Brain Glymphatic and Lymphatic Systems in Migraine: Mechanistic Insights and Neuromodulation Perspectives with an Emphasis on Ultrasound-Based Approaches

1. Glymphatic system

The glymphatic system operates at the parenchymal level and facilitates convective exchange between CSF and ISF along perivascular spaces. CSF enters the brain predominantly via periarterial pathways, mixes with ISF within the parenchyma, and exits along perivenous routes, thereby contributing to the clearance of metabolic byproducts and neuroactive solutes.11 Glymphatic transport is strongly state dependent, with enhanced CSF-ISF exchange during sleep and suppression during wakefulness, reflecting physiological regulation of brain waste clearance.12 From a clinical standpoint, this framework is relevant to migraine, a disorder in which sleep disturbance is both a common trigger and a frequent consequence of attacks, potentially predisposing patients to impaired brain clearance.

2. Meningeal lymphatic system

In contrast to the parenchymal glymphatic pathway, the meningeal lymphatic system functions at the dural level and represents a conventional lymphatic outflow route. Meningeal lymphatic vessels drain CSF-derived solutes, macromolecules, and immune cells toward the deep cervical lymph nodes, linking intracranial fluid dynamics with peripheral immune surveillance.13,14 Because migraine pain arises from meningeal and trigeminovascular structures, alterations in meningeal lymphatic drainage may be particularly relevant to migraine pathophysiology.

3. Functional interaction and clinical relevance

Although distinct, the glymphatic and meningeal lymphatic systems are functionally interconnected. Solutes cleared from the brain parenchyma via glymphatic pathways ultimately rely on meningeal lymphatic vessels for extracranial drainage, and dysfunction at either level may compromise overall brain clearance efficiency.13-15 In migraine, mechanisms such as sleep disturbance and neurogenic inflammation may disrupt this coordinated clearance network, providing a conceptual basis for emerging biomarker and therapeutic research.

1. Indirect human imaging evidence of altered brain clearance

In humans, direct visualization of glymphatic flow remains technically challenging. As a result, most clinical evidence in migraine relies on indirect imaging markers that reflect perivascular fluid dynamics. Diffusion tensor imaging–based analysis along perivascular spaces (DTI-ALPS) has been proposed as a surrogate marker of glymphatic function and has been applied to patients with migraine. DTI-ALPS is based on the anatomical observation that perivascular spaces surrounding penetrating arteries and veins serve as major conduits for glymphatic fluid transport. Because diffusion along these spaces is directionally constrained, DTI can be used to estimate preferential water diffusivity parallel to perivascular pathways. The ALPS index therefore provides an indirect surrogate of perivascular fluid movement rather than a direct measure of glymphatic flow. Several studies report altered ALPS indices or perivascular imaging features in migraine compared with controls, although the direction and magnitude of these changes vary across cohorts.3

In migraine, DTI-ALPS studies have reported heterogeneous findings. Some studies suggest altered ALPS indices in chronic migraine compared with episodic migraine or controls, whereas data comparing migraine with and without aura remain limited and inconsistent. Importantly, several studies have reported null or variable results, and correlations between ALPS indices and clinical variables such as headache frequency or disease duration have not been consistently demonstrated.3,4,8 Additional radiological findings associated with migraine, such as enlarged perivascular spaces and white matter hyperintensities-have also been discussed in the context of impaired ISF clearance.16 However, these features are nonspecific and may reflect cumulative vascular, inflammatory, or aging-related processes rather than direct evidence of glymphatic dysfunction.

2. Experimental evidence linking migraine-related mechanisms to meningeal lymphatics

Beyond imaging, experimental studies provide more direct mechanistic insight. Recent preclinical work has demonstrated that meningeal lymphatic vessels are functionally responsive to migraine-related signaling pathways. In particular, CGRP signaling—central to migraine pathophysiology—has been shown to modulate meningeal lymphatic function, influencing CSF efflux, immune interactions, and pain-related behaviors in animal models. These findings suggest that meningeal lymphatics may represent an interface through which trigeminovascular activation and immune signaling converge.17

3. Sleep disturbance as a modifier of clearance in migraine

Sleep disturbance is one of the most consistent clinical features associated with migraine, acting as both a trigger and a consequence of attacks. Experimental studies outside the migraine field demonstrate that sleep strongly enhances glymphatic transport, whereas sleep deprivation suppresses CSF-ISF exchange. In migraine, recurrent sleep disruption may therefore represent a physiological mechanism by which brain clearance efficiency is reduced, potentially facilitating the accumulation of pro-inflammatory or pro-nociceptive mediators.12,18

4. Limitations of current evidence

Despite growing interest, several limitations should be acknowledged. Human studies largely rely on indirect imaging markers with variable reproducibility, while experimental models may not fully capture the complexity of migraine phenotypes. Moreover, whether observed clearance alterations are a cause, consequence, or epiphenomenon of migraine remains unresolved. These gaps underscore the need for standardized biomarkers and longitudinal studies integrating imaging, physiological measures, and clinical outcomes.

1. Why neuromodulation is conceptually attractive in a clearance framework

From a translational standpoint, clearance dysfunction—if present in migraine—may not be optimally addressed by conventional analgesic or anti-inflammatory approaches alone. Neuromodulation offers a potentially complementary route by targeting upstream physiology that shapes CSF movement (e.g., vascular pulsatility, perivascular transport, and state-dependent fluid exchange). In this model, the therapeutic hypothesis is not limited to “pain inhibition,” but extends to “restoring a physiological state that facilitates clearance.”

2. Transcranial ultrasound: direct in vivo evidence of enhanced cerebrospinal fluid movement and clearance modulation

Among neuromodulation modalities, transcranial low-intensity ultrasound has particular relevance because it has been shown using real-time optical imaging to enhance CSF movement and cortical CSF influx in vivo, providing mechanistic support for the concept that stimulation may influence clearance-related fluid dynamics.9 Clinically, this evidence is valuable because it establishes a measurable intermediate endpoint (CSF movement/CSF influx) that can be linked to imaging biomarkers and, ultimately, headache outcomes in future trials.

Consistent with this physiological effect on CSF dynamics, a related body of work in neurodegeneration provides proof-of-concept that ultrasound-based interventions can influence glymphatic–lymphatic drainage at a systems level. Focused ultrasound combined with microbubbles has been reported to enhance the drainage of soluble amyloid-β from the brain to CSF spaces and onward toward deep cervical lymph nodes, supporting the broader plausibility of ultrasound-mediated clearance modulation.19 This line of evidence does not imply direct clinical efficacy for migraine, but it strengthens the mechanistic rationale that clearance pathways are modifiable rather than purely passive.

3. Other neuromodulation modalities

Beyond transcranial ultrasound, other neuromodulation techniques have been investigated for their potential influence on CSF dynamics and brain clearance pathways. Clinically patterned vagus nerve stimulation (VNS) has been shown to enhance CSF tracer penetrance in animal models, suggesting that VNS may alter CSF/ISF exchange and clearance mechanisms.20 Low-frequency auricular VNS increased arterial vasomotion and cortical CSF influx in vivo, further supporting the concept that modulation of autonomic pathways can influence perivascular fluid movement.21 Transcranial electrical stimulation (tES) modalities, such as transcranial direct current or alternating current stimulation, primarily target cortical excitability but also influence neural oscillations and neurovascular coupling. While direct evidence linking tES to glymphatic clearance is currently limited, recent studies demonstrate that slow vascular and neural rhythms—which can be influenced by neuromodulatory interventions such as tES-are associated with enhanced CSF movement and glymphatic function during states such as non-rapid eye movement sleep.22,23 Photobiomodulation has been proposed to augment brain lymphatic and glymphatic drainage in preclinical models, potentially via vasodilatory effects on vascular and lymphatic pathways.24 Although these modalities do not yet have direct clinical evidence of clearance modulation in migraine, their physiological effects on autonomic tone, vascular dynamics, or neural rhythms provide a plausible mechanistic basis for future investigation in headache and pain disorders.

In addition to clearance-oriented neuromodulation strategies, several neuromodulation approaches have been investigated in migraine and pain disorders, primarily with the aim of modulating nociceptive processing or cortical excitability. For example, noninvasive stimulation techniques, including motor cortex stimulation and other brain stimulation paradigms, have demonstrated modulatory effects on pain perception and migraine-related symptoms in both experimental and clinical settings.25-27 These approaches are generally conceptualized as preventive or abortive interventions depending on stimulation timing and target engagement. In contrast, focused ultrasound-based neuromodulation may occupy a distinct conceptual position. Rather than directly targeting pain networks, ultrasound has been shown to influence CSF movement and perivascular transport, suggesting a potential role in modulating the physiological state that shapes migraine susceptibility. From this perspective, ultrasound-based approaches may be more appropriately framed as modulators of underlying brain physiology, which could complement established preventive or abortive strategies rather than replace them.

4. Translational implications for migraine

In migraine, a clearance-oriented neuromodulation strategy is best framed as hypothesis-driven and staged. Near-term goals include identifying patients with the most convincing clearance-related signatures (e.g., indirect glymphatic markers or meningeal lymphatic-related imaging patterns), and testing whether neuromodulation produces measurable changes in CSF dynamics and clearance surrogates alongside clinical endpoints such as attack frequency and disability. Longer-term, mechanistic integration with established migraine biology-particularly meningeal neuroinflammation and CGRP-linked pathways-may help determine whether “clearance modulation” represents a distinct therapeutic mechanism or a convergent downstream effect.

1. Biomarkers and patient stratification

At present, assessment of brain clearance function in humans relies largely on indirect imaging markers, including perivascular diffusion-based metrics and radiological features associated with altered ISF dynamics. While these measures are imperfect, they provide a practical foundation for exploratory studies in migraine, particularly in patients with chronic migraine, prominent sleep disturbance, or treatment-refractory disease. Standardization and validation across centers will be essential before such markers can inform routine clinical decision-making.3,12

2. Translational implications for neuromodulation

Neuromodulation approaches may offer a means to influence physiological processes that shape CSF dynamics and clearance efficiency. Among these, focused ultrasound is of particular interest because it has been shown to enhance CSF movement in vivo, providing a measurable intermediate endpoint that can be integrated into translational study designs. Importantly, early-phase studies should combine clinical outcomes with physiological or imaging-based measures to clarify whether neuromodulation effects are mediated through clearance-related mechanisms, pain network modulation, or both.9,19

3. Integration with established migraine mechanisms

Clearance-based concepts should be viewed as complementary to established migraine biology rather than as competing models. Interactions among CGRP signaling, meningeal immune activation, sleep disruption, and clearance efficiency may converge to influence migraine susceptibility and long-term disease course. Determining whether altered clearance represents a driver, amplifier, or downstream consequence of migraine attacks will require carefully designed longitudinal and interventional studies.13,17