Effects of vagus nerve stimulation on pupillary function☆
Introduction
Chronic vagus nerve stimulation (VNS) is recognized as a safe and effective treatment for medically refractory epilepsy and depression (Ben-Menachem et al., 1994, Elger et al., 2000, Rush et al., 2000). VNS usually consists of a chronic intermittent stimulation of the left vagus nerve at the level of the neck, delivered by implanted electrodes and operated by a subcutaneous generator. The mechanisms underlying the central effects of VNS are still not fully understood. The vagus nerve is a major route of sensory visceral information to the brain arising from end organs and projecting to the nucleus of the tractus solitarius (NTS) which projects to the dorsal raphe nucleus, parabrachial nucleus (PBN) and the locus coeruleus (LC) in the brainstem as well as to the amygdala, hypothalamus, thalamus and cortex (Takigawa and Mogenson, 1977, Ter Horst et al., 1989).
VNS can induce changes in activity in a number of brain regions including limbic system, prefrontal cortex, thalamus and cerebellum (Conway et al., 2013, Chae et al., 2003, Henry et al., 2004, Kosel et al., 2011, Nahas et al., 2007, Zobel et al., 2005). There is a growing body of evidence that antiepileptic and antidepressant effects of VNS result at least in part from a modulation of ascending monoaminergic pathways in the brain (see Krahl and Clark, 2012 for a review). In rats, chronic VNS produces increased extracellular norepinephrine levels in the prefrontal cortex and hippocampus as well as increased extracellular dopamine levels in the prefrontal cortex and nucleus accumbens (Manta et al., 2009, Manta et al., 2013, Roosevelt et al., 2006). Lesions to the LC, the main source of forebrain noradrenergic neuromodulation, prevent antidepressant-like effects of VNS in animals (Grimonprez et al., 2015).
Investigations on VNS would profit from the development of reliable biomarkers to help monitor and predict its effects. VNS can affect EEG (Koo, 2001, Marrosu et al., 2005) but its effects on basal EEG independent of epileptic activity are unclear (Hammond et al., 1992a, Hammond et al., 1992b, Salinsky and Burchiel, 1993). VNS affects autonomic activity, as it has been reported to increase cardiac sympathetic activity in patients suffering from refractory epilepsy (Jansen et al., 2011). Also, electrical stimulation of the afferent vagus nerve in rats gives rise to bilateral intensity-dependent pupil dilation (Bianca and Komisaruk, 2007). The effects of VNS on human pupillary activity have yet to be examined.
The aim of the present study was to examine pupil activity as a marker of the effects of VNS on human patients. Pupillometry has long been recognized as a simple non-invasive technique sensitive to autonomic modulation (Bremner, 2009, Lowenfeld and Lowenstein, 1993). Pupil diameter is under a dual autonomic innervation. The parasympathetic control of the pupil involves fibers projecting from the Edinger-Westphal (EW) nucleus to the ciliary ganglion (CG), and finally to the iris sphincter muscle, while the sympathetic control of the pupil consists of fibers projecting from the posterior hypothalamus to the spinal cord to the superior cervical ganglion, and finally to the dilator muscle. Two brainstem nuclei that are modulated by VNS (PBN and LC) project to the cholinergic part of the EW nucleus controlling the pupil (Akert et al., 1980, Berridge and Waterhouse, 2003, Breen et al., 1983, Bremner, 2009, Kozicz et al., 2011). Also, pupil diameter has been shown to correlate with mesencephalic activity in the region of the locus coeruleus in humans (Murphy et al., 2014). The resting diameter of the pupil, as well as its reactivity during the light reflex could thus provide valuable information on the effects of VNS on the autonomic nervous system, as well as providing a marker of brainstem modulation by VNS.
Section snippets
Participants
Thirty-four subjects (22 with refractory epilepsy, 12 with refractory depression) treated with VNS therapy were recruited for the study. Inclusion criteria were: being actively treated with VNS therapy; being able to detect the presence of the trains of stimulation through throat sensations as, until now, it is the only reliable way to determine when the stimulation is active; having normal or corrected-to-normal vision; and being able to refrain from blinking for a few seconds. Exclusion
Results
Clinical and demographic data on patients are presented in Table 1. The mean age was 41.0 yrs. (S.D. = 11.1 yrs) and patients in the epilepsy group were slightly but significantly younger (mean age = 36.9 yrs) than those in the depression group (mean age = 49.1 yrs), (t (19) = 2.7, p = .013, partial η2 = 0.28). Mean stimulation intensity was 1.2 mA (0.25–2.25) and the two patient groups did not differ significantly on this parameter (t (19) = −.696, p = .495). The amount of time that patients had received VNS
Discussion
The primary goal of this study was to examine the pupillary effects of VNS. The results indicate that compared to periods without VNS, periods with VNS showed significant increases in resting pupillary diameter. This increase cannot be attributed to medication or changes in symptomatology, as these factors did not change between consecutive ON and OFF stimulation intervals. Also, the effect is not linked to variations in attention or vigilance between the two conditions, as patients were
Acknowledgments
The authors would like to thanks Maxime Philibert PhD and Alain Bouthillier MD for their collaboration, as well as Elise LaGarde MSc RN and Sylvie Tieu BSc RN, for her assistance in clinical data collection. The authors declare no competing financial interests.
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Short bursts of transcutaneous auricular vagus nerve stimulation enhance evoked pupil dilation as a function of stimulation parameters
2023, CortexCitation Excerpt :Electrical stimulation of the afferent fibres of the VN is believed to modulate the LC via its connection to the nucleus of the solitary tract innervating the LC (Grimonprez, Raedt, Baeken, Boon, & Vonck, 2015; Ruffoli et al., 2011; Vonck et al., 2014). This hypothesis is based on evidence from rat studies showing that the invasive form of VNS (iVNS) increases LC firing rates (e.g., Chen & Williams, 2012; Dorr & Debonnel, 2006) as a function of stimulation parameters (Hulsey et al., 2017). In particular, longer pulse widths and higher intensities seem to drive greater LC firing rates in rats (Hulsey et al., 2017).
Characterization of vagus nerve stimulation-induced pupillary responses in epileptic patients
2022, Brain StimulationCitation Excerpt :Specifically, an indicator of the sustained pupil dilation response (PDR) along the stimulation train was shown to increase as a function of the VNS total electric charge administered [13]. In humans, it has been shown that during VNS the average pupil diameter is larger compared to when VNS is turned off [14]. However, no stimulation-locked modifications of pupil size were reported.
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Abstract: Desbeaumes V, Nguyen DK, Philibert M, Fournier-Gosselin MP, Lespérance P, Richer F. Effects of vagus nerve stimulation on pupil function. In: Society for Neuroscience; 2014; Washington D.C.; Abstract nr Y7 615.27