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fMRI in vagus nerve stimulation for migraine: a biomarker-based approach to pain research
  1. Tina L Doshi1 and
  2. Peter S Staats2
  1. 1Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland, USA
  2. 2National Spine and Pain Centers, Atlantic Beach, Florida, USA
  1. Correspondence to Dr Tina L Doshi, Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD 21218, USA; tina.doshi{at}jhmi.edu

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The use of electrical stimulation in the management of headaches has been around for thousands of years, with the earliest known use being attributed to the Greek physician Scribonius Largus in 47CE.1 He is credited with applying the large black torpedo fish, an aquatic animal capable of an electric discharge, on the heads of patients with headache and other disorders, curing his patients of their headaches. Over 1900 years later, James Leonard Corning would propose vagus nerve stimulation (VNS) for epilepsy,2 but it did not become common practice until after the US Food and Drug Administration (FDA) approved the first implanted VNS device in 1997. Just a few years later, it was noted that implanted VNS in patients being treated for epilepsy also resulted in a reduction in severity and number of headaches.

The first FDA approval of a non-invasive approach to stimulating the vagus nerve was granted in 2017. Cervical non-invasive VNS (nVNS) was initially indicated for episodic cluster headache, then was FDA approved in 2018 for the acute treatment of migraine and the prevention of cluster headache, and in 2020, for migraine prevention. Thus, the approach of stimulating the vagus nerve to prevent or treat headaches is not new, and in many cases, now considered standard treatment. Best practice recommendations suggest cervical nVNS as an appropriate strategy for managing cluster and migraine headaches, and more recently, expert consensus lists cervical nVNS as a first-line therapy for cluster headache.3

Most of the evidence for nVNS in primary headache disorders refers to stimulation of the cervical portion of the vagus nerve, but the vagus nerve may also be targeted at the auricular branch. The therapeutic effects of VNS are believed to be mediated through thick afferent Aβ (myelinated) fibers.4 The cervical branches of the vagus nerve contain approximately 80% afferent and 20% efferent fibers,4 with 5 to 6 times more myelinated fibers compared with the auricular branch and wide interindividual variability in fiber composition of auricular branch compared with the cervical.5 However, it is unclear whether these anatomic differences translate to a difference in clinical effectiveness between the two sites. Thus, the superficial location of the auricular branch makes it an appealing target for comparison with the cervical branches and for mechanistic studies of the vagus nerve.

Human and animal studies have suggested several potential mechanisms for VNS in migraine, including decreased activation of trigeminal nociceptive afferents, decreased firing of neurons in the trigeminal nucleus, modulation of neurotransmitters involved in descending pain inhibition and migraine pathogenesis, and inhibition of cortical spreading depression.3 Consistent with these mechanisms, functional MRI (fMRI) studies of VNS in healthy volunteers have associated both auricular and cervical VNS with differential activation of the trigeminal and vagal systems, as well as cortical and subcortical structures involved in pain modulation and perception.6 7 fMRI has indicated that cervical nVNS may modulate the trigeminal autonomic reflex through changes in functional connectivity among spinal, cortical and subcortical structures.8 Acute migraine attacks have been associated with fMRI changes in functional connectivity between the thalamus and cortical regions associated with pain processing.9 In fact, thalamocortical modulation is a putative mechanism for another non-invasive stimulation treatment for acute migraine: transcranial magnetic stimulation of the occipital cortex.10

In a recent issue of Regional Anesthesia & Pain Medicine, Zhang et al present an fMRI study of transauricular vagus nerve stimulation (taVNS) for migraine and suggest thalamocortical modulation as a potential mechanism.11 The design of this study was single blinded, which has significant disadvantages in distinguishing placebo effects from treatment effects in human pain conditions; as such, results and suggested mechanisms need to be interpreted with caution.12 In single-blinded studies, investigators may inadvertently signal active versus sham therapy (eg, via body language, facial expression, or intonation) and therefore functionally unblind a participant. In addition, the increased risk of conscious and unconscious observer biases in single-blinded studies renders them more difficult to compare across studies, since specific investigator biases vary greatly depending on the individual study or investigator. Cervical nVNS studies have typically been double-blinded, randomized and sham controlled13 to reduce the risks of placebo effects, lack of blinding and observer biases. Notably, the placebo (sham) response rate in the present study was low compared with other studies of nVNS, with a 0.7 day decrease in number of migraine days, compared with 1.8 days with sham cervical VNS.13 This difference is likely a consequence of Zhang et al having fairly permissive inclusion criteria, requiring only two migraine days per month, whereas participants in other nVNS trials have typically been required to have five or more migraine days per month. There are also significant differences in VNS protocol beyond anatomic location: the Zhang study administered 12, 30 min sessions of physician-administered active or sham taVNS over 4 weeks, while cervical nVNS is self-administered by the patient 2 to 3 times daily for 2 min or more. The International Headache Society guidelines for controlled trials of episodic migraine prevention recommend a minimum treatment period of 12 weeks to allow adequate time for treatment benefits to manifest and to provide more stable estimates of outcomes.14

Despite study design characteristics that limit overall generalizability and comparison to studies of cervical VNS in migraine, Zhang et al provide intriguing evidence that a 4-week course of taVNS significantly reduced the mean number of migraine days by 2.5 days, compared with 0.7 days in the sham group.11 Mean pain intensity and attack duration were also significantly reduced. Moreover, the authors present fMRI data that suggest a neurophysiological basis for these observed differences. In their analyses, the thalamus was parceled into six functional subregions (seeds), and the functional connectivity of each seed to other regions of the brain was assessed. The researchers found increased connectivity between the motor thalamus and rostral anterior cingulate cortex/medial prefrontal cortex after treatment with taVNS compared with sham. However, there was no significant correlation between the degree of these changes and clinical outcome in either group. Active taVNS was also associated with decreased connectivity between the occipital thalamus and the postcentral gyrus; this change was significantly correlated with reduction in migraine days in the active taVNS group, versus no such correlation in the sham group.

Beyond presenting clinical evidence to suggest the efficacy of taVNS for migraine, this study illustrates two important potential applications of neuroimaging in pain research. First, it demonstrates how functional neuroimaging can identify neuroanatomical correlates to observed differences between treatments. In other words, neuroimaging may clarify how a pain therapy works. The findings from the present suggest that VNS provides migraine relief via modulation of thalamocortical circuits. Second, this study indicates thalamocortical connectivity as a possible imaging-based, pharmacodynamic biomarker of reduction of migraine days in response to taVNS. Interestingly, thalamocortical connectivity has previously been associated with responders to VNS in medically intractable epilepsy.15 Only one other study of VNS in patients with migraine has identified a similar potential biomarker: Garcia et al reported correlation between brainstem connectivity on fMRI and time to next migraine attack.16 It is also important to note that only one of the two thalamocortical changes observed on fMRI was correlated with clinical improvement. Thus, not all changes observed may necessarily be biomarkers of treatment mechanism or outcome, especially when multiple statistical tests are performed, increasing the risk of type I error. As interest in personalized pain medicine grows, the discovery of such biomarkers will be critical to defining individual pain pathophysiology, identifying novel treatments, and assessing analgesic efficacy.17 Variations in treatment protocols and techniques, such as those seen with nVNS for migraine, may correspond to differences in both clinical treatment effects and surrogate biomarkers, creating an additional challenge in identifying and validating pain biomarkers. However, the present study shows that the exploration of novel biomarkers and their incorporation into the pain research paradigm can still provide valuable insights into the neurophysiological mechanisms of pain and its treatment, and guide a more informed, precision medicine approach to care.

References

Footnotes

  • Twitter @dr_tinadoshi

  • Contributors Both authors contributed to the design and writing of this editorial.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests PSS is cofounder and part-time Chief Medical Officer of electroCore, a company that sells and markets technology related to this editorial.

  • Patient consent for publication Not required.

  • Provenance and peer review Commissioned; externally peer reviewed.