We observed both significantly reduced amygdala volume and significantly increased amygdala response to emotional stimuli in a sample of adolescents with BD relative to HCs. The structural and functional neuroimaging data for each participant were acquired in the same session. Moreover, an association was revealed between the structural and functional abnormalities, such that adolescents with BD who had the smallest amygdala volume exhibited the highest amygdala activation when processing emotional stimuli. These findings are consistent with reports in the literature of structural and functional amygdala abnormalities in youth with BD. To the best of our knowledge, this work represents the first report where the two findings are reported in the same sample of adolescents with BD and the first demonstration of an association between these abnormalities in BD. Intriguingly, our findings also provide some early evidence in BD to suggest a pathophysiological link between amygdala structural abnormalities and abnormal responding to emotional stimuli. This is supported by the association between amygdala structure and function.
In the adolescents with BD, age was associated with response to positive emotional stimuli, such that the youngest participants with BD exhibited the highest amygdala activation when processing positive emotional stimuli. Thus, age was used as a covariate in analyses. When age is not included as a covariate in the analyses, while the association between diagnosis and amygdala volume remains statistically significant, the association between diagnosis and amygdala activation is no longer significant.
The pathophysiological mechanisms that may contribute to these amygdala abnormalities cannot be determined based on this work. Decreased amygdala volume reported herein could be a consequence of a number of different cellular processes, including decreased density of neuronal processes, altered ratio of small and large cell types, or loss or atrophy of neurons or glia. Postmortem study of the amygdala in BD has generated report of reduced number and density of neurons, as well as volume, in the lateral nucleus (LN) and reduced neuron density in the accessory basal nucleus (ABN).36
Furthermore, Bezchlibnyk et al.37
found decreased neuron somal size in the LN and the parvocellular portion of the ABN in individuals with BD. Finally, Bowley et al.38
reported decreased glial cell density in the amygdala of participants with BD.
The association between structural and functional abnormalities in the amygdala suggests the presence of a single pathophysiological mechanism that may contribute to these two abnormalities. A plausible pathway towards these outcomes could be disruption of an inhibitory neurotransmitter system in the amygdala, such as gamma-aminobutyric acid (GABA), with release of inhibition resulting in elevated function. GABAergic cell loss in limbic structures in individuals with BD has been reported in postmortem studies.39-41
Loss of inhibitory GABAergic interneurons in amygdala is one potential mechanism that could contribute to both decreased volume and increased excitatory activity in the amygdala in youth with BD. Glial loss has also been postulated to be a cellular mechanism that could disrupt the balance between glutamatergic and GABAergic systems resulting in excessive limbic activity in BD.42, 43
Other possibilities include cellular changes associated with other neurotransmitter systems that modulate amygdala activity, such as serotonin and dopamine,44, 45
or conversely activity changes in amygdala that lead to cellular changes. For example, Siegle et al.20
suggested that excessive amygdala activation may increase excitotoxic effects of glutamate, given the glutamatergic projections within the amygdala, resulting in smaller amygdala volume. Future studies that elucidate the mechanisms underlying the development of the associated structure-function changes in BD may yield new insights into its pathophysiology and potentially suggest novel treatment approaches.
Amygdala abnormalities are not specific to BD and have been reported in other childhood-onset psychiatric conditions, including volumetric abnormalities in childhood-onset schizophrenia46
and unipolar depression.47
Amygdala activation abnormalities have also been reported in a pediatric depressed sample.48
However, in unipolar depression elevated amygdala activation is observed in response to negative stimuli, while in youth with BD we, as well as others, observed elevated amygdala activation in response to both negative and positive stimuli.17
Altered responding to positively-valenced stimuli may be especially important in contributing to the unique predisposition to manic states in pediatric BD.49
This phenotype may be salient to distinguishing youth with BD from those with other psychiatric conditions. While the possible particular relevance of abnormal responding to positive stimuli in pediatric BD is of interest, the absence of an interaction between diagnosis and emotion type and the fact that the inverse association between amygdala volume and activation was only significant for response to positive stimuli and not for response to negative stimuli, highlight the preliminary nature of our findings and the need for replication.
Preliminary evidence suggests that mood-stabilizing treatments for BD may exert their effects by normalizing structural and functional abnormalities in the amygdala.12, 21
We did not detect significant effects of presence of medication. However, our ability to detect effects could have been limited by inadequate power. Future studies to systematically assess potential influences of treatment on amygdala structure and function are warranted. Replication in larger, more homogenous samples, e.g., a sample of euthymic participants with BD, will be important to address these limitations.
In summary, this study provides evidence to support a structure-function relationship in the amygdala in adolescents with BD characterized by a significant inverse association between volume and response to emotional stimuli. These findings provide preliminary evidence to suggest a possible pathophysiological link between abnormalities in amygdala structure and amygdala response to emotional stimuli in BD.