Vagus nerve stimulation induces widespread cortical and behavioral activation

Collins, Lindsay; Boddington, Laura; Steffan, Paul J.; McCormick, David A.

doi:10.1016/j.cub.2021.02.049

Cited by 95 publications

(75 citation statements)

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“…Left VNS has also been found to speed extinction and prevent reinstatement of drug seeking ( Childs et al, 2017 , 2019 ) and of conditioned fear ( Peña et al, 2013 , 2014 ; Childs et al, 2015 ; Burger et al, 2016 ; Noble et al, 2017 , 2019 ; Szeska et al, 2020 ; Souza et al, 2021 ). These effects of l-VNS are thought to depend on the coordinated activation of multiple neuromodulatory systems, including broadly projecting cholinergic, noradrenergic, and serotonergic systems ( Detari et al, 1983 ; Krahl et al, 1998 ; Dorr and Debonnel, 2006 ; Osharina et al, 2006 ; Cunningham et al, 2008 ; Manta et al, 2009 ; Ruffoli et al, 2011 ; Hays, 2016 ; Hulsey et al, 2016 , 2019 ; Meyers et al, 2019 ; Collins et al, 2021 ). Consistent with the results of the current study, we recently demonstrated that cortical dopamine is not required for l-VNS induced neuroplasticity to occur ( Brougher et al, 2021 ), nor is l-VNS typically found to be inherently rewarding ( Noble et al, 2019 ; Hickman et al, 2021 ; Müller et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

“…Cervical VNS is currently under investigation for multiple other neurological and neurodegenerative disorders, including Alzheimer’s disease ( Chang et al, 2018 ; Slater and Wang, 2021 ), trauma and anxiety disorders ( Marin et al, 2014 ; Noble et al, 2019 ), and autism ( Engineer et al, 2017 ; van Hoorn et al, 2019 ), among others ( Hays, 2016 ; Wang et al, 2021 ). Though the mechanisms of l-VNS efficacy are incompletely understood, it has been shown that VNS exerts wide-ranging neurological effects in part through activation of the broadly projecting nucleus of the solitary tract and several downstream neuromodulatory nuclei, which include the noradrenergic locus coeruleus (LC), the serotonergic raphe nuclei, and the cholinergic medial forebrain ( Detari et al, 1983 ; Krahl et al, 1998 ; Dorr and Debonnel, 2006 ; Osharina et al, 2006 ; Cunningham et al, 2008 ; Manta et al, 2009 ; Ruffoli et al, 2011 ; Collins et al, 2021 ). Coordinated activation of these neuromodulatory systems is thought to promote therapeutic neuroplasticity, resulting in improved clinical outcomes ( Hays et al, 2013 ; Conway and Xiong, 2018 ; Wang et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

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Self-Administration of Right Vagus Nerve Stimulation Activates Midbrain Dopaminergic Nuclei

et al. 2021

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Background: Left cervical vagus nerve stimulation (l-VNS) is an FDA-approved treatment for neurological disorders including epilepsy, major depressive disorder, and stroke, and l-VNS is increasingly under investigation for a range of other neurological indications. Traditional l-VNS is thought to induce therapeutic neuroplasticity in part through the coordinated activation of multiple broadly projecting neuromodulatory systems in the brain. Recently, it has been reported that striking lateralization exists in the anatomical and functional connectivity between the vagus nerves and the dopaminergic midbrain. These emerging findings suggest that VNS-driven activation of this important plasticity-promoting neuromodulatory system may be preferentially driven by targeting the right, rather than the left, cervical nerve.Objective: To compare the effects of right cervical VNS (r-VNS) vs. traditional l-VNS on self-administration behavior and midbrain dopaminergic activation in rats.Methods: Rats were implanted with a stimulating cuff electrode targeting either the right or left cervical vagus nerve. After surgical recovery, rats underwent a VNS self-administration assay in which lever pressing was paired with r-VNS or l-VNS delivery. Self-administration was followed by extinction, cue-only reinstatement, and stimulation reinstatement sessions. Rats were sacrificed 90 min after completion of behavioral training, and brains were removed for immunohistochemical analysis of c-Fos expression in the dopaminergic ventral tegmental area (VTA) and substantia nigra pars compacta (SNc), as well as in the noradrenergic locus coeruleus (LC).Results: Rats in the r-VNS cohort performed significantly more lever presses throughout self-administration and reinstatement sessions than did rats in the l-VNS cohort. Moreover, this appetitive behavioral responding was associated with significantly greater c-Fos expression among neuronal populations within the VTA, SNc, and LC. Differential c-Fos expression following r-VNS vs. l-VNS was particularly prominent within dopaminergic midbrain neurons.Conclusion: Our results support the existence of strong lateralization within vagal-mesencephalic signaling pathways, and suggest that VNS targeted to the right, rather than left, cervical nerve preferentially activates the midbrain dopaminergic system. These findings raise the possibility that r-VNS could provide a promising strategy for enhancing dopamine-dependent neuroplasticity, opening broad avenues for future research into the efficacy and safety of r-VNS in the treatment of neurological disease.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Self-Administration of Right Vagus Nerve Stimulation Activates Midbrain Dopaminergic Nuclei

et al. 2021

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“…While pupil dilation has been considered as a potential biosensor for successful VNS, particularly following findings in animal model studies [62,63], our results show no effect of taVNS on resting pupil size in humans in line with a number of other studies [27][28][29]64]. There are several reasons why we may have failed to detect pupil dilation changes under taVNS relative to the sham condition: (1) the transcutaneous protocol used was insufficient to stimulate the vagus nerve sufficiently, perhaps due to the stimulation parameters (pulse width, frequency and amplitude) which still need further optimization [6,65]; however our current study did find both eye-gaze and oxytocin concentration changes after the stimulation, which suggest that the taVNS parameters chosen do have functional effects; (2) the procedure used to measure pupil dilation (i.e., the way we defined baseline pupil size and selection of time points) might also have influenced the results.…”

Section: Discussionmentioning

confidence: 99%

Transcutaneous auricular vagus nerve stimulation increases eye-gaze on salient facial features and oxytocin release

Zhu

Qing

Zhang

et al. 2021

Preprint

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Background: Transcutaneous auricular vagus nerve stimulation (taVNS) is a non-invasive neuromodulation technique with promising therapeutic potential in the context of epilepsy, pain, and depression and which may also have beneficial effects on social cognition. However, the underlying mechanisms of taVNS are unclear and evidence regarding its role in social cognition improvement is limited. Objective: In order to investigate the impact of taVNS on social cognition we have studied its effects on gaze towards emotional faces using an eye-tracking task and also on release of the neuropeptide oxytocin which plays a key role in influencing social cognition and motivation. Methods: A total of fifty-four subjects were enrolled in a sham-controlled, participant-blind crossover experiment, consisting of two treatment sessions, separated by one week. In one session participants received 30-min taVNS (tragus), and in the other, they received 30-min sham (earlobe) stimulation with the treatment order counterbalanced across participants. Gaze duration towards the faces and facial features (eyes, nose, and mouth) were measured together with resting pupil size. Additionally, saliva samples were taken for the measurement of oxytocin concentrations by enzyme-linked immunoassay. Results: Saliva oxytocin concentrations increased significantly after taVNS compared to sham stimulation, while resting pupil size did not. In addition, taVNS increased fixation time on the nose region irrespective of face emotion, and this was positively correlated with increased saliva oxytocin concentrations. Conclusion: Our findings suggest that taVNS biases visual attention towards socially salient facial features across different emotions and this is associated with its effects on increasing endogenous oxytocin release.

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“…(D) During stimulation, a sigmoid-like relationship was found between the pupil dilation and the charge per pulse ( Mridha et al, 2021 ). An increased pupil diameter was observed with an increasing current intensity and duration in a dose-dependent manner ( Collins et al, 2021 ). (E) A significant increased NE was reached in the cortex following VNS with an intensity of 1 mA (20 Hz, 500 μs pulse width, and 30 s duration) ( Roosevelt et al, 2006 ).…”

Section: Introductionmentioning

confidence: 99%

“…Another study observed an increased level of extracellular NE in the prefrontal cortex after long-term VNS (2 weeks, 0.25 mA, 20 Hz, and 500 μs pulse width) ( Manta et al, 2013 ). (F) A study using GCaMP6s imaging in Thy1-GCaMP6s mice revealed an increased fluorescence in NE axons within the dorsal cerebral cortex during VNS, with larger and longer lasting effects for higher intensities and longer pulse width stimulations ( Collins et al, 2021 ). (G) An increase in ΔFosB was observed in the DRN after chronic VNS (3 weeks), but no increase in c-Fos was observed after acute VNS (2 h) in the DRN (0.25 mA, 20 Hz, 250 μs pulse width, 30 s ON, and 5 min OFF) ( Cunningham et al, 2008 ).…”

Section: Introductionmentioning

confidence: 99%

How Is the Norepinephrine System Involved in the Antiepileptic Effects of Vagus Nerve Stimulation?

et al. 2021

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Vagus Nerve Stimulation (VNS) is an adjunctive treatment for patients suffering from inoperable drug-resistant epilepsy. Although a complete understanding of the mediators involved in the antiepileptic effects of VNS and their complex interactions is lacking, VNS is known to trigger the release of neurotransmitters that have seizure-suppressing effects. In particular, norepinephrine (NE) is a neurotransmitter that has been associated with the clinical effects of VNS by preventing seizure development and by inducing long-term plastic changes that could restore a normal function of the brain circuitry. However, the biological requisites to become responder to VNS are still unknown. In this review, we report evidence of the critical involvement of NE in the antiepileptic effects of VNS in rodents and humans. Moreover, we emphasize the hypothesis that the functional integrity of the noradrenergic system could be a determining factor to obtain clinical benefits from the therapy. Finally, encouraging avenues of research involving NE in VNS treatment are discussed. These could lead to the personalization of the stimulation parameters to maximize the antiepileptic effects and potentially improve the response rate to the therapy.

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Vagus nerve stimulation induces widespread cortical and behavioral activation

Cited by 95 publications

References 62 publications

Self-Administration of Right Vagus Nerve Stimulation Activates Midbrain Dopaminergic Nuclei

Self-Administration of Right Vagus Nerve Stimulation Activates Midbrain Dopaminergic Nuclei

Transcutaneous auricular vagus nerve stimulation increases eye-gaze on salient facial features and oxytocin release

How Is the Norepinephrine System Involved in the Antiepileptic Effects of Vagus Nerve Stimulation?

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