Effects of vagus nerve stimulation on pupillary function

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Highlights

  • We investigated the influence of vagus nerve stimulation (VNS) on the human central autonomic nervous system.

  • We recorded pupil measures during ON and OFF VNS conditions.

  • Acute VNS induced an increase in resting pupil diameter but no changes in parameters of the light reflex.

Abstract

Background

Chronic vagus nerve stimulation (VNS) is a recognized treatment for refractory epilepsy and depression. The vagus nerve projects to several brainstem autonomic structures. As pupillary measures are an easy and non-invasive method to evaluate autonomic functioning, we used resting diameter and light reflex measures to investigate the influence of VNS on the human central autonomic nervous system.

Method

We studied 21 patients (7 with major depression, 14 with epilepsy) treated with chronic VNS (30 s ON, 5 min OFF stimulation trains). Resting pupil size and light reflex measures were compared in consecutive intervals with (ON) and without stimulation (OFF).

Results

Compared to the OFF condition, the ON condition was associated with a significant increase in resting pupil diameter, but did not affect light reflex measures. There was no group difference between the two populations of patients (depression and epilepsy) on any of the pupil measures.

Conclusion

VNS at clinically significant levels increases resting pupil diameter.

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.

References (48)

  • M.C. Koss

    Pupillary dilation as an index of central nervous system alpha 2-adrenoceptor activation

    J. Pharmacol. Methods

    (1986)
  • M. Lomarev et al.

    Vagus nerve stimulation (VNS) synchronized BOLD fMRI suggests that VNS in depressed adults has frequency/dose dependent effects

    J. Psychiatry Res.

    (2002)
  • F. Marrosu et al.

    Increase in 20–50 Hz (gamma frequencies) power spectrum and synchronization after chronic vagal nerve stimulation

    Clin. Neurophysiol.

    (2005)
  • R.W. Roosevelt et al.

    Increased extracellular concentrations of norepinephrine in cortex and hippocampus following vagus nerve stimulation in the rat

    Brain Res.

    (2006)
  • A.J. Rush et al.

    Vagus nerve stimulation (VNS) for treatment-resistant depressions: a multicenter study

    Biol. Psychiatry

    (2000)
  • M. Takigawa et al.

    A study of inputs to antidromically identified neurons of the locus coeruleus

    Brain Res.

    (1977)
  • A. Zobel et al.

    Changes in regional cerebral blood flow by therapeutic vagus nerve stimulation in depression: an exploratory approach

    Psychiatry Res.

    (2005)
  • G. Aston-Jones et al.

    The brain nucleus locus coeruleus: restricted afferent control of a broad efferent network

    Science

    (1986)
  • E. Ben-Menachem et al.

    Vagus nerve stimulation for treatment of partial seizures: 1. A controlled study of effect on seizures. First International Vagus Nerve Stimulation Study Group

    Epilepsia

    (1994)
  • P. Bitsios et al.

    Comparison of the effects of venlafaxine, paroxetine and desipramine on the pupillary light reflex in man

    Psychopharmacology

    (1999)
  • F. Bremner

    Pupil evaluation as a test for autonomic disorders

    Clin. Auton. Res.

    (2009)
  • C.E. Bye et al.

    Changes in the human light reflex as a measure of the anticholinergic effects of drugs. A comparison with other measures

    Eur. J. Clin. Pharmacol.

    (1979)
  • V. Desbeaumes Jodoin et al.

    Chronic Vagus Nerve Stimulation in Treatment Refractory Depression: Long-Term Cognitive Effects

    (2015)
  • C.J. Ellis

    The pupillary light reflex in normal subjects

    Br. J. Ophthalmol.

    (1981)
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