Chronic pain (CP) and major depressive disorder (MDD) are highly disabling global diseases, and their high comorbidity creates a bidirectional vicious cycle, significantly exacerbating functional impa Show more
Chronic pain (CP) and major depressive disorder (MDD) are highly disabling global diseases, and their high comorbidity creates a bidirectional vicious cycle, significantly exacerbating functional impairment and treatment resistance. Multidisciplinary evidence suggests that the comorbid nature arises from deep functional coupling and neural network remodeling between the sensory-pain and emotional systems, rather than merely a symptom overlap. Neuroimaging, animal models, and neuromodulation studies demonstrate that key brain regions, including the prefrontal cortex (PFC), anterior cingulate cortex (ACC), amygdala, hippocampus, insula, and reward system, show consistent abnormalities in the comorbid state, creating a cross-brain network that jointly regulates pain, emotion, and cognition. This paper systematically reviews the central structures, neural circuits, and neurotransmitter regulatory mechanisms of CP-MDD comorbidity and proposes an integrated emotion-perception coupling network model. We highlight the mechanisms and translational potential of multi-pathway intervention strategies, with a focus on neuromodulation techniques (rTMS, tDCS), combined with ketamine, BDNF modulators, and anti-inflammatory drugs. Additionally, it is emphasized that future research must integrate multimodal imaging, multi-omics data, and computational modeling to establish a mechanism-driven personalized stratification system. With the support of high spatiotemporal resolution brain connectomics technology, this will facilitate the transition from a 'symptom control' to a 'mechanism repair' paradigm in treating comorbidities. Show less
The aging process is associated with gradual cognitive decline resulting from deficits in synaptic plasticity, the brain's natural ability to adapt and reshape its neural circuitry. This review highli Show more
The aging process is associated with gradual cognitive decline resulting from deficits in synaptic plasticity, the brain's natural ability to adapt and reshape its neural circuitry. This review highlights the importance of synaptic plasticity in cognitive function. It provides a full overview of the molecular, cellular, and systemic mechanisms involved in enhanced or diminished synaptic plasticity in the aging brain. We also go over issues in neurotransmitter systems, calcium signaling, neurotrophic support (ex., BDNF-TrkB), cellular signaling pathways (e.g. mTOR, CaMK, CREB, and MAPK/ERK), and neuroinflammation, oxidative stress, and vascular integrity, all of which redirect the trajectory of synaptic failure associated with cognitive decline in aging. Therapeutic approaches toward increasing or restoring synaptic plasticity are evaluated, including pharmacological (e.g., nootropics, cholinesterase inhibitors, NMDA receptor modulators), natural (e.g., curcumin, resveratrol, bacoside A), and new interventions (e.g., psychoplastogens, gene therapy, nanocarriers, and digital therapeutics). Lifestyle approaches, especially physical exercise, cognitive training, intermittent fasting, and mindfulness approaches to stimulation, have highly potent effects on plasticity enhancements and employ multiple neurobiological mechanisms. Despite much promise, there remain substantial translational challenges, including limited clinical efficacy, lack of personalized biomarkers, and ethical considerations concerning cognitive enhancement. As we look ahead, a multidisciplinary integrative approach that includes molecular therapeutics, lifestyle interventions, and next-generation neurotechnologies will be most useful for protecting cognitive health and enhancing brain resilience in aging individuals. This review highlights the immediate necessity for personalized, ethical, and evidence-based approaches to take advantage of synaptic plasticity for healthy cognitive aging. Show less