Work

Amygdala-centered mechanisms of pain amplification and chronification in fibromyalgia and migraine: Narrative review

Year: 2026

Type: review

Abstract: This review aimed to examine the role of the amygdala as a central hub in the pathophysiology of chronic pain, with a specific focus on fibromyalgia and migraine. We synthesize evidence on how structural, functional, and neurochemical alterations within amygdala-centered circuits contribute to pain amplification, emotional dysregulation, and central sensitization, and discuss their implications for circuit-based therapeutic strategies. A comprehensive, theory-driven literature synthesis was conducted, integrating findings from neuroimaging, neuromodulation, molecular neuroscience, and clinical studies. We examined alterations in amygdala structure, function, and connectivity with cortical and brainstem regions involved in nociceptive processing, emotional regulation, and descending pain modulation. Pharmacological and non-pharmacological interventions targeting limbic–brainstem circuits were also analyzed. Converging evidence indicates that both fibromyalgia and migraine are associated with significant volumetric, functional, and connectivity-related alterations of the amygdala. These changes are characterized by limbic hyperexcitability and aberrant coupling with the prefrontal cortex, hypothalamus, periaqueductal gray (PAG), and rostral ventromedial medulla (RVM), biasing descending pain control toward facilitation rather than inhibition. This network reorganization amplifies both the sensory and affective dimensions of pain and promotes symptom persistence. Neurochemical dysregulation—encompassing glutamatergic, monoaminergic, GABAergic, and peptidergic systems—further sustains maladaptive plasticity within amygdala-centered circuits. Emerging therapeutic approaches, including cognitive-behavioral interventions, neuromodulation, pharmacological modulation, and immersive technologies, show potential to reshape dysfunctional limbic–cortical networks and attenuate pain amplification. The amygdala emerges as a key integrative node linking nociceptive, emotional, and autonomic processes in fibromyalgia and migraine. Through its influence on descending pain modulatory systems, amygdala-centered circuits play a critical role in pain chronification and affective sensitization. These findings support a circuit-based framework for chronic pain, highlighting the amygdala as a promising target for individualized, multimodal therapeutic strategies aimed at restoring adaptive emotional–nociceptive integration. • The amygdala emerges as a central integrative hub linking nociception, emotion, and autonomic regulation in chronic pain, shaping both sensory amplification and affective salience in fibromyalgia and migraine. • Structural, functional, and connectivity-based alterations of the amygdala bias descending pain modulation toward facilitation, promoting central sensitization and pain chronification. • Stage-dependent limbic plasticity is proposed as a unifying mechanism, with early hyperexcitability evolving into maladaptive remodeling across chronic pain trajectories. • Neurochemical dysregulation within amygdala-centered circuits (glutamatergic, monoaminergic, GABAergic, and peptidergic systems) sustains emotional–nociceptive coupling, reinforcing vulnerability to recurrent pain. • A circuit-based therapeutic framework is advanced, highlighting the amygdala as a target for multimodal interventions, including neuromodulation, psychotherapy, pharmacological modulation, and immersive technologies.

Source: Behavioural Brain Research

DOI: 10.1016/j.bbr.2026.116071