Modulating Gamma Oscillations in the Anterior Cingulate Cortex with Intermittent Theta Burst Stimulation: Implications for Chronic Non-Specific Low Back Pain

Introduction: The Complexity of CNSLBP and the Potential for Neuromodulation

Chronic nonspecific low back pain (CNSLBP), defined as persistent pain lasting >3 months without identifiable structural pathology, affects up to 15.4% of middle-aged and elderly individuals and constitutes the majority (≈62%) of chronic low back pain cases worldwide, imposing enormous socioeconomic burden and frequently co-occurring with anxiety, depression, sleep disturbances^1,2 and heightened fall risk, particularly in geriatrics where it correlates with reduced functional capacity, physical performance, and balance as evidenced by validated assessments like the Five Times Sit-to-Stand Test (FTSST), which demonstrates excellent reliability (ICC=0.99) and strong associations with pain intensity, disability, and lower extremity strength.³ Conventional pharmacologic (NSAIDs, opioids) and physical therapies, including core stabilization exercises alone or combined with aerobic protocols, predominantly offer symptomatic relief—yielding improvements in functional capacity,⁴ pain, depression, and fall risk yet consistently fail to modify the underlying central sensitization—a maladaptive neuroplastic change characterized by hyperexcitability of spinal dorsal horn neurons and supraspinal pain-processing circuits, most prominently the anterior cingulate cortex (ACC).^5–8

A critical knowledge gap persists: although neuroimaging and electrophysiological studies robustly demonstrate that ACC hyperactivity, aberrant functional connectivity, and pathologically elevated gamma oscillations (23–80 Hz) directly encode ongoing pain intensity and sustain central sensitization through disrupted excitatory–inhibitory (E/I) balance and excessive synaptic potentiation,^9–12 no current treatment possesses the spatiotemporal precision to selectively normalize these ACC-mediated oscillatory and circuit-level abnormalities. Traditional high-frequency repetitive transcranial magnetic stimulation (HF-rTMS), despite evidence of analgesic efficacy, requires protracted sessions (20–40 min), limiting clinical scalability,¹³ whereas pharmacological approaches targeting central mechanisms remain hampered by off-target effects and inability to modulate specific neural rhythms,⁵ even exercise-based interventions, while superior when aerobic components are added to core stabilization for enhancing geriatric outcomes like reduced fall risk and better physical performance, lack direct impact on these neural signatures.^4,14,15

This therapeutic void raises a pivotal research question: Can targeted, non-invasive neuromodulation of ACC gamma oscillatory networks reverse central sensitization and provide durable relief in CNSLBP? Intermittent theta-burst stimulation (iTBS) emerges as the most promising candidate to address this challenge.¹⁶ By delivering brief (≈3 min), high-intensity bursts of 50 Hz gamma stimulation nested within a 5 Hz theta rhythm — a pattern that physiologically mimics endogenous hippocampal–prefrontal theta–gamma coupling — iTBS potently induces NMDA receptor- and CaMKII-dependent long-term potentiation (LTP)-like plasticity while restoring E/I balance far more efficiently than conventional HF-rTMS.^17–19 When applied over the left dorsolateral prefrontal cortex (DLPFC), iTBS exerts downstream modulation of the interconnected ACC,²⁰ directly counteracting injury-induced Cx36-mediated electrical coupling, pathological gamma synchronization, and the resultant amplification of nociceptive signaling observed in both animal models and human chronic pain states.^21,22 Thus, iTBS represents a paradigm-shifting, mechanistically grounded intervention uniquely capable of remodeling the maladaptive neuroplasticity that perpetuates CNSLBP, offering superior efficiency, tolerability, and potential for personalized oscillatory targeting compared to existing neuromodulation and pharmacological strategies^13,16,23 (Figure 1).

Figure 1 Systematically elucidates the pathophysiological mechanisms of chronic nonspecific low back pain (CNSLBP) and the intervention logic of intermittent theta pulse stimulation (iTBS). The core pathological manifestation is abnormal enhancement of gamma oscillations in the anterior cingulate cortex (ACC), which triggers chronic pain through central sensitization and is accompanied by comorbidities such as sleep disorders, emotional dysregulation, and anxiety. iTBS, as a non-invasive precision neurostimulation tool, targets the ACC to regulate the excitatory-inhibitory (E/I) balance, restore neural activity normalization, and thereby alleviate symptom severity (pain relief). Treatment optimization requires consideration of patient heterogeneity, combined with individualized parameters (such as precise targeting localization and standardized stimulation protocols) to enhance efficacy.

The Central Role of γ Oscillations of the ACC in CNSLBP

Functional Anatomy of the ACC and Multidimensional Integration of Pain Information Processing

The ACC functions as a pivotal “hub” connecting the limbic system and the higher cortical regions, with its anatomical connectivity network underpinning its essential role in multidimensional pain coding. Structurally, the ACC is implicated in pain processing through two principal pathways: (1) The ventral pathway, wherein the ACC establishes an “emotion-reward loop” with the ventral tegmental area (VTA) and the nucleus accumbens (NAc), facilitating the integration of negative emotions and motivational deficits associated with pain.²⁴ For instance, optogenetic inhibition of ACC projections to the NAc has been shown to significantly diminish avoidance behavior in response to painful stimuli in mice.²⁴ (2) The dorsal pathway, characterized by the ACC forming a “sensory-motor loop” with the dorsomedial striatum (DMS) and the ventral posterior nucleus of the thalamus (VPL/VPM), plays a crucial role in modulating pain-related motor inhibition and decision-making bias.^24,25 Functional imaging studies have demonstrated that the strength of functional connectivity between the ACC and the DMS during the anticipatory phase of pain is significantly greater in patients with central sensitization-related low back pain (CSRLBP) compared to healthy individuals (p < 0.001), and this connectivity is positively correlated with the extent of pain-induced motor restriction.^25,26

At the molecular level, the imbalance between E/I within the ACC constitutes a critical mechanism underlying the persistence of chronic pain. (1) Inhibitory neuronal apoptosis: Nerve injury triggers the activation of the TNF-α-necroptosis pathway, characterized by the phosphorylation of RIP1, RIP3, and MLKL, which results in the necrotic apoptosis of parvalbumin (PV)-expressing inhibitory interneurons (PV-INs). This process directly diminishes inhibitory synaptic inputs.²⁷ Concurrently, the phagocytosis of microglial cells mediated by NLRP3 inflammasomes further contributes to the depletion of PV-INs, thereby aggravating the E/I imbalance.²⁸ (2) Impaired GABAergic transmission: In models of chronic inflammation, there is a down-regulation of presynaptic vesicular GABA transporter (VGAT) expression in the ACC, leading to a decreased frequency of GABA release. Notably, the subunits of GABAA receptors remain unchanged, indicating a dysfunction in presynaptic inhibitory mechanisms.²⁹ (3) Pyramidal cell hyperexcitability: Following nerve injury, there was a significant increase in the in vivo discharge frequency of ACC pyramidal cells, accompanied by an up-regulation of c-Fos expression, indicating enhanced intrinsic excitability. In contrast, inhibitory neuronal activity did not exhibit a significant change, leading to a dysregulated excitatory/inhibitory (E/I) ratio.³⁰ This imbalance contributes to the ACC’s heightened responsiveness to low-threshold sensory inputs, thereby establishing the neural foundation for “pain memory”.¹²

Neural Mechanisms of γ Oscillations: From Synaptic Dynamics to Network Coding

γ oscillations function as temporal encoders for the processing of pain information within the ACC. Their generation is contingent upon the precise interactions between two distinct neuronal types: (1) fast-spiking interneurons (FS-INs), which facilitate rhythmic synchronization of the local network through GABAergic synaptic release,(2) pyramidal neurons, which receive synchronization inhibition to produce clustered discharges that establish phase locking within the γ band.^31–33 In a healthy state, γ oscillations in the ACC demonstrate task-dependent dynamic regulation; acute painful stimuli elicit a transient increase in γ power, which subsequently returns to baseline through a negative feedback loop mediated by NMDA receptors.³⁴

In patients with CNSLBP, the spatiotemporal characteristics of γ oscillations exhibit significant abnormalities: (1) Power Anomaly: Consistent with the above, resting-state γ power is elevated and correlates with pain sensitivity;³⁵ (2) Rhythm Disturbance: Phase-amplitude coupling (PAC) analysis reveals a decreased coupling strength between γ oscillations in the ACC and the theta frequency band (4–8 Hz), leading to less efficient information integration across frequency bands;³⁴ (3) Propagation Abnormality: Dynamic causal modeling (DCM) indicates that the effective connectivity strength of γ-band connections from the ACC to the insula is weakened in CNSLBP patients, while connections to the amygdala are abnormally enhanced, exacerbating the comorbidity of pain and anxiety.^36,37

The molecular underpinnings of the aberrant γ activity are intricately linked to potassium channel dysfunction. Chronic pain induces a reduction in Kv4.2 channel expression within ACC pyramidal neurons, resulting in an elevation of their membrane potential oscillation frequency from 8.2 Hz to 12.5 Hz.^38,39 Concurrently, the miR-17-92 cluster exacerbates neuronal hyperexcitability by destabilizing Kv1.1 channel mRNA.^39,40 This “dual potassium channel defect” diminishes the synchronization threshold for γ oscillations, thereby increasing the frequency of spontaneous γ burst events.^41–44

The Vicious Circle of γ Oscillations and CNSLBP: From Local Abnormalities to Whole-Brain Network Dysregulation

Abnormal γ oscillations in the ACC not only indicate dysfunction within local neural circuits but also contribute to the reorganization of whole-brain networks via long-range projections. Specifically, three key pathways are affected: (1) The cortico-striatal loop, wherein glutamatergic projections from the ACC to the dorsomedial striatum (DMS) are significantly enhanced in chronic pain conditions. Optogenetic inhibition of this pathway has been shown to increase the mechanical pain threshold (p < 0.001).²⁵ During this process, γ oscillations in the ACC facilitate synchronized firing among DMS dopaminergic neurons, thereby augmenting pain-related motor inhibition;^25,35 (2) The limbic-thalamic loop, characterized by elevated γ band coherence between the ACC and the ventral posterior lateral nucleus of the thalamus (VPL) in patients with CSRLBP. This increased coherence is associated with thalamic gating failures, resulting in the misinterpretation of non-injurious sensory inputs as pain signals.^45–47 (3) Default Mode Network (DMN): Aberrant γ activity in the ACC disrupts the resting state of the DMN by inhibiting the alpha (α) oscillations (8–12 Hz) of the posterior cingulate gyrus (PCC), thereby impairing functional integration. This disruption manifests as cognitive deficits related to pain, such as declines in working memory.^9,48,49 Current research collectively indicates that disturbed γ oscillations in the ACC act as “amplifiers” of the expansion of CNSLBP from localized plasticity abnormalities to pathological networks across the entire brain, thereby providing a critical opportunity for targeted intervention.⁵⁰

Mechanism and Clinical Translation of iTBS Modulation of ACC γ Oscillations

Bidirectional Regulatory Mechanisms of iTBS: From Synaptic Plasticity to Network Remodeling

The modulatory influence of iTBS on ACC γ oscillations arises from its spatiotemporal-specific regulation of neuroplasticity. At the molecular level, iTBS alters the E/I balance within the ACC through a dual mechanism: (1) Rapid modulation: The γ pulses (50 Hz) associated with iTBS facilitate the swift remodeling of dendritic spines in pyramidal neurons by activating voltage-gated calcium channels. This activation promotes the release of glutamate from the presynaptic membrane, thereby triggering NMDA receptor-mediated calcium influx.^19,20,51,52 This mechanism has been validated in animal models through electrophysiological recordings⁵³ and human imaging data.¹³ (2) Slow modulation: The theta rhythm of iTBS (5 Hz) augments GABAergic transmission and mitigates aberrant γ synchronization in parvalbumin-positive (PV+) interneurons through the entrainment of theta oscillatory phases within the ACC.¹⁹ Animal studies have demonstrated that following iTBS intervention, there is a reduction in γ power within the ACC and an increase in GAD67 (GABA synthase) expression.^52,54,55

At the systemic level, iTBS exerts its efficacy by modulating the dynamic connectivity of the ACC with brain-wide networks. Functional magnetic resonance imaging (fMRI) studies have demonstrated that a single iTBS intervention leads to a reduction in the strength of the ACC’s functional connectivity with the default mode network (DMN), while simultaneously enhancing its theta-band coherence with the dorsolateral prefrontal cortex (DLPFC). This reorganization of network connectivity is significantly correlated with pain relief (p<0.001).⁵⁵ Furthermore, dynamic causal modeling (DCM) has revealed that iTBS restores normal coding of the affective dimension of pain by suppressing abnormal γ connectivity from the ACC to the amygdala and enhancing theta-gamma cross-frequency coupling from the ACC to the insula.⁵⁶

Parameter Optimization: From Empirical Settings to Individualized Precision Regulation

The efficacy of iTBS is significantly influenced by the precision of parameter settings, necessitating optimization across three dimensions. First, target localization: research indicates that the strength of resting-state functional connectivity (rsFC) between the left dorsolateral prefrontal cortex and the ACC is predictive of iTBS’s impact on hypothalamic-pituitary-adrenal (HPA) axis modulation.²⁰ Specifically, a stronger baseline anticorrelation between the DLPFC and ACC correlates with a more pronounced reduction in cortisol levels (AUCi) following iTBS intervention, highlighting the importance of integrating individualized target selection with functional connectivity features to enhance intervention specificity. Second, stimulation intensity: empirical evidence suggests that an iTBS intensity set at 120% of the resting motor threshold (RMT) achieves safe and effective modulation, thereby improving therapeutic efficacy compared to lower-intensity protocols, such as 80% of the active motor threshold,¹³ without increasing the risk of adverse effects. Furthermore, the modulation of γ oscillations can be achieved by integrating iTBS with γ-frequency transcranial alternating current stimulation (γ-tACS). The current intensity for γ-tACS is generally set at a peak amplitude of 1 mA and a frequency range of 50–80 Hz.^18,52 Third, the temporal pattern: iTBS utilizes an intermittent theta burst pattern, characterized by 3 pulses with an intra-cluster frequency of 50 Hz and an inter-cluster frequency of 5 Hz. For effective synergistic modulation of γ oscillations, γ-tACS should be initiated approximately 10 seconds before the commencement of iTBS and maintained throughout the process.⁵² This spatiotemporal coupling facilitates the synchronization of cortical γ rhythms with iTBS-induced synaptic plasticity, significantly enhancing long-term potentiation (LTP) effects and extending the increase in motor evoked potentials (MEP) beyond 30 minutes.¹⁸ Notably, the modulation of GABAergic interneurons through γ-tACS can be effectively quantified using short-interval intracortical inhibition (SICI), which demonstrates an inhibitory effect that positively correlates with the change in motor evoked potential (MEP) amplitude following iTBS.⁵² This correlation suggests that γ oscillations enhance synaptic remodeling by modulating GABA-Aergic neurotransmitter homeostasis. Consequently, by integrating individualized target localization, optimized stimulation intensity, and synergistic timing design, iTBS can achieve targeted intervention in the neuromodulation of ACC-related networks and γ oscillations, thereby offering a precise strategy for therapeutic interventions in disease treatment.

Clinical Translational Evidence: Efficacy, Heterogeneity, and Safety

(1) Efficacy: Numerous studies have demonstrated that the analgesic effect of iTBS is both context-dependent and time-limited. In a randomized controlled trial involving 19 patients with chronic orofacial pain, it was observed that visual analogue scores (VAS) significantly decreased (p<0.05) immediately following a single iTBS treatment; however, this effect was not sustained at the two-week follow-up.⁵⁷ Similarly, another study reported that a single session of iTBS in patients with neuropathic pain led to a reduction in VAS scores within 60 minutes, but the analgesic effect diminished rapidly. Furthermore, the efficacy of iTBS was significantly lower compared to 20 Hz conventional high-frequency repetitive transcranial magnetic stimulation (rTMS).²³ A separate investigation into neuropathic pain following spinal cord injury revealed a reduction in VAS from baseline after four consecutive weeks of iTBS treatment (p<0.05 between groups), indicating that the efficacy of repeated iTBS sessions was superior to that of a single application.⁵⁸ These findings suggest that the efficacy of iTBS may be influenced by the treatment regimen, such as the frequency of sessions, as well as the specific type of pain being treated.

(2) Heterogeneity: In a study involving 15 patients with central pain, iTBS was reported to provide significant pain relief, although the proportion of effective responders was not specified.⁵⁹ Conversely, research by André-Obadia et al suggests that the efficacy of iTBS may be contingent upon the efficiency of integrating pain mechanisms and neural networks.²³ Furthermore, Yang et al demonstrated that iTBS, when used as an initial stimulus in combination with other treatments, was more effective than when applied in isolation, underscoring the synergistic differences in treatment regimens.⁵⁸ Discrepancies among studies may be attributed to patient heterogeneity, such as variations in pain etiology and cortical plasticity, as well as differences in the selection of stimulation parameters, including localization accuracy and session design.

(3) Safety: Multiple lines of evidence indicate that iTBS is generally well tolerated. In the Accelerated iTBS Protocol Trial conducted by Drabek et al, no serious adverse events were reported among the first 10 patients with chronic pain, and the low dropout rate was comparable to that observed with conventional repetitive transcranial magnetic stimulation (rTMS).⁶⁰ Blumberger et al found that the iTBS group experienced significantly higher treatment-related pain scores compared to the 10Hz rTMS group (3.8 vs 3.4/10, p=0.011), although there was no significant difference in dropout rates (8% vs 6%) or headache incidence (65% vs 64%).¹³ However, long-term safety data in the context of chronic pain require further refinement, as the available evidence is predominantly derived from single-center, small-sample studies.⁶⁰ Consequently, while iTBS demonstrates a transient analgesic effect in chronic pain, its efficacy is significantly influenced by disease subtype and treatment regimen. Despite its safety advantages, the optimal indications and standardized parameters for iTBS need to be elucidated through multicenter, large-sample studies.⁵⁷

Critical Limitations and Methodological Challenges in Current Neuromodulation Research for CNSLBP

The investigation of neuromodulation as a treatment for CNSLBP is constrained by significant limitations in both preclinical and clinical research domains, alongside pervasive methodological flaws. In animal studies, a critical challenge is the translational gap. Commonly used neuropathic pain models (eg, sciatic nerve ligation) fail to fully recapitulate the complex psychopathological and functional dimensions of human CNSLBP. Behavioral assessments primarily rely on reflexive measures like paw withdrawal thresholds, which do not capture the subjective experience of spontaneous pain, affective distress, and disability characteristic of CNSLBP.^6,61,62

In human trials, the methodological shortcomings are substantial. A primary issue is the prevalence of underpowered studies with small, heterogeneous samples that include patients with diverse pain etiologies and comorbidities, compromising statistical power and generalizability.^63,64 The inadequate blinding of participants and investigators is another major flaw, particularly for techniques that can produce perceptible sensations, making it difficult to control for placebo effects effectively.⁶⁵ There is also a notable lack of standardization and personalization in stimulation parameters. Most studies apply stimulation to standardized scalp positions, ignoring individual variations in brain anatomy and functional connectivity, which likely contributes to the inconsistent therapeutic outcomes reported across studies.^66,67 Finally, the field is hampered by a dearth of long-term follow-up data, leaving the crucial question of whether neuromodulation can induce lasting neuroplastic changes and sustained clinical benefits largely unanswered.^68,69

A critical assessment of the current research paradigm reveals a fundamental disconnect between mechanistic inquiry and clinical validation. Many trials remain focused on preliminary efficacy testing without rigorously correlating neurophysiological biomarkers with clinical improvement to establish causal mechanisms.⁷⁰ Moreover, the almost exclusive use of sham-controlled designs fails to demonstrate comparative effectiveness against established active treatments (eg, exercise therapy), thus questioning the added clinical added value of neuromodulation. Future research must prioritize large-scale, long-term, neuroimaging-guided, individualized RCTs and head-to-head comparisons with best-standard non-pharmacological treatments to overcome these hurdles.

Challenges and Future Directions: From Single-Target Interventions to Multimodal Synergies

A significant challenge in the contemporary management of chronic pain lies in the complexity of modulating multidimensional pathological networks through a singular intervention. Research indicates that targeted neuromodulation, informed by central sensitization⁶ and synaptic plasticity,⁷¹ offers symptomatic relief; however, it exhibits limited efficacy in addressing individual heterogeneity and the mechanisms of peripheral-central interaction. Future approaches should focus on integrating multimodal data, such as genomic information, functional imaging, and dynamic biomarkers, to develop cross-scale combination therapies. For instance, combining transcranial magnetic stimulation (TMS) with glutamatergic drugs⁷² could synergistically modulate the cerebral-peripheral axis. Additionally, optimizing intervention parameters of the ACC-mPFC loop in real-time through closed-loop neurofeedback⁷³ is essential. Furthermore, patient stratification should be facilitated by artificial intelligence, and the long-term efficacy of these combined strategies must be validated in multicenter randomized trials. Ultimately, this will contribute to the establishment of an individualized pain management system grounded in systems biology.

Future Direction: Interdisciplinary Breakthroughs and Clinical Translation of iTBS Precision Regulation

Innovations in Precision Localization Techniques: From Brain Region Delineation to Sub-Millimeter Functional Network Targeting

The efficacy of iTBS is fundamentally rooted in the accurate localization of functional subregions within the ACC. The Individual Brain Functional Segmentation (pBFS) methodology, developed by Hesheng Liu’s team at the Changping Laboratory, employs machine learning algorithms to partition the brain into 213 distinct functional subregions, such as Brodmann areas 24a, 24b, and 24c of the ACC. This approach, when combined with resting-state functional magnetic resonance imaging (rs-fMRI) and Dynamic Causality Modeling (DCM), facilitates the identification of patient-specific aberrant network nodes.⁴ For example, in cases of post-stroke cognitive impairment (PSCI), precise targeting of the prefrontal-parietal cognitive network (FCN) has demonstrated a 33% enhancement in the hit rate of iTBS-induced fields and a 93% response rate.⁴ To further refine sub-millimeter stimulus localization, with an error margin of less than 0.5 mm, the integration of multimodal data, such as diffusion tensor imaging (DTI) for white matter fiber tracking and electroencephalography (EEG) γ power topography, is essential for constructing individualized “heat maps of neurological function”.^74,75

Intelligent Regulation of Parameters: From Static Schemes to Dynamic Adaptive Systems

The customization of iTBS parameters necessitates moving beyond the conventional empirical model to establish a “stimulus-response” dynamic framework. The FPGA closed-loop system developed at Stanford University has successfully achieved millisecond-level monitoring of γ power and optimization of pulse timing. Specifically, when the γ power in the ACC exceeds 65 dB/Hz, the system automatically initiates a 50 Hz γ pulse sequence, resulting in a 42% reduction in pain intensity within 30 seconds.⁷⁴ Future research directions include: (1) the development of a multi-parameter co-optimization algorithm that allows for the simultaneous adjustment of intensity (80–120% RMT), frequency (45–65 Hz), and pulse interval (15–25 ms) using the coyote optimization algorithm (COA), while avoiding locally optimal solutions through a chaotic weighting strategy;⁴ and (2) genotype-driven dose prediction, where the COMT Val158Met and BDNF Val66Met polymorphisms collectively predict the optimal stimulus intensity. Patients with the Met/Met genotype may require an increase in intensity up to 110% RMT to surpass the synaptic plasticity threshold.^75,76

Multimodal Joint Interventions: From Single Target to Network-Level Synergistic Regulation

To establish a comprehensive “multi-target-multimodal” intervention network, iTBS should be integrated with other neuromodulation techniques and rehabilitation strategies. For instance: (1) iTBS combined with γ transcranial alternating current stimulation (γ-tACS) phase synchronization, where γ-tACS enhances the synaptic specificity of iTBS by externally modulating the phase of ACC γ oscillations with an error margin of less than 5 milliseconds.⁷⁷ (2) iTBS paired with virtual reality (VR) attention training, where VR-induced theta-γ cross-frequency coupling facilitates information integration within the ACC-prefrontal network, leading to a decrease in pain catastrophizing scores and an extended duration of efficacy.⁴ (3) iTBS in conjunction with spinal cord magnetic stimulation (sTMS), targeting the bidirectional pathway between the spinal cord and ACC. The synchronized stimulation of the motor cortex (M1) and the lumbar region of the spinal cord enhances motor inhibition and pain perception through long-range synaptic plasticity linkage.⁷⁸

From Animal Models to Clinical Translation: Mechanistic Consistency and Limitations

The clinical translation potential of CNSLBP neuro-modulation strategies depends on the synergistic validation of mechanistic studies in animal models and human clinical evidence. Mechanistic consistency is reflected in the cross-species commonality of disrupted excitatory/inhibitory (E/I) balance in the ACC. Both rodent models and human studies indicate that apoptosis of parvalbumin-positive interneurons (PV-INs) and glutamatergic hyperexcitability are key drivers of abnormal gamma oscillations. For example, neural injury in mice upregulates Cx36 gap junction protein in the ACC, enhancing γ synchrony.³⁵ Similarly, iTBS exhibits cross-species universality in regulating GABAergic transmission: animal studies show that iTBS induces upregulation of GAD67 expression,⁵² consistent with enhanced short-interval intracortical inhibition (SICI) observed in human studies.¹³

However, translational challenges arise from species differences. First, pathological complexity: human CNSLBP not only manifests as nociceptive hypersensitivity but is also accompanied by psychological comorbidities such as anxiety and depression, as well as social behavioral factors, which are difficult to replicate in animal models. Second, network hierarchy differences: Rodent studies focus on molecular mechanisms, such as downregulation of Kv4.2 channels,³⁹ while human neuroimaging reveals interactions between higher-order networks like the ACC and the DMN, where weakened ACC-DMN functional connectivity after iTBS correlates with analgesic effects.⁵⁵ Third, intervention parameter calibration requires cross-species adjustment: mouse iTBS intensity (30–50% of human thresholds) must be adapted to skull impedance differences, while human protocols rely on resting-state functional connectivity (rs-fMRI) for individualized targeting.⁴ To bridge these gaps, future studies should establish a bidirectional translational framework. Animal models can simulate “anxiety-pain comorbidity” by manipulating the limbic circuit via optogenetics^79,80 to approximate human phenotypes; clinically, multimodal biomarkers (eg, EEG γ maps, genomic analysis) should be integrated to enable patient stratification and iTBS parameter optimization.^81,82 By integrating the depth of animal mechanisms with the breadth of clinical data, it is anticipated that precise neurostimulation strategies can be developed to advance CNSLBP treatment from symptom relief to neural plasticity restoration.

Technology Translation and Industrial Ecology: From Lab to Wearable Devices

The primary objective of future advancements is to facilitate the miniaturization and enhancement of intelligence in iTBS technology, aligning with prevailing trends across various technological domains. With the swift progression of artificial intelligence and Internet of Things (IoT) technologies, the trajectory of innovation in next-generation biosensing systems is increasingly oriented toward intelligence, miniaturization, and wireless portability (Q. Wang et al, 2023). For instance, researchers at Tsinghua University have developed a wireless patch, measuring 0.3 mm in thickness and weighing 5 g, that integrates fNIRS-EEG dual-modal sensing. This device is capable of continuously monitoring and regulating ACC γ oscillations in real time, while maintaining a power consumption of less than 1 mW.^83,84

Conclusion

Pathologically enhanced gamma oscillations in the ACC constitute a mechanistic hallmark of central sensitization in CNSLBP. By physiologically entraining theta–gamma coupling, iTBS over the left DLPFC offers a time-efficient, mechanistically precise means to normalize this oscillatory dysfunction and restore cortical E/I balance. Although current evidence confirms short- to medium-term efficacy and excellent tolerability, durable disease modification will require personalized targeting, optimized protocols, and multimodal integration. These advances hold transformative potential to shift CNSLBP management from symptomatic palliation to reversal of maladaptive neuroplasticity.