Basic Research| Volume 26, ISSUE 3, P601-606, April 2023

Download started.


Vagus Nerve Stimulation Modulates Phase-Amplitude Coupling in Thalamic Local Field Potentials



      The antiseizure effects of vagus nerve stimulation (VNS) are thought to be mediated by the modulation of afferent thalamocortical circuitry. Cross-frequency phase-amplitude coupling (PAC) is a mechanism of hierarchical network coordination across multiple spatiotemporal scales. In this study, we leverage local field potential (LFP) recordings from the centromedian (CM) (n = 3) and anterior (ATN) (n = 2) nuclei in five patients with tandem thalamic deep brain stimulation and VNS to study neurophysiological changes in the thalamus in response to VNS.

      Materials and Methods

      Bipolar LFP data were recorded from contact pairs spanning target nuclei in VNS “on” and “off” states.


      Active VNS was associated with increased PAC between theta, alpha, and beta phase and gamma amplitude in CM (q < 0.05). Within the ATN, PAC changes also were observed, although these were less robust. In both nuclei, active VNS also modulated interhemispheric bithalamic functional connectivity.


      We report that VNS is associated with enhanced PAC and coordinated interhemispheric interactions within and between thalamic nuclei, respectively. These findings advance understanding of putative neurophysiological effects of acute VNS and contextualize previous animal and human studies showing distributed cortical synchronization after VNS.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Doruk Camsari D.
        • Kirkovski M.
        • Croarkin P.E.
        Therapeutic applications of invasive neuromodulation in children and adolescents.
        Psychiatr Clin North Am. 2018; 41: 479-483
        • Murphy J.V.
        • Patil A.A.
        Stimulation of the nervous system for the management of seizures: current and future developments.
        CNS Drugs. 2003; 17: 101-115
        • Elliott R.E.
        • Rodgers S.D.
        • Bassani L.
        • et al.
        Vagus nerve stimulation for children with treatment-resistant epilepsy: a consecutive series of 141 cases.
        J Neurosurg Pediatr. 2011; 7: 491-500
        • Hachem L.D.
        • Wong S.M.
        • Ibrahim G.M.
        The vagus afferent network: emerging role in translational connectomics.
        Neurosurg Focus. 2018; 45: E2
        • Ibrahim G.M.
        • Sharma P.
        • Hyslop A.
        • et al.
        Presurgical thalamocortical connectivity is associated with response to vagus nerve stimulation in children with intractable epilepsy.
        NeuroImage Clin. 2017; 16: 634-642
        • Fisher R.
        • Salanova V.
        • Witt T.
        • et al.
        Electrical stimulation of the anterior nucleus of thalamus for treatment of refractory epilepsy.
        Epilepsia. 2010; 51: 899-908
        • Koeglsperger T.
        • Mehrkens J.H.
        • Bötzel K.
        Bilateral double beta peaks in a PD patient with STN electrodes.
        Acta Neurochir (Wien). 2021; 163: 205-209
        • Cummins D.D.
        • Kochanski R.B.
        • Gilron R.
        • et al.
        Chronic sensing of subthalamic local field potentials: comparison of first and second generation implantable bidirectional systems within a single subject.
        Front Neurosci. 2021; 15725797
        • Jimenez-Shahed J.
        Device profile of the percept PC deep brain stimulation system for the treatment of Parkinson’s disease and related disorders.
        Expert Rev Med Devices. 2021; 18: 319-332
        • Beckstead R.M.
        • Morse J.R.
        • Norgren R.
        The nucleus of the solitary tract in the monkey: projections to the thalamus and brain stem nuclei.
        J Comp Neurol. 1980; 190: 259-282
        • Liu W.C.
        • Mosier K.
        • Kalnin A.J.
        • Marks D.
        BOLD fMRI activation induced by vagus nerve stimulation in seizure patients.
        J Neurol Neurosurg Psychiatry. 2003; 74: 811-813
        • Canolty R.T.
        • Knight R.T.
        The functional role of cross-frequency coupling.
        Trends Cogn Sci. 2010; 14: 506-515
        • Lakatos P.
        • Shah A.S.
        • Knuth K.H.
        • Ulbert I.
        • Karmos G.
        • Schroeder C.E.
        An oscillatory hierarchy controlling neuronal excitability and stimulus processing in the auditory cortex.
        J Neurophysiol. 2005; 94: 1904-1911
        • Von Stein A.
        • Sarnthein J.
        Different frequencies for different scales of cortical integration: from local gamma to long range alpha/theta synchronization.
        Int J Psychophysiol. 2000; 38: 301-313
        • Fries P.
        • Womelsdorf T.
        • Oostenveld R.
        • Desimone R.
        The effects of visual stimulation and selective visual attention on rhythmic neuronal synchronization in macaque area V4.
        J Neurosci. 2008; 28: 4823-4835
        • Buzsáki G.
        Neural syntax: cell assemblies, synapsembles, and readers.
        Neuron. 2010; 68: 362-385
        • Canolty R.T.
        • Edwards E.
        • Dalal S.S.
        • et al.
        High gamma power is phase-locked to theta oscillations in human neocortex.
        Science. 2006; 313: 1626-1628
        • Opri E.
        • Cernera S.
        • Okun M.S.
        • Foote K.D.
        • Gunduz A.
        The functional role of thalamocortical coupling in the human motor network.
        J Neurosci. 2019; 39: 8124-8134
        • Chacko R.V.
        • Kim B.
        • Jung S.W.
        • et al.
        Distinct phase-amplitude couplings distinguish cognitive processes in human attention.
        Neuroimage. 2018; 175: 111-121
        • Malekmohammadi M.
        • Elias W.J.
        • Pouratian N.
        Human thalamus regulates cortical activity via spatially specific and structurally constrained phase-amplitude coupling.
        Cereb Cortex. 2015; 25: 1618-1628
        • Ibrahim G.M.
        • Wong S.
        • Morgan B.R.
        • et al.
        Phase-amplitude coupling within the anterior thalamic nuclei during seizures.
        J Neurophysiol. 2018; 119: 1497-1505
        • Ibrahim G.M.
        • Wong S.M.
        • Anderson R.A.
        • et al.
        Dynamic modulation of epileptic high frequency oscillations by the phase of slower cortical rhythms.
        Exp Neurol. 2014; 251: 30-38
        • Martire D.J.
        • Wong S.
        • Mikhail M.
        • et al.
        Thalamocortical dysrhythmia in intraoperative recordings of focal epilepsy.
        J Neurophysiol. 2019; 121: 2020-2027
        • Weiss S.A.
        • Banks G.P.
        • McKhann G.M.
        • et al.
        Ictal high frequency oscillations distinguish two types of seizure territories in humans.
        Brain. 2013; 136: 3796-3808
        • Goyal A.
        • Goetz S.
        • Stanslaski S.
        • et al.
        The development of an implantable deep brain stimulation device with simultaneous chronic electrophysiological recording and stimulation in humans.
        Biosens Bioelectron. 2021; 176112888
        • Horn A.
        • Li N.
        • Dembek T.A.
        • et al.
        Lead-DBS v2: Towards a comprehensive pipeline for deep brain stimulation imaging.
        Neuroimage. 2019; 184: 293-316
        • Gramfort A.
        • Luessi M.
        • Larson E.
        • et al.
        MEG and EEG data analysis with MNE-Python.
        Front Neurosci. 2013; 7: 267
        • Zandvoort C.S.
        • Nolte G.
        Defining the filter parameters for phase-amplitude coupling from a bispectral point of view.
        J Neurosci Methods. 2021; 350109032
        • Imperatori L.S.
        • Betta M.
        • Cecchetti L.
        • et al.
        EEG functional connectivity metrics wPLI and wSMI account for distinct types of brain functional interactions.
        Sci Rep. 2019; 9: 8894
        • Virtanen P.
        • Gommers R.
        • Oliphant T.E.
        • et al.
        SciPy 1.0: fundamental algorithms for scientific computing in Python.
        Nat Methods. 2020; 17: 261-272
        • Chauvin A.
        • Worsley K.J.
        • Schyns P.G.
        • Arguin M.
        • Gosselin F.
        Accurate statistical tests for smooth classification images.
        J Vis. 2005; 5: 659-667
      1. Seabold S, Perktold J. Econometric and statistical modeling with Python. Paper presented at: Proceedings of the 9th Python in Science Conferences; June 28–July 3, 2010; Austin, Texas.

        • Mithani K.
        • Mikhail M.
        • Morgan B.R.
        • et al.
        Connectomic profiling identifies responders to vagus nerve stimulation.
        Ann Neurol. 2019; 86: 743-753
        • Guye M.
        • Régis J.
        • Tamura M.
        • et al.
        The role of corticothalamic coupling in human temporal lobe epilepsy.
        Brain. 2006; 129: 1917-1928
        • Voloh B.
        • Valiante T.A.
        • Everling S.
        • Womelsdorf T.
        Theta-gamma coordination between anterior cingulate and prefrontal cortex indexes correct attention shifts.
        Proc Natl Acad Sci U S A. 2015; 112: 8457-8462
        • Cao J.
        • Lu K.H.
        • Powley T.L.
        • Liu Z.
        Vagal nerve stimulation triggers widespread responses and alters large-scale functional connectivity in the rat brain.
        PLoS One. 2017; 12e0189518
        • Zhu J.
        • Xu C.
        • Zhang X.
        • et al.
        The thalamus-precentral gyrus functional connectivity changes in epilepsy patients following vagal nerve stimulation.
        Neurosci Lett. 2021; 751135815