Amygdala-HPA axis interactions in temporal lobe epilepsy with anxiety comorbidity

Temporal lobe epilepsy (TLE) is the most common type of focal epilepsy and is frequently associated with various psychiatric and psychological comorbidities, among which anxiety is one of the most common and clinically significant symptoms. Anxiety not only significantly reduces patients' quality of life and treatment adherence but may also increase susceptibility to seizures, thereby exacerbating the burden of the disease. However, the neurobiological mechanisms underlying the comorbidity of TLE and anxiety have not yet been fully elucidated. A growing body of basic and clinical research indicates that the amygdala and the hypothalamic-pituitary-adrenal (HPA) axis may be involved in the interaction between epilepsy-related activity, stress regulation, and anxiety-related phenotypes between epilepsy and anxiety. As a key component of the limbic system, the amygdala is involved in emotional regulation, stress responses, and the propagation of epileptic seizures. Recurrent seizures may be accompanied by alterations in neural activity in the amygdala and other parts of the limbic system, as well as changes in the HPA axis and stress hormone levels. Long-term HPA axis dysfunction can affect the structure and function of the hippocampus and prefrontal cortex, promoting emotional abnormalities and neural network instability. Neuroendocrine studies, neuroimaging evidence, and behavioral research suggest a potential association of amygdala-HPA dysfunction in the comorbidity of TLE and anxiety. Previous reviews have focused separately on the roles of stress and the HPA axis in epilepsy, as well as the epidemiology and neurobiological basis of psychiatric comorbidity in TLE; however, there has been limited integration of the relationships between the amygdala, the HPA axis, and different anxiety phenotypes. Accordingly, this review integrates evidence from experimental and human studies to examine anxiety-related manifestations in TLE across three temporal dimensions-during seizures, periseizure, and interictal periods-with a particular focus on the relationship between changes in amygdala-related neural circuits, HPA axis function, and limbic system networks and different anxiety phenotypes. Furthermore, this review distinguishes between anxiety-specific evidence and indirect evidence derived from studies on depression or other psychiatric symptoms. It discusses the potential role of amygdala-HPA axis abnormalities in the psychiatric symptoms of TLE and their cross-diagnostic implications, while also clarifying the limitations of the current evidence. This analysis provides a foundation for further understanding the relationships among epileptic activity, stress regulation, and psychiatric symptoms in TLE.