[en] The locus coeruleus–norepinephrine system is thought to be involved in the clinical effects of vagus nerve stimulation. This system is known to prevent seizure development and induce long-term plastic changes, particularly with the release of norepinephrine in the hippocampus. However, the requisites to become responder to the therapy and the mechanisms of action are still under investigation. Using MRI, we assessed the structural and functional characteristics of the locus coeruleus and microstructural properties of locus coeruleus-hippocampus white matter tracts in patients with drug-resistant epilepsy responding or not to the therapy. Twenty-three drug-resistant epileptic patients with cervical vagus nerve stimulation were recruited for this pilot study, including 13 responders or partial responders and 10 non-responders. A dedicated structural MRI acquisition allowed in vivo localization of the locus coeruleus and computation of its contrast (an accepted marker of LC integrity). Locus coeruleus activity was estimated using functional MRI during an auditory oddball task. Finally, multi-shell diffusion MRI was used to estimate the structural properties of locus coeruleus-hippocampus tracts. These characteristics were compared between responders/partial responders and non-responders and their association with therapy duration was also explored. In patients with a better response to the therapy, trends toward a lower activity and a higher contrast were found in the left medial and right caudal portions of the locus coeruleus, respectively. An increased locus coeruleus contrast, bilaterally over its medial portions, correlated with duration of the treatment. Finally, a higher integrity of locus coeruleus-hippocampus connections was found in patients with a better response to the treatment. These new insights into the neurobiology of vagus nerve stimulation may provide novel markers of the response to the treatment and may reflect neuroplasticity effects occurring in the brain following the implantation.
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Bibliography
Andersson J. L. Sotiropoulos S. N. (2016). An integrated approach to correction for off-resonance effects and subject movement in diffusion MR imaging. Neuroimage 125 1063–1078. 10.1016/j.neuroimage.2015.10.019 26481672
Aston-Jones G. Ennis M. Pieribone V. A. Thompson Nickell W. Shipley M. T. (1986). The brain nucleus locus coeruleus: Restricted afferent control of a broad efferent. Science 234 734–737. 10.1126/science.3775363 3775363
Aston-Jones G. Shipley M. T. Chouvet G. Ennis M. van Bockstaele E. Pieribone V. et al. (1991). Afferent regulation of locus coeruleus neurons: Anatomy, physiology and pharmacology. Prog. Brain Res. 88 47–75.
Beck D. de Lange A. M. Maximov I. I. Richard G. Andreassen O. A. Nordvik J. E. et al. (2021). White matter microstructure across the adult lifespan: A mixed longitudinal and cross-sectional study using advanced diffusion models and brain-age prediction. Neuroimage 224:117441. 10.1016/j.neuroimage.2020.117441 33039618
Bell T. R. Elman J. A. Beck A. Fennema-Notestine C. Gustavson D. E. Hagler D. J. et al. (2023). Rostral-middle locus coeruleus integrity and subjective cognitive decline in early old age. J. Int. Neuropsychol. Soc. 29 763–774. 10.1017/S1355617722000881 36524301
Berger A. Koshmanova E. Beckers E. Sharifpour R. Paparella I. Campbell I. et al. (2023). Structural and functional characterization of the locus coeruleus in young and late middle-aged individuals. Front. Neuroimaging 2: 1207844. 10.3389/fnimg.2023.1207844 37554637
Berger A. Vespa S. Dricot L. Dumoulin M. Iachim E. Doguet P. et al. (2021). How is the norepinephrine system involved in the antiepileptic effects of vagus nerve stimulation? Front. Neurosci. 15:790943. 10.3389/fnins.2021.790943 34924947
Betts M. J. Cardenas-Blanco A. Kanowski M. Spottke A. Teipel S. J. Kilimann I. et al. (2019). Locus coeruleus MRI contrast is reduced in Alzheimer’s disease dementia and correlates with CSF Aβ levels. Alzheimers Dement. 11 281–285.
Bowden D. M. German D. C. Douglas Poynter W. (1978). An autoradiographic, semistereotaxic mapping of major projections from locus coeruleus and adjacent nuclei in Macaca mulatta. Brain Res. 145 257–276. 10.1016/0006-8993(78)90861-2 416887
Brazdil M. Chadim P. Daniel P. Kuba R. Rektor I. Novak Z. et al. (2001). Effect of vagal nerve stimulation on auditory and visual event-related potentials. Eur. J. Neurol. 8 457–461.
Calarco N. Cassidy C. M. Selby B. Hawco C. Voineskos A. N. Diniz B. S. et al. (2022). Associations between locus coeruleus integrity and diagnosis, age, and cognitive performance in older adults with and without late-life depression: An exploratory study. Neuroimage Clin. 36:103182. 10.1016/j.nicl.2022.103182 36088841
Canteras N. S. Swanson L. W. (1992). Projections of the ventral subiculum to the amygdala, septum, and hypothalamus: A PHAL anterograde tract-tracing study in the rat. J. Comp. Neurol. 324 180–194. 10.1002/cne.903240204 1430328
Cunningham J. T. Mifflin S. W. Gould G. G. Frazer A. (2008). Induction of c-Fos and ΔFosB immunoreactivity in rat brain by vagal nerve stimulation. Neuropsychopharmacology 33 1884–1895. 10.1038/sj.npp.1301570 17957222
Dahl M. J. Mather M. Düzel S. Bodammer N. C. Lindenberger U. Kühn S. et al. (2019). Rostral locus coeruleus integrity is associated with better memory performance in older adults. Nat. Hum. Behav. 3 1203–1214.
De Taeye L. Vonck K. van Bochove M. Boon P. Van Roost D. Mollet L. et al. (2014). The P3 event-related potential is a biomarker for the efficacy of vagus nerve stimulation in patients with epilepsy. Neurotherapeutics 11 612–622. 10.1007/s13311-014-0272-3 24711167
Delinte N. Gosse C. Dricot L. Dessain Q. Simon M. Macq B. et al. (2021). “Microstructural alterations in the white matter of children with dyslexia assessed by multi-fascicle diffusion compartment imaging,” in Proceedings of the International Society for Magnetic Resonance in Medicine, (Chichester: John Wiley and Sons Inc).
Desbeaumes Jodoin V. Lespérance P. Nguyen D. K. Fournier-Gosselin M. P. Richer F. (2015). Effects of vagus nerve stimulation on pupillary function. Int. J. Psychophysiol. 98 455–459.
Doppler C. E. Kinnerup M. B. Brune C. Farrher E. Betts M. Fedorova T. D. et al. (2021). Regional locus coeruleus degeneration is uncoupled from noradrenergic terminal loss in Parkinson’s disease. Brain 144 2732–2744.
Dorr A. E. Debonnel G. (2006). Effect of vagus nerve stimulation on serotonergic and noradrenergic transmission. J. Pharmacol. Exp. Ther. 318 890–898.
Englot D. J. Rolston J. D. Wright C. W. Hassnain K. H. Chang E. F. (2016). Rates and predictors of seizure freedom with vagus nerve stimulation for intractable epilepsy. Neurosurgery 79 345–353.
Ennis M. Aston-Jones G. (1988). Activation of locus coeruleus from nucleus new excitatory amino acid pathway in brain. J. Neurosci. 8 3644–3657.
Ennis M. Aston-Jones G. (1989). GABA-mediated inhibition of locus coeruleus from the dorsomedial rostra1 medulla. J. Neurosci. 8 2973–2981. 10.1523/JNEUROSCI.09-08-02973.1989 2769374
Follesa P. Biggio F. Gorini G. Caria S. Talani G. Dazzi L. et al. (2007). Vagus nerve stimulation increases norepinephrine concentration and the gene expression of BDNF and bFGF in the rat brain. Brain Res. 1179 28–34. 10.1016/j.brainres.2007.08.045 17920573
Fornai F. Ruffoli R. Giorgi F. S. Paparelli A. (2011). The role of locus coeruleus in the antiepileptic activity induced by vagus nerve stimulation. Eur. J. Neurosci. 33 2169–2178.
Galgani A. Lombardo F. Della Latta D. Martini N. Bonuccelli U. Fornai F. et al. (2021). Locus coeruleus magnetic resonance imaging in neurological diseases. Curr. Neurol. Neurosci. Rep. 21:2. 10.1007/s11910-020-01087-7 33313963
Garyfallidis E. Brett M. Amirbekian B. Rokem A. van der Walt S. Descoteaux M. et al. (2014). Dipy, a library for the analysis of diffusion MRI data. Front. Neuroinform. 8:8. 10.3389/fninf.2014.00008 24600385
Groves D. A. Bowman E. M. Brown V. J. (2005). Recordings from the rat locus coeruleus during acute vagal nerve stimulation in the anaesthetised rat. Neurosci. Lett. 379 174–179. 10.1016/j.neulet.2004.12.055 15843058
Hammond E. J. Uthman B. M. Wilder B. J. Ben-Menachem E. Hamberger A. Hedner T. et al. (1992). Neurochemical effects of vagus nerve stimulation in humans. Brain Res. 583 300–303.
Hansen N. (2017). The longevity of hippocampus-dependent memory is orchestrated by the locus coeruleus-noradrenergic system. Neural Plast. 2017:2727602. 10.1155/2017/2727602 28695015
Hansen N. (2021). Locus coeruleus malfunction is linked to psychopathology in prodromal dementia with lewy bodies. Front. Aging Neurosci. 13:641101. 10.3389/fnagi.2021.641101 33732141
Hödl S. Carrette S. Meurs A. Carrette E. Mertens A. Gadeyne S. et al. (2020). Neurophysiological investigations of drug resistant epilepsy patients treated with vagus nerve stimulation to differentiate responders from non-responders. Eur. J. Neurol. 27 1178–1189. 10.1111/ene.14270 32310326
Hulsey D. R. Riley J. R. Loerwald K. W. Rennaker R. L. Kilgard M. P. Hays S. A. (2017). Parametric characterization of neural activity in the locus coeruleus in response to vagus nerve stimulation. Exp. Neurol. 289 21–30. 10.1016/j.expneurol.2016.12.005 27988257
Jacobs H. I. Becker J. A. Kwong K. Engels-Domínguez N. Prokopiou P. C. Papp K. V. et al. (2021). In vivo and neuropathology data support locus coeruleus integrity as indicator of Alzheimer’s disease pathology and cognitive decline. Sci. Transl. Med. 13:2511. 10.1126/scitranslmed.abj2511 34550726
Joshi S. Li Y. Kalwani R. M. Gold J. I. (2016). Relationships between pupil diameter and neuronal activity in the locus coeruleus, colliculi, and cingulate cortex. Neuron 89 221–234. 10.1016/j.neuron.2015.11.028 26711118
Kayyali H. Abdelmoity S. Bansal L. Kaufman C. Smith K. Fecske E. et al. (2020). The efficacy and safety of rapid cycling vagus nerve stimulation in children with intractable epilepsy. Pediatr. Neurol. 109 35–38. 10.1016/j.pediatrneurol.2020.04.003 32461031
Keren N. I. Lozar C. T. Harris K. C. Morgan P. S. Eckert M. A. (2009). In vivo mapping of the human locus coeruleus. Neuroimage 47 1261–1267.
Krahl S. E. Clark K. B. (2012). Vagus nerve stimulation for epilepsy: A review of central mechanisms. Surg. Neurol. Int. 3(Suppl. 4) S255–S259.
Krahl S. E. Clark K. B. Smith D. C. Browning R. A. (1998). Locus coeruleus lesions suppress the seizure-attenuating effects of vagus nerve stimulation. Epilepsia 39 709–714. 10.1111/j.1528-1157.1998.tb01155.x 9670898
Kulkarni V. A. Jha S. Vaidya V. A. (2002). Depletion of norepinephrine decreases the proliferation, but does not influence the survival and differentiation, of granule cell progenitors in the adult rat hippocampus. Eur. J. Neurosci. 16 2008–2012.
Kwan P. Arzimanoglou A. Berg A. T. Brodie M. J. Hauser W. A. Mathern G. et al. (2010). Definition of drug resistant epilepsy: Consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia 51 1069–1077. 10.1111/j.1528-1167.2009.02397.x 19889013
Langley J. Huddleston D. E. Liu C. Hu X. (2017). Reproducibility of locus coeruleus and substantia nigra imaging with neuromelanin sensitive MRI. Magn. Reson. Mater. Phys. Biol. Med. 30 121–125.
Liu K. Y. Kievit R. A. Tsvetanov K. A. Betts M. J. Düzel E. Rowe J. B. et al. (2020). Noradrenergic-dependent functions are associated with age-related locus coeruleus signal intensity differences. Nat. Commun. 11:1712. 10.1038/s41467-020-15410-w 32249849
Loughlin S. E. Foora S. L. Grzanna R. (1986). Efferent projections of nucleus locus coeruleus: Morphologic subpopulations have different efferent targets. Neuroscience 18 307–319. 10.1016/0306-4522(86)90156-9 3736861
Luppi P. H. Aston-Jones G. Akaoka H. Chouvet G. Jouvet M. (1995). Afferent projections to the rat locus coeruleus demonstrated by retrograde and anterograde tracing with cholera-toxin B subunit and phaseolus vulgaris leucoagglutinin. Neuroscience 65 119–160. 10.1016/0306-4522(94)00481-j 7753394
Malberg J. E. Eisch A. J. Nestler E. J. Duman R. S. (2000). Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J. Neurosci. 20 9104–9110.
Manta S. Dong J. Debonnel G. Blier P. (2009). Enhancement of the function of rat serotonin and norepinephrine neurons by sustained vagus nerve stimulation. J. Psychiatry Neurosci. 34 272–280. 19568478
Marien M. R. Colpaert F. C. Rosenquist A. C. (2004). Noradrenergic mechanisms in neurodegenerative diseases: A theory. Brain Res Rev. 45 38–78.
Marzo A. Totah N. K. Neves R. M. Logothetis N. K. Eschenko O. (2014). Unilateral electrical stimulation of rat locus coeruleus elicits bilateral response of norepinephrine neurons and sustained activation of medial prefrontal cortex. J. Neurophysiol. 111, 2570–2588. 10.1152/jn.00920.2013 24671530
Mason S. T. Fibiger H. C. (1979). Regional topography within noradrenergic locus coeruleus as revealed by retrograde transport of horseradish peroxidase. J. Comp. Neurol. 187 703–724. 10.1002/cne.901870405 90684
Mathôt S. Schreij D. Theeuwes J. (2012). OpenSesame: An open-source, graphical experiment builder for the social sciences. Behav. Res. Methods 44 314–324.
Mccrea R. A. Baker R. (1985). Anatomical connections of the nucleus prepositus of the cat. J. Comp. Neurol. 237:407.
McDonald A. J. (1998). Cortical pathways to the mammalian amygdala. Prog. Neurobiol. 55 257–332. 10.1016/s0301-0082(98)00003-3 9643556
Megemont M. McBurney-Lin J. Yang H. (2022). Pupil diameter is not an accurate realtime readout of locus coeruleus activity. Elife 11: e70510.
Meisner O. C. Nair A. Chang S. W. (2022). Amygdala connectivity and implications for social cognition and disorders. Handb Clin Neurol. 187 381–403.
Murphy P. R. Robertson I. H. Balsters J. H. O’connell R. G. (2011). Pupillometry and P3 index the locus coeruleus-noradrenergic arousal function in humans. Psychophysiology. 48 1532–1543. 10.1111/j.1469-8986.2011.01226.x 21762458
Murphy P. O’Connell R. O’Sullivan M. Robertson I. H. Balsters J. H. (2014). Pupil diameter covaries with BOLD activity in human locus coeruleus. Hum. Brain Mapp. 35 4140–4154. 10.1002/hbm.22466 24510607
Naritoku D. K. Terry W. J. Helfert R. H. (1995). Regional induction of fos immunoreactivity in the brain by anticonvulsant stimulation of the vagus nerve. Epilepsy Res. 22 53–62. 10.1016/0920-1211(95)00035-9 8565967
Nieuwenhuis S. Aston-Jones G. Cohen J. D. (2005). Decision making, the P3, and the locus coeruleus-norepinephrine system. Psychol. Bull. 131 510–532.
Pickel V. M. Segal M. Bloom F. E. (1974). A radioautographic study of the efferent pathways of the nucleus locus coeruleus. J. Comp. Neurol. 155 15–41. 10.1002/cne.901550103 4836061
Pitakänen A. Pikkarainen M. Nurminen N. Ylinen A. (2000). Reciprocal connections between the amygdala and the hippocampal formation, perirhinal cortex, and postrhinal cortex in rat: A review. Ann. N. Y. Acad. Sci. 911 369–391. 10.1111/j.1749-6632.2000.tb06738.x 10911886
Poe G. R. Foote S. Eschenko O. Johansen J. P. Bouret S. Aston-Jones G. et al. (2020). Locus coeruleus: A new look at the blue spot. Neuroscience 21 644–659. 10.1038/s41583-020-0360-9 32943779
Porat S. Sibilia F. Yoon J. Shi Y. Dahl M. J. Werkle-Bergner M. et al. (2022). Age differences in diffusivity in the locus coeruleus and its ascending noradrenergic tract. Neuroimage 251:119022. 10.1016/j.neuroimage.2022.119022 35192943
Raedt R. Clinckers R. Mollet L. Vonck K. El Tahry R. Wyckhuys T. et al. (2011). Increased hippocampal noradrenaline is a biomarker for efficacy of vagus nerve stimulation in a limbic seizure model. J. Neurochem. 117 461–469. 10.1111/j.1471-4159.2011.07214.x 21323924
Rensonnet G. (2019). In vivo diffusion magnetic resonance imaging of the white matter microstructure from dictionaries generated by Monte Carlo simulations: Development and validation. Lausanne: EPFL.
Rensonnet G. Scherrer B. Girard G. Jankovski A. Warfield S. K. Macq B. et al. (2019). Towards microstructure fingerprinting: Estimation of tissue properties from a dictionary of Monte Carlo diffusion MRI simulations. Neuroimage 184 964–980. 10.1016/j.neuroimage.2018.09.076 30282007
Revesz D. Tjernstrom M. Ben-Menachem E. Thorlin T. (2008). Effects of vagus nerve stimulation on rat hippocampal progenitor proliferation. Exp. Neurol. 214 259–265.
Reyes B. A. van Bockstaele E. J. (2006). Divergent projections of catecholaminergic neurons in the nucleus of the solitary tract to limbic forebrain and medullary autonomic brain regions. Brain Res. 1117 69–79. 10.1016/j.brainres.2006.08.051 16962080
Roosevelt R. W. Smith D. C. Clough R. W. Jensen R. A. Browning R. A. (2006). Increased extracellular concentrations of norepinephrine in cortex and hippocampus following vagus nerve stimulation in the rat. Brain Res. 1119 124–132. 10.1016/j.brainres.2006.08.048 16962076
Sarlo G. L. Holton K. F. (2021). Brain concentrations of glutamate and GABA in human epilepsy: A review. Seizure 91 213–227.
Satoh K. Tohyama M. Yamamoto K. Sakumoto T. Shimizu N. (1977). Noradrenaline innervation of the spinal cord studied by the horseradish peroxidase method combined with monoamine oxidase staining. Exp. Brain Res. 30 175–186. 10.1007/BF00237249 74341
Saunders R. C. Rosene D. L. Van Hoesen G. W. (1988). Comparison of the efferents of the amygdala and the hippocampal formation in the rhesus monkey: II. Reciprocal and non-reciprocal connections. J. Comp. Neurol. 271 185–207. 10.1002/cne.902710203 2454247
Schevernels H. van Bochove M. E. De Taeye L. Bombeke K. Vonck K. Van Roost D. et al. (2016). The effect of vagus nerve stimulation on response inhibition. Epilepsy Behav. 64 171–179.
Schwarz L. A. Luo L. (2015). Organization of the locus coeruleus-norepinephrine system. Curr. Biol. 25 R1051–R1056.
Shen H. Fuchino Y. Miyamoto D. Nomura H. Matsuki N. (2012). Vagus nerve stimulation enhances perforant path-CA3 synaptic transmission via the activation of β-adrenergic receptors and the locus coeruleus. Int. J. Neuropsychopharmacol. 15 523–530.
Shibata E. Sasaki M. Tohyama K. Otsuka K. Sakai A. (2007). Reduced signal of locus ceruleus in depression in quantitative neuromelanin magnetic resonance imaging. Neuroreport 18 415–418. 10.1097/WNR.0b013e328058674a 17496795
Stewart S. A. (2005). The effects of benzodiazepines on cognition. J. Clin. Psychiatry 66(Suppl. 2) 9–13.
Toffa D. H. Touma L. El Meskine T. Bouthillier A. Nguyen D. K. (2020). Learnings from 30 years of reported efficacy and safety of vagus nerve stimulation (VNS) for epilepsy treatment: A critical review. Seizure 83 104–123. 10.1016/j.seizure.2020.09.027 33120323
van Bochove M. E. De Taeye L. Raedt R. Vonck K. Meurs A. Boon P. et al. (2018). Reduced distractor interference during vagus nerve stimulation. Int. J. Psychophysiol. 128 93–99.
van Bockstaele E. J. Pieribone V. A. Astonjones G. (1989). Diverse merents converge on the nucleus paragigantocelldark in the rat ventrolateral medulla: retrograde and anterograde tracing studies. J. Comp. Neurol. 290 561–584.
van der Pluijm M. Cassidy C. Zandstra M. Wallert E. de Bruin K. Booij J. et al. (2021). Reliability and reproducibility of neuromelanin-sensitive imaging of the substantia nigra: A comparison of three different sequences. J. Magn. Reson. Imaging 53 712–721. 10.1002/jmri.27384 33037730
Veraart J. Novikov D. S. Christiaens D. Ades-aron B. Sijbers J. Fieremans E. (2016). Denoising of diffusion MRI using random matrix theory. Neuroimage 142 394–406.
Vespa S. Stumpp L. Liberati G. Delbeke J. Nonclercq A. Mouraux A. et al. (2022). Characterization of vagus nerve stimulation-induced pupillary responses in epileptic patients. Brain Stimul. 15 1498–1507.
Wang H. J. Tan G. Zhu L. N. Chen D. Xu D. Chu S. S. et al. (2019). Predictors of seizure reduction outcome after vagus nerve stimulation in drug-resistant epilepsy. Seizure 66 53–60.
Watanabe T. Tan Z. Wang X. Martinez-Hernandez A. Frahm J. (2019). Magnetic resonance imaging of noradrenergic neurons. Brain Struct. Funct. 224 1609–1625.
Wengler K. He X. Abi-Dargham A. Horga G. (2020). Reproducibility assessment of neuromelanin-sensitive magnetic resonance imaging protocols for region-of-interest and voxelwise analyses. Neuroimage 208:116457. 10.1016/j.neuroimage.2019.116457 31841683
Xu C. Lin H. Xu J. Zhang X. Hao G. Liu Q. Q. et al. (2022). Long-term outcomes and prognosis factors of vagus nerve stimulation in patients with refractory epilepsy. Acta Epileptol. 4:38.
Yeh F. C. Wedeen V. J. Tseng W. Y. (2010). Generalized q-sampling imaging. IEEE Trans. Med. Imaging 29 1626–1635.
Yushkevich P. A. Piven J. Hazlett H. C. Smith R. G. Ho S. Gee J. C. et al. (2006). User-guided 3D active contour segmentation of anatomical structures: Significantly improved efficiency and reliability. Neuroimage 31 1116–1128. 10.1016/j.neuroimage.2006.01.015 16545965
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