Hong Jiang

A key theme emerging from this collection is that neuromodulation should not be viewed as a uniform analgesic intervention, but rather as a set of mechanism-informed strategies that may act on distinct pain generators. In their narrative review, Zhu et al. discuss electroacupuncture for temporomandibular disorder-related pain, a condition characterized by joint dysfunction, masticatory muscle involvement, inflammation, and central sensitization. The authors synthesize clinical evidence suggesting that electroacupuncture may alleviate pain and improve functional and psychological outcomes, while also highlighting possible mechanisms involving activation of sensory afferents, enhanced local blood flow, tissue repair, endogenous analgesic systems, and immunomodulation. Importantly, the review also points to a recurring challenge in the field: encouraging clinical signals must be interpreted in light of heterogeneous protocols, variable patient populations, and the need for standardized stimulation parameters.Two articles focus on brain stimulation approaches for chronic craniofacial pain and headache disorders. Lin et al. review non-invasive brain stimulation for neuropathic orofacial pain, emphasizing repetitive transcranial magnetic stimulation and transcranial direct current stimulation. Their synthesis highlights the primary motor cortex as a major target for analgesic stimulation and raises the important possibility that pain phenotype may influence treatment response. For example, paroxysmal and persistent pain states may differ in the degree of central sensitization, descending inhibitory dysfunction, and cortical excitability changes, which could shape responsiveness to rTMS or tDCS. This phenotype-based perspective is particularly valuable because it moves the field beyond the question of whether stimulation works, toward the more clinically actionable question of which patients are most likely to benefit. Xiao et al. further extend this mechanistic framework in their review of electrophysiological indicators in transcranial magnetic stimulation treatment for medication-overuse headache. Medication-overuse headache is closely associated with central sensitization, habituation deficits, altered cortical silent period duration, and abnormal pre-activation levels. By discussing these measurable electrophysiological features, the authors underscore the potential value of objective biomarkers in guiding neuromodulation. Such biomarkers may help identify abnormal cortical excitability, monitor treatment response, and eventually support individualized stimulation protocols. This is an important direction for the field, because clinical pain scores alone may not fully capture the neural changes induced by neuromodulatory therapies.The topic also includes clinical evidence for peripheral or regionally targeted physical neuromodulation. Huang et al. report a randomized controlled trial comparing lowintensity pulsed ultrasound with tamsulosin in patients with chronic prostatitis type IIIb/chronic pelvic pain syndrome. Both interventions improved symptoms, but lowintensity pulsed ultrasound showed greater benefit for pain relief, whereas tamsulosin had stronger effects on urinary symptoms. This distinction is clinically informative because chronic pelvic pain syndrome is a multidimensional disorder involving pelvic discomfort, urinary symptoms, sexual dysfunction, inflammation, and psychosocial burden. The findings suggest that physical neuromodulation may be particularly relevant for paindominant phenotypes and may complement pharmacological strategies that target other symptom domains.Finally, Gupta et al. explore an important practical dimension of implantable neuromodulation: how stimulation dosing can be optimized without sacrificing clinical benefit. Their study of extreme pulse dosing in 10 kHz spinal cord stimulation for chronic back or leg pain suggests that some patients may maintain pain relief and quality-of-life benefits with markedly reduced stimulation duty cycles. Beyond improving device convenience and reducing recharge burden, pulse dosing raises broader mechanistic questions about the minimum neural input required to sustain analgesia, the role of intermittent versus continuous stimulation, and whether reduced dosing might mitigate habituation to therapy over time.Taken together, these five articles highlight several priorities for the next stage of chronic pain neuromodulation research. First, stimulation protocols require greater standardization, including dose, frequency, duration, anatomical targeting, and treatment schedules. Second, patient stratification should become central to trial design. Pain location, phenotype, duration, sensory profile, emotional comorbidity, and evidence of central sensitization may all influence therapeutic outcomes. Third, mechanistic studies should be integrated into clinical trials wherever possible. Electrophysiology, quantitative sensory testing, neuroimaging, inflammatory markers, and autonomic or behavioral readouts may provide complementary insight into how neuromodulation changes painprocessing networks. Fourth, long-term follow-up is essential, as chronic pain treatment must be judged not only by short-term analgesia but also by durability, functional recovery, safety, adherence, and quality of life.In conclusion, this research topic reflects a broader shift in chronic pain therapy from symptom suppression toward nervous-system modulation. The included articles demonstrate that neuromodulatory approaches can act across multiple biological scales, from local tissue inflammation and peripheral afferent signaling to cortical excitability, descending pain control, and spinal network modulation. While important questions remain regarding mechanisms, patient selection, and optimal protocols, the field is moving toward more precise, personalized, and mechanism-based interventions. Continued collaboration among clinicians,...

Hypocretin, also known as orexin, is a hypothalamic neuropeptide that regulates essential physiological processes including arousal, energy metabolism, feeding behavior, and emotional states. Through widespread projections and two G-protein-coupled receptors—HCRT-1R and HCRT-2R—the hypocretin system exerts diverse modulatory effects across the central nervous system. The role of hypocretin in maintaining wakefulness is well established, particularly in narcolepsy type 1 (NT1), where loss of hypocretin neurons leads to excessive daytime sleepiness and cataplexy. However, the mechanisms by which hypocretin stabilizes transitions between sleep stages remain incompletely understood. Additionally, while hypocretin integrates metabolic signals such as glucose, leptin, and ghrelin to promote feeding and energy expenditure, NT1 patients paradoxically experience weight gain despite reduced caloric intake—highlighting unresolved questions about hypocretin’s role in energy homeostasis. In the affective domain, preclinical studies suggest hypocretin enhances stress resilience and modulates anxiety- and depression-related behaviors. Yet, human data remain inconsistent, in part due to methodological variability and the limited availability of cerebrospinal fluid sampling to accurately assess central hypocretin function. Therapeutically, the hypocretin system is a promising target across several domains. Dual hypocretin receptor antagonists (DORAs), such as suvorexant and daridorexant, are clinically approved for insomnia. Selective HCRT-2R agonists—including TAK-861 and ALKS-2680—are in clinical trials for NT1 and show encouraging results. Additionally, HCRT-2R antagonists like seltorexant are being explored for major depressive disorder. This review will highlight the anatomical distribution, receptor mechanisms, and physiological functions of the hypocretin system. It will also focus to discuss its role in narcolepsy, metabolic regulation, and mood disorders, while addressing key challenges and open questions that must be resolved to fully harness hypocretin’s therapeutic potential.

The lateral hypothalamic area (LHA) serves as a central integrative hub for the regulation of energy homeostasis and motivational behaviors, including feeding and arousal. Recent advances in single-cell transcriptomics have revealed remarkable molecular heterogeneity within the LHA, identifying more than 30 distinct neuronal subtypes, such as GABAergic (LHA^Vgat), glutamatergic (LHA^Vglut2), orexin, melanin-concentrating hormone (MCH), and leptin receptor-expressing (LHA^Lepr) neurons. These neuronal populations sense peripheral metabolic signals—such as leptin, insulin, and glucose—both directly and indirectly, and they coordinate appropriate physiological and behavioral responses through local circuits and reciprocal connections with other hypothalamic nuclei. Furthermore, the LHA interfaces with extrahypothalamic regions, including the ventral tegmental area (VTA), nucleus accumbens (NAc), and lateral habenula (LHb), thereby linking metabolic state to reward processing and behavioral prioritization. In this review, we summarize and integrate recent molecular and functional findings to present a comprehensive view of the LHA as a dynamic, multifunctional center in the central regulation of metabolism. A deeper understanding of these mechanisms may offer new therapeutic avenues for addressing obesity and related metabolic disorders.

Gamma-aminobutyric acid (GABAergic) neuron, as one of important cell types in synaptic transmission, has been widely involved in central nervous system (CNS) regulation of organismal physiologies including cognition, emotion, arousal and reward. However, upon their distribution in various brain regions, effects of GABAergic neurons in the brain are very diverse. In current report, we will present an overview of the role of GABAergic mediated inhibitory neurocircuitry in the hypothalamus, underlying mechanism of feeding and sleep homeostasis as well as the characteristics of latest transcriptome profile in order to call attention to the GABAergic system as potentially a promising pharmaceutical intervention or a deep brain stimulation target in eating and sleep disorders.