Abstract
Introduction
Transnasal cooling has been shown to improve symptoms in patients with migraine headaches in a recent clinical trial. However, the mechanism underlying this phenomenon is unclear.
Methods
We sought to explore the potential autonomic responses to transnasal cooling in 10 patients by measuring changes in facial temperature and heart rate.
Results
We observed a decrease in average facial temperatures at the end of intervention compared to baseline in all regions measured, namely the forehead (−0.55 ± 0.58°F, p = 0.007), the opposite cheek (−0.44 ± 0.34°F, p = 0.027), and the same cheek (−0.64 ± 0.91°F, p = 0.001). The average baseline heart rate was 70.1 ± 10.5 bpm and did not undergo a change throughout the three phases (p = 0.22).
Conclusion
Bilateral facial temperature reduction despite unilateral cooling, prolonged cooling effect post-intervention, and no significant change in heart rate suggest a local sympathetic response to transnasal cooling.
Introduction
Transnasal intervention has gained traction as an abortive therapy for acute migraine, which is a complex neurovascular disorder characterized by trigeminovascular system-mediated inflammation and vasodilation.1,2 Hypotheses have been proposed to explain the improvement of symptoms in these cohorts, ranging from the local modulation of the sphenopalatine ganglion (SPG) to the triggering of a central trigeminovascular autonomic reflex.3,4 However, there is no consensus on the exact physiological mechanism. Transnasal intervention traditionally involves the administration of an anesthetic targeting the SPG, and studies have highlighted the clinical benefit of this approach.5–7
Vanderpol et al. conducted the earliest pilot study on transnasal cooling in migraines and utilized a device with bilateral nasal prongs called RhinoChill that provided symptomatic relief to most patients. The authors hypothesized that symptomatic relief resulted from temperature changes transmitted to the brain parenchyma via direct conduction or venous circulation leading to cooling of brain parenchyma and subsequent vasoconstriction. 8 Singhal et al. showed that delivery of high flow oxygen or medical air via non-rebreather face masks both improved symptoms but did not differ significantly from each other. 9 We have previously shown that evaporative cooling of nasal cavity by unilateral high flow dry air ameliorates migraine headaches and leads to better pain relief than high flow dry or humidified oxygen. 10 The exact mechanism is unclear; however, extracranial vasomotor regulation by autonomic neuromodulation may underlie this analgesic effect. Autonomic sympathetic fibers innervate facial capillary beds, and, thus, the local temperature is a reliable biomarker of sympathetic nerve activity. As such, changes in facial temperature can be used to monitor sympathetic activation in the trigeminal territory. 11 In this study, we highlight the effects of unilateral transnasal cooling on facial temperature and heart rate to characterize the autonomic response to therapy. Moreover, unilateral cooling offers an opportunity to distinguish local cooling from an autonomic response by monitoring temperature changes on the contralateral side.
Methods
Ten healthy volunteers with no history of headache disorders and no active medication or drug use were recruited for the study. Informed consent was obtained prior to the procedure. One volunteer underwent the same study three times on three consecutive days to ensure the reproducibility of the study findings. Informed consent was obtained from this volunteer for the use of their facial thermal images in Figure 1.
Study methods: (a) Illustration of unilateral transnasal cooling with dry air at 6L/min and in-ear photoplethysmography. (b) Facial temperature representation on the Bosch GTC 400C thermal camera with markers on the face: M1 (Opposite Cheek), M2 (Forehead), and M3 (Same Cheek).
Tests were performed in an ambient temperature room (21°C). Before the study, volunteers remained in the room for 30 min to allow for environmental acclimatization. An in-ear photoplethysmography (PPG) device (STAT-health, Boston, MA) was used to monitor heart rate at a 1 Hz sampling rate. Facial temperature data was collected using a Bosch GTC 400C thermal camera (Bosch Healthcare, Germany) across three phases: 5-min baseline period (Phase 0), 15-min intervention period (Phase 1), and 15-min post-intervention period (Phase 2). IR camera emissivity settings were set to 0.98 to match the known emissivity of human skin.
During the intervention period, desiccated ambient air was administered via a single nostril at a flow rate of 6 L/min for 15 min using a single-prong nasal cannula (Figure 1(a)). Saline solution was administered via a nasal spray into the nostrils to prevent drying of the nasal passages.
A thermal data processing script was developed and utilized to convert each grayscale thermal image into the corresponding temperature values at selected points on the face, utilizing the Python OpenCV image processing library. Temperatures were sampled every 15 s, 2 cm below the outer canthus of the eye on the zygomatic arch on the same and opposite sides of treatment administration, and at a single forehead point corresponding to 2 cm above the glabella (Figure 1(b)). Results are presented as mean ± SD. Statistical analysis was done using paired t-test with p-value < 0.05 considered significant. Analysis was performed using SPSS 27.0 (IBM Corp, Armonk, NY).
Results
Ten volunteers (8/10 male, mean age = 35 ± 13, 7 Caucasians and 3 Asians) successfully completed the study. After acclimatization, baseline skin temperatures were within a narrow range for each subject. No significant change in temperature (p > 0.05) was observed in any of the measured facial areas from phase 0 to the end of phase 1. However, there was a significant decrease in average facial temperatures at the end of phase 2 compared to phase 0 in all regions measured, namely the forehead (−0.55 ± 0.58°F, p = 0.007), the opposite cheek (−0.44 ± 0.34°F, p = 0.027), and the same cheek (−0.64 ± 0.91°F, p = 0.001) (Figure 2). A decrease in facial temperature was observed in at least 70% of participants with the maximum reduction in temperature of 1.8°F in the same cheek, 1.3 °F in the forehead, and 0.8°F in the opposite cheek.
Summary of changes in temperature. n.s. indicates no significance, statistical significance (p < 0.05) is indicated with asterisk.
The average baseline heart rate was 70.1 ± 10.5 bpm and did not undergo any significant changes throughout the three phases (p = 0.22). Key results are reported in Table 1.
Changes in temperature and heart rate between the different phases and regions of the face.
One volunteer underwent three studies on consecutive days in the same environment to test reproducibility of the findings. A consistent reduction in temperature was observed in all the areas at the end of phase 2, namely the forehead (−0.68 ± 1.03°F), the opposite cheek (−0.92 ± 1.06°F), and the same cheek (−0.78 ± 0.83°F). The average baseline heart rate in this volunteer was 68.8 ± 7.6 bpm and was measured to be 67.9 ± 7.8 bpm at the end of phase 2.
4/10 volunteers endorsed nasal congestion and rhinorrhea for a maximum of 30 min post-intervention, although this was not systematically assessed in this study. No other adverse events were reported.
Discussion
Migraine is a headache disorder that is hypothesized to be a result of inappropriate trigeminovascular system activation leading to neuropeptide release with subsequent neurogenic inflammation and vasodilation. 1 Sensory afferents from the meningovascular complex are believed to converge on trigeminal nuclei in the brainstem which ultimately project to central autonomic control centers. 2 Activation of this pathway along with central sensitization contributes to enhanced pain perception and autonomic dysfunction in migraine. 1 Conventional abortive therapies work by vasoconstriction and inhibiting neuropeptide release leading to a reduction in pain and autonomic symptoms. 1
Transnasal interventions are thought to improve symptoms by vasoconstriction directly or by inhibiting vasodilation through neuronal pathways via afferents of the nasal mucosa.3–5 Our results show that unilateral cooling of the nasal passages elicits a vasoconstrictor effect both in the ipsilateral and contralateral side of the face with no change in heart rate. In our study, we sought to explore an autonomic basis for our findings. As autonomic neuromodulation (i.e., external vagal nerve stimulators) has been demonstrated to improve symptoms in cluster headache and a subset of chronic migraine patients, we believe it is plausible for autonomic neuromodulation to underlie the therapeutic effect of transnasal cooling. 12
Our study extends the findings of prior reports that have demonstrated small but significant temperature changes during intranasal lidocaine administration. 11 Facial temperature changes observed were unlikely due to direct thermal conduction or generalized cooling because of the low cooling power of 6 L/min of air (∼8 Watts) even considering maximal evaporative cooling, and the lag in decrease of temperature observed that continued well after the intervention. Moreover, despite unilateral application of cooling, the observed facial temperature decrease was bilateral, further strengthening an argument against direct cooling due to thermal conduction. In fact, at the end of cooling, there was a small but non-significant rise in facial temperature in some patients, which declined gradually to drop well below the baseline temperatures. Kim et al. conducted a similar facial temperature measurement and reported a bilateral vasoconstrictor response despite a unilateral transnasal lidocaine block. 11 These findings and the published reports lead us to conclude that cooling elicits autonomic responses akin to transnasal SPG block. The lack of changes in heart rate suggests that this may represent an autonomic reflex arc and neither a global autonomic response nor a response to generalized cooling. This could be clinically relevant from a safety standpoint in patients with multiple comorbidities who may not tolerate the cardiovascular side effects of conventional abortive medications. In addition, reproducibility of the cooling response and lack of change in heart rate was supported by the persistence of the overall trend across several trials of experimentation in the same volunteer.
Limitations include the small sample size and mostly male cohort as females are more prone to headache disorders. In addition, our study did not include a control group. We aimed to mitigate the effect of this by including a baseline period (Phase 0) to allow each volunteer to effectively serve as their own control. Lastly, chronic headache patients may have different autonomic responses at baseline compared to healthy counterparts.
Conclusion
Transnasal intervention has shown to be a promising method for the treatment of migraine. The need for a self-administered, noninvasive modality has led to the development of transnasal cooling that has been shown to relieve symptoms in clinical trials. The results of this study emphasize that unilateral transnasal cooling causes a global reduction in temperature of the face with no change in heart rate, suggesting an augmented autonomic reflex arc. The observed effects of transnasal cooling suggest that this intervention may result in sympathetic activation leading to vasoconstriction of facial cutaneous vessels in the trigeminal territory. These data provide a mechanistic explanation in favor of transnasal cooling as a treatment for acute migraine and may be further investigated in ongoing clinical trials (NCT06051604).
Key findings
A statistically significant decrease in facial temperature was observed post-transnasal cooling intervention.
As facial capillary tone is controlled by autonomic sympathetic fibers, this finding suggests that transnasal cooling may contribute to localized vasoconstriction and autonomic response.
Supplemental Material
sj-docx-1-rep-10.1177_25158163241276487 - Supplemental material for Analysis of autonomic responses during transnasal cooling via facial temperature and heart rate monitoring
Supplemental material, sj-docx-1-rep-10.1177_25158163241276487 for Analysis of autonomic responses during transnasal cooling via facial temperature and heart rate monitoring by Akhilesh Gonuguntla, Ananya Tandri, Hemantkumar Tripathi, Aravindan Kolandaivelu and Harikrishna Tandri in Cephalalgia Reports
Footnotes
Declaration of conflicting interests
HT is the co-founder of CoolTech LLC, which is developing a trans-nasal cooling device for use in migraine.
Ethics
A written informed consent was obtained from all individual participants included in the study. All procedures performed in this study involving human participants were approved by the Research Ethics Committee.
Funding
The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Cooltech provided funding for the thermal camera used in the study.
Supplemental material
Supplemental material for this article is available online.
References
Supplementary Material
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