The anterior cingulate cortex as an integrative hub: Mechanisms underlying pain and anxiety comorbidity

Chronic pain and anxiety disorders are highly comorbid, forming a mutually exacerbating vicious cycle that poses a significant clinical and socioeconomic burden. The limited efficacy of traditional treatment paradigms suggests the need to move beyond symptom description and deeply uncover their shared neural mechanisms. This review proposes that dysfunction in the functional plasticity of the anterior cingulate cortex (ACC), a key integrative hub, constitutes the core neural substrate of pain and anxiety comorbidity. Macro-level neuroimaging evidence shows abnormal activation patterns, disrupted functional connectivity, and structural degeneration in the ACC of comorbid individuals. Therapeutic neuromodulation (e.g., deep brain stimulation, transcranial magnetic stimulation) directly targeting the ACC could simultaneously alleviate both symptoms, confirming its causal role. At the micro-level, long-term potentiation (LTP) of excitatory synaptic transmission, disruption of inhibitory control, aberrant neuroimmune interactions, and epigenetic reprogramming within the ACC collectively lead to a breakdown of local excitation-inhibition (E-I) balance. At the circuit level, dysfunctional dynamic interactions between the ACC and key regions such as the amygdala, thalamus, periaqueductal gray, and prefrontal cortex drive affective amplification and cognitive control deficits. Based on these mechanisms, emerging therapeutic strategies, including drugs targeting glutamate/GABA imbalance, immunomodulators, epigenetic interventions, and closed-loop, cell-type-specific precision neuromodulation within the ACC, are current research hotspots. Future studies need to integrate multilevel methods to uncover ACC pathophysiology in pain and anxiety comorbidity, thereby paving the way for the development of therapies targeting its comorbid mechanisms.