Table 2.

A summary of functional magnetic resonance imaging (fMRI) studies that have investigated the brain regions secondarily activated by auricular transcutaneous vagal nerve stimulation.

Reference	n	Subjects	Location of auricular stimulation	Location of sham stimulation	Parameters	Key findings	Effect on the autonomic nervous system (cardiovascular parameters)	One‐line summary
(Kraus et al. 2007)	22	Healthy controls	Left external acoustic meatus on the inner side of the tragus	Earlobe	20 μs 8 Hz 30 s On 120 s Off	Tragus vs. Control: BOLD‐signal ↓ in limbic and temporal brain areas, including bilateral amygdala, parahippocampal gyrus, precuneus region, middle temporal gyrus, posterior cingulate cortex, paracentral lobe, superior frontal gyrus and the left hippocampus BOLD‐signal ↑ in the insula and precentral gyrus on both sides and in the right thalamus (ventral lateral nucleus) and right anterior cingulate cortex	There were no significant differences in heart rate and blood pressure (before vs. after auricular tVNS) in the experimental vs. control group (unpublished data)	Auricular tVNS at the left external acoustic meatus on the inner side of the tragus shares brain activation patterns observed during invasive vagal nerve stimulation
(Dietrich et al. 2008)	4	Healthy controls	Inner wall of the left tragus	No (compared with baseline)	250 μs 25 Hz 50 s On 100 s Off	Tragus vs. baseline: BOLD‐signal ↑ in left locus coeruleus, thalamus (left >> right), left prefrontal cortex, right and left postcentral gyrus, left posterior cingulate gyrus and left insula BOLD‐signal ↓ in right nucleus accumbens and right cerebellar hemisphere	Not reported	Auricular tVNS at the inner wall of the left tragus is appropriate for accessing cerebral vagus nerve structures
(Kraus et al. 2013)	16	Healthy controls	Inner wall of the left tragus vs. posterior side of the left ear canal	Earlobe	20 μs 8 Hz 30 s On 60 s Off	Tragus vs. Control BOLD‐signal ↑ in the left insula and in the left medial frontal gyrus Significantly less activation during anterior stimulation as compared with sham stimulation in the left parahippocampal gyrus. Furthermore, there was a tendency toward the same effect in the left posterior and the right thalamus pulvinar, which both failed to be significant Posterior side of the left ear canal vs. sham Significantly less activation during posterior stimulation vs. sham stimulation in the left and right superior frontal gyrus, the right medial frontal gyrus, and the left subgenual cingulate Tendency toward the same effect in the left anterior cingulate and the left uncus which both failed to be significant Anterior side of the left ear canal vs. posterior side In most cortical areas, BOLD‐signal changes were in the opposite direction when comparing anterior vs. posterior stimulation of the left auditory canal. The only exception was in the insular cortex, where both stimulation types evoked positive BOLD‐signal changes Anterior versus posterior stimulation In most brain regions, stimulation of the anterior wall leads to higher BOLD‐signal changes vs. posterior wall In the left parahippocampal gyrus, the left posterior cingulate and the right thalamus pulvinar, the effect was the other way round, i.e. posterior stimulation evoked higher BOLD‐signal changes vs. anterior stimulation Brain stem regions In the brain stem areas (locus coeruleus, solitary tract), effects were only found when comparing stimulations of the anterior wall with sham stimulation, with a stronger BOLD signal decrease during anterior stimulation	Not reported	Vagal afferents can be stimulated at the outer canal of the ear, especially if done at the anterior side of the external acoustic meatus
(Frangos et al. 2015)	12	Healthy controls	L cymba concha	Earlobe	250 μs 25 Hz 7 min On 11 min Off	Cymba concha vs. control BOLD‐signal ↑ ipsilateral nucleus of the solitary tract, bilateral spinal trigeminal nucleus, dorsal raphe, locus coeruleus, and contralateral parabrachial area, amygdala, and nucleus accumbens BOLD‐signal ↑ paracentral lobule bilaterally BOLD‐signal ↓ hippocampus and hypothalamus	No significant effect on heart rate (unpublished data)	The cymba concha is a biologically active site for auricular tVNS
(Yakunina et al. 2017)	37	Healthy controls	The left inner tragus, left inferoposterior wall of the ear canal, left cymba concha	Earlobe	500 μs 25 Hz 6 min On 90 s Off	Stimulation of the inferoposterior wall of the ear canal produced the weakest activation of the nucleus of solitary tract and locus coeruleus Stimulation of the inner tragus and cymba concha activated nucleus of solitary tract and locus coeruleus as compared to sham Only stimulation of the cymba concha produced a significantly stronger activation in the nucleus of solitary tract and locus coeruleus vs. sham stimulation	No subjects experienced bradycardia (heart rate < 60 bpm) or abnormal cardiac behavior during the auricular tVNS course	Both the cymba concha and inner tragus are active vagal sites, however, the cymba concha is the more biologically active site
(Badran et al. 2018b)	17	Healthy controls	Left tragus	Earlobe	500 μs 25 Hz 60 s On 60 s Off	Tragus vs. control BOLD‐signal ↑ right caudate, bilateral anterior cingulate, cerebellum, left prefrontal cortex, and mid‐cingulate gyrus	Results published in a separate article (Badran et al. 2017) with a different group of healthy participants (n = 15) Auricular tVNS resulted in a 1.1 beats per minute mean reduction in heart rate (P < 0.05)	The inner tragus is an active vagal stimulation site

The number of subjects, location of stimulation, site of sham stimulation, parameters of stimulation and pertinent findings are listed for each study.

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