Pain, as an evolutionarily conserved defense alarm, is ubiquitous in daily life and particularly prevalent in medical practice. It induces multifaceted impairments encompassing both physical and emotional domains, such as cognitive dysfunction, depression, sleep disturbances, social disabilities, and diminished motor skills (Antunes et al., 2024). The International Association for the Study of Pain currently defines pain as ‘an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage (Raja et al., 2020). Because the perception and management of pain rely on the higher neural centers, research predominantly focuses on alterations in the central nervous system. Neural oscillations represent rhythmic or repetitive neuronal activities within this system, generated through diverse mechanisms primarily driven by interactions between individual neurons or neuronal networks (Kim and Davis, 2020). Accumulating clinical evidence demonstrates that distinct oscillatory patterns and their inter-regional synchrony play pivotal roles in pain processing (Tan et al., 2021), such as facilitating the integration and encoding of nociceptive information.

Pain-related neural oscillations span a broad frequency spectrum, ranging from infraslow fluctuations (<0.1 Hz) through theta, alpha, and beta bands up to gamma band oscillations (GBOs; Ploner et al., 2017). GBOs (30–100 Hz) are ubiquitously distributed throughout the brain, endowing neurons with millisecond temporal precision (Kim and Davis, 2020). These oscillations integrate features of sensory stimuli by generating synchrony across discrete cortical regions (Whittington et al., 1998). The generation of GBO primarily involves interactions between gamma-aminobutyric acid-ergic (GABAergic) parvalbumin-positive (PV) interneurons, or between PV interneurons and pyramidal cells (Buzsáki and Wang, 2012), with their frequency and patterning being stringently governed by GABAergic kinetics (Traub et al., 1996).

The association between GBO activity and pain has been robustly evidenced across diverse conditions, including but not limited to: short-term acute pain (Zhou et al., 2018; Tiemann et al., 2010; Liu et al., 2015), persistent pain (Schulz et al., 2015; Peng et al., 2014), chronic pain (Cardoso-Cruz et al., 2013), as well as pain sensitivity (Hsiao et al., 2020) and tolerance (Zhou et al., 2020), etc., as summarized in Table 1.

Significant findings have emerged regarding the attributes of GBO in pain processing. Specifically, GBO amplitude demonstrates a close correlation with perceived pain intensity (Gross et al., 2007) and reliably predicts interindividual variations in pain sensitivity (Hsiao et al., 2020). Through time-frequency analysis of electroencephalogram (EEG) signals, Lyu et al. identified two distinct consecutive GBO components implicated in pain processing. The early-latency GBO amplitude showed positive correlations with both intensity and unpleasantness ratings, while the emotion-modulation effect (negative vs. positive contexts) of late-latency GBO amplitude positively correlated with pain unpleasantness (Lyu et al., 2022).

However, the effects of GBO are broad and not limited to pain. GBOs have been extensively recorded across broad cortical and subcortical regions, including but not limited to visual, auditory, somatosensory, motor (Ichim et al., 2024) and olfactory cortices, thereby playing roles in accurately perceiving the types of odors (Yang et al., 2022), the successful formation and retrieval of episodic memory (Griffiths and Jensen, 2023), and the fine calibration of motor movements, etc. (Tamás et al., 2018). They also have feedback effects on stimuli such as vision, hearing, and attention, and can be modulated by auditory (Schadow et al., 2007), visual (Holt et al., 2024), attentional (Tiesinga and Sejnowski, 2009), and even olfactory stimuli (Neville and Haberly, 2003). Their effects include, but are not limited to: A distinct dependence between sound intensity and GBOs (Schadow et al., 2007). Enhanced oscillatory power driven by auditory beat stimuli (Anjos et al., 2024). Strong and locally synchronized 20–70 Hz oscillatory responses triggered by visual stimuli (Gray and Prisco, 1997). Increased high GBO activity with heightened directed attention (Hauck et al., 2007), etc.

It is feasible to regulate GBOs through their important roles in vision, hearing, attention, and other areas to achieve therapeutic goals, and certain results have already been achieved. For example, in the case of Alzheimer’s disease, researchers have found that optogenetic activation of PV interneurons at 40 Hz, which induces robust GBOs has also been shown to reduce amyloid load in 5XFAD mice (Adaikkan et al., 2019). Another study used light flickering to induce GBOs and found that gamma frequency light flickering enhanced the transport of amyloid precursor protein to the plasma membrane, reducing β-amyloid load in Alzheimer’s disease (Shen et al., 2022).

GBOs are generated by the interaction between excitatory neurons and inhibitory neurons within a brain region (Ichim et al., 2024). PV neurons inhibit excitatory pyramidal cells through rapid firing and electrical synapses (Druga et al., 2023). GABA, as the primary inhibitory neurotransmitter, is released to activate GABAa receptors, suppressing the activity of excitatory neurons. This process confines neuronal firing within a narrow time window, ultimately giving rise to gamma rhythmicity (Milicevic et al., 2023). The core mechanism of GBO formation is shown in Figure 1.

These findings collectively suggest that interventions specifically targeting GBOs hold promise for alleviating pain symptoms and related disorders, underscoring the unique research value of GBOs compared to other neural oscillatory bands. Additionally, we highlight age-dependent variations in pain processing linked to cortical maturation. Studies have identified significant age-related differences in pain tolerance (Lautenbacher, 2012), with experimental data demonstrating that such tolerance positively correlates with prefrontal functional capacity. Notably, individuals with impaired prefrontal function exhibit increased GBOs characterized by a more dispersed spatial pattern. Furthermore, Noxious stimuli evoke gamma-frequency oscillations in both infants and adults. However, infants display markedly delayed gamma response onset (>500 ms post-stimulus), contrasting sharply with the immediate (<200 ms) and sustained (up to 2.5 s) GBOs observed in adults (Fabrizi et al., 2016; Price, 2000). Cortical functions in infants appear to engage wider cortical areas and evoke broader interactions across brain regions compared to adults. If the differences in GBOs across different cortical regions can be understood, optimal analgesic methods could be chosen during pain management.

This article reviews research on the cortical areas influenced by GBOs under pain conditions and the associated pain relief measures.

Many cortical regions are involved in processing information related to pain. The current pain processing pathways are the medial pathway, lateral pathway, and descending pathway. The medial pathway primarily involves the dorsal ACC and anterior insula, encoding the unpleasantness and distress of pain (Rainville et al., 1997; Price, 2000). The lateral pathway primarily involves the somatosensory cortex, handling the discrimination and sensation of pain (Flor et al., 1995; Bushnell et al., 2013). The descending pathway includes the pregenual ACC, periaqueductal gray, hypothalamus, and others (Kong et al., 2010), responsible for stress-mediated pain inhibition (Yilmaz et al., 2010) and placebo analgesia (Eippert et al., 2009). GBOs play a role or have been observed in multiple cortical regions, and due to the close relationship between the two, we review the cortical regions affected by pain-induced GBOs. The changes of GBOs in the relevant cerebral cortex are shown in Figure 2.

The primary somatosensory cortices (S1) and secondary somatosensory cortices (S2) predominantly process sensory discrimination, providing critical information regarding pain duration, intensity, and spatial localization. These regions also contribute significantly to the recognition and memorization of noxious events (Schnitzler and Ploner, 2000). Studies by Gross et al. have shown that selective nociceptive stimulation induces GBOs between 60 and 95 Hz in S1 (Gross et al., 2007). Yue et al. revealed robust temporal and phase coupling between superficial S1 layers and epidural GBOs (Yue et al., 2020). Notably, optogenetically induced GBOs in S1 enhance nociceptive sensitivity and evoke aversive avoidance behaviors (Tan et al., 2019).

S2 and posterior insular cortex likely constitute primary neural hubs that mediate attentional modulation of behavioral pain responses and subjective pain experience encoding (Lorenz and Garcia-Larrea, 2003). Studies have shown that pain-induced GBOs within S2 and insular regions are intrinsically modulated by directed attention (Lorenz and Garcia-Larrea, 2003). Betti et al. has specifically clarified this internal regulation that directly observing others’ pain elicits significantly enhanced GBO synchronization (33–90 Hz) in the observer’s sensorimotor system (Betti et al., 2009).

Schulz et al. established a positive correlation between pain intensity and GBOs during tonic pain. Furthermore, they demonstrated that GBOs in the medial PFC selectively encode the subjective perception of persistent pain (Schulz et al., 2015). Xuezhu Li et al. implanted electrodes in four pain related regions such as ACC, orbitofrontal cortex, and S1, and found that the power of the GBO was increased by applying harmful laser stimulation (Li et al., 2017).

ACC and insula are activated during pain anticipation or attentional engagement. Empathy—characterized by the capacity to understand others through shared intentions, emotions, and sensations (Preston and Waal, 2002)—engages pain empathy networks primarily involving the anterior insula and ACC (Hein and Singer, 2008). Ortega et al. discovered that during natural sleep in unanesthetized mice, somatosensory inputs from noxious versus innocuous stimuli differentially project to S1 and ACC, evoking complex transient and sustained responses across three frequency bands including GBOs (Sandoval Ortega et al., 2024). Furthermore, systemic hyperalgesia induces enhanced GBOs in the ACC (Kenefati et al., 2023).

Time-frequency analysis of EEG reveals that noxious stimuli elicit significant enhancement of GBOs in the insular cortexl (Liberati et al., 2018). Experimental evidence further confirms that activation of the anterior insula scales proportionally with magnitude ratings of both painful and visual stimuli (Baliki et al., 2009). Notably, patients with fibromyalgia exhibit persistent peak overactivation within the GBO across the left anterior insular cortex, primary motor cortex, and S1 (Lim et al., 2016).

Current approaches to pain management encompass diverse therapeutic modalities, broadly categorized into pharmacological and non-pharmacological interventions. Mounting evidence recognizing the role of neural oscillations in neurological disorders which frequently manifest pain symptoms has spurred scientific interest in correlating specific pain phenotypes with GBOs to identify novel therapeutic targets.

Pain constitutes an essential life experience that permeates human existence, with its perception representing a complex neurobiological phenomenon. Neural oscillations—rhythmic neuronal activities within the central nervous system—play a pivotal role in this process. GBOs ubiquitously distributed across cortical and subcortical regions are intrinsically linked to fundamental cognitive functions including attention, memory, and executive control. As synthesized in this review, GBOs demonstrate robust associations with pain pathophysiology, exemplified by the positive correlation between gamma power and subjective pain intensity. Critically, these oscillations serve as biomarkers for diverse pain conditions, such as chronic neuropathic pain and persistent back pain.

The therapeutic landscape targeting GBOs encompasses diverse modalities, ranging from pharmacological agents (e.g., ketamine, tramadol, and propofol) to non-pharmacological interventions (e.g., electroacupuncture, dorsal root ganglion stimulation, VR, and TENS). This diversity provides a framework to rationally harness GBOs in pain-prominent disorders, evolving beyond their role as biomarkers to serve as objective metrics for analgesic efficacy evaluation, and novel targets for analgesic development.

This review highlights the promising analgesic efficacy of both VR and music-based interventions, wherein GBOs play an integral role in their underlying neuromodulatory mechanisms. These approaches represent a paradigm shift in the therapeutic application of GBOs for pain management. While traditional non-pharmacological therapies predominantly rely on acupuncture and electrical stimulation, emerging strategies utilizing photo-acoustic stimuli to entrain GBOs have demonstrated considerable success. Current evidence suggests that physical signal-based neuromodulation targeting neural oscillations holds unprecedented potential for mechanistic exploration and clinical translation. This review synthesizes evidence on GBO-mediated analgesia across pharmacological and non-pharmacological therapies. Nevertheless, current research exhibits significant limitations, including: Insufficient standardization of experimental pain conditions when evaluating oscillatory responses to interventions. Methodological heterogeneity in quantifying GBOs (e.g., power versus amplitude metrics).

This systematic review has identified multiple pharmacologic and non-pharmacologic therapies that exert analgesic effects through GBO modulation. However, significant limitations persist in current GBO research. First, numerous studies simplistically attribute analgesia efficacy to gross GBO alterations, while overlooking critical inconsistencies in directional trends of waveform parameters—including spatial topography, amplitude, power spectral density, and peak frequency—across experimental paradigms. Although neural oscillations are classified by frequency bands with functionally distinct roles, GBOs fundamentally represent artificially defined rhythmic activities (30–100 Hz) that encode heterogeneous neural functions spanning pain subtypes and non-pain processes. Functionally distinct GBOs exhibit divergent patterns across these multidimensional attributes, which cannot be accurately discerned through human visual inspection. EEG, capturing direct neuroelectrical dynamics with high temporal resolution, remains the optimal modality for investigating oscillatory mechanisms. Integrating EEG data with AI-driven machine learning enables.

Systematic investigation of location- and phenotype-specific pain signatures. Extraction of discriminative waveform features. Development of diagnostic algorithms balancing specificity (>85%) and sensitivity (>90%). This approach facilitates mechanistic exploration beyond pain states to include emerging analgesics and neuromodulatory interventions. Quantifying intervention-induced gamma dynamics across cortical regions provides. Precision guidance for clinical treatment selection. Mechanistic biomarkers for novel analgesic development. Establishing an evidence-based framework for therapeutic innovation.

Second, a critical schism exists between pharmacological and non-pharmacological research paradigms. Pharmacological studies emphasize molecular pathways while neglecting neuroanatomical correlates, whereas non-pharmacological research focuses on local EEG dynamics without mechanistic depth. This disconnect precludes identification of shared mechanistic pathways for cross-modality analysis, confining efficacy assessments to macro-level outcomes—an approach that proves insufficient. In clinical practice, combined pharmacological and neuromodulatory therapies are frequently employed to enhance analgesic outcomes. However, the absence of comparative mechanistic data forces such combinations to rely predominantly on clinicians’ empirical judgment rather than evidence-based medical principles, often failing to yield optimal regimens. Compounding this challenge, the vast heterogeneity in pain phenotypes and underlying mechanisms necessitates mechanism-targeted matching between specific pain entities and therapeutic modalities, which constitutes a critical determinant for selecting first-line clinical strategies.

Finally, the prevalent limitation of small sample sizes merits critical attention. Given the methodological complexity of inducing targeted pain states in animal or human subjects prior to intervention, most studies are constrained to cohorts ranging from as few as 4 to several dozen participants. While such sample sizes may demonstrate proof-of-concept under current constraints, they remain inadequate for generating robust, statistically powered conclusions. To establish high-grade evidence per evidence-based medicine standards, large-scale multicenter randomized controlled trials are imperative. However, practical challenges arise: the non-life-threatening nature of most chronic pain conditions and patients’ preserved activities of daily living limit willingness for prolonged hospitalization. Consequently, standardized monitoring and intervention delivery prove difficult to implement. Large-scale longitudinal real-world studies represent a viable alternative pathway, leveraging digital phenotyping to capture ecological treatment responses across extended observation periods.

Furthermore, current research has not fully elucidated the causal relationship between GBOs and pain. Most literature focuses on the unidirectional causality where pain induces neural oscillations. However, emotions such as depression and empathic responses can also lead to somatic pain (Hein and Singer, 2008; Dudeney et al., 2024), with somatization in depression serving as a classic manifestation. This evidence suggests a bidirectional causality between the two phenomena.

In summary, while GBO research has established a rich foundation for pain therapeutics, these methodological limitations necessitate paradigm-shifting approaches.