intracranial volume measurements, and z‐scores were calculated by comparing patient amygdala and nuclei volumes to control subjects' volumetry.

FIGURE 3

Amygdala nuclei volumes in the cohort of 87 patients with drug‐resistant focal epilepsy. The maximal normalized total amygdala and nuclei volume per patient (z‐scores vs. healthy controls) are shown. For each structure, the mean z‐scores are indicated by the red triangles and the medians by the black lines. The gray lines show the cut‐off z‐score values for a moderate (> 1.5) and significant (≥ 2.0) amygdala or nuclei enlargement, or an atrophy (≤ 1.5), respectively. AAA, anterior amygdaloid area; AMY, amygdala; ASTA, amygdalo‐striatal transition area; ATA, periamygdaloid cortex; BL, basolateral nucleus; BM, accessory basal nucleus; CEN, central nucleus; CMB, corticomedial nucleus; La, lateral nucleus; PL, paralaminar nucleus.

FIGURE 4

Correlations between the amygdala volume and the psychiatric scores. In the whole cohort (A–C), there was no correlation between the amygdala volume and the level of anxiety (A, GAD‐7), depression (B, NDDI‐E), or PTSD (C, PCL‐5) defined by clinical scores. Likewise, no correlation was found in the subgroup of patients without amygdala enlargement (not shown). In the subset of patients with amygdala enlargement (AE, D–F), no correlation was found between the amygdala volume and the level of anxiety (D). However, the amygdala volume positively correlated with the level of depression (E), as well as of PTSD (F), when bilateral AE (ipsi/contra) was present, while there was no correlation in cases of unilateral AE, whether ipsi‐ or contralateral to the epilepsy site.

FIGURE 5

Psychiatric scores depending on the side of amygdala enlargement or the presence of enlarged vs non enlarged nuclei. There were more severe anxiety (A, GAD‐7) and PTSD (C, PCL‐5) symptoms in the presence of bilaterally compared to ipsilaterally significantly enlarged (z‐score ≥ 2.0) amygdala (ANOVA). The same trend was observed for depression (B, NDDI‐E), however not reaching statistical significance. Central nucleus (D) and amygdalo‐striatal transition area (ASTA, E) enlargement were associated with significantly higher anxiety (GAD‐7) scores compared to the patients without enlargement of these nuclei.

FIGURE 6

Psychiatric scores in patients with ipsilateral versus contralateral or bilateral enlargement of amygdala nuclei with respect to the epilepsy side. There were more severe PTSD (A–C) symptoms in the presence of bilateral compared to ipsilateral, significant enlargement (z‐scores ≥ 2.0) of the paralaminar (PL), basolateral (BL), or accessory basal (BM) nuclei (ANOVA). Depression symptoms (D–F) were more severe in presence of bilateral versus ipsi‐ or contralateral PL enlargement (D), with the same trend for the BL, not reaching statistical significance (E), and no difference for the BM (F). No statistically significant link with the side of PL, BL or BM nuclei enlargement was present for the anxiety scores (G–I).