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Rapid Remission of Conditioned Fear Expression with Extinction Training Paired with Vagus Nerve Stimulation

Published:December 14, 2012DOI:https://doi.org/10.1016/j.biopsych.2012.10.021

      Background

      Fearful experiences can produce long-lasting and debilitating memories. Extinction of conditioned fear requires consolidation of new memories that compete with fearful associations. In human subjects, as well as rats, posttraining stimulation of the vagus nerve enhances memory consolidation. Subjects with posttraumatic stress disorder show impaired extinction of conditioned fear. The objective of this study was to determine whether vagus nerve stimulation (VNS) can enhance the consolidation of extinction of conditioned fear.

      Methods

      Male Sprague-Dawley rats were trained on an auditory fear conditioning task followed by 1 to 10 days of extinction training. Treatment with vagus nerve or sham stimulation was administered concurrently with exposure to the fear conditioned stimulus. Another group was given VNS and extinction training but the VNS was not paired with exposure to conditioned cues. Retention of fear conditioning was tested 24 hours after each treatment.

      Results

      Vagus nerve stimulation paired with exposure to conditioned cues enhanced the extinction of conditioned fear. After a single extinction trial, rats given VNS stimulation demonstrated a significantly lower level of freezing, compared with that of sham control rats. When extinction trials were extended to 10 days, paired VNS accelerated extinction of the conditioned response.

      Conclusions

      Extinction paired with VNS is more rapid than extinction paired with sham stimulation. As it is currently approved by the Federal Food and Drug Administration for depression and seizure prevention, VNS is a readily available and promising adjunct to exposure therapy for the treatment of severe anxiety disorders.

      Key Words

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      References

        • Bouton M.E.
        Context, ambiguity, and unlearning: Sources of relapse after behavioral extinction.
        Biol Psychiatry. 2002; 52: 976-986
        • Nemeroff C.B.
        • Bremner J.D.
        • Foa E.B.
        • Mayberg H.S.
        • North C.S.
        • Stein M.B.
        Posttraumatic stress disorder: A state-of-the-science review.
        J Psychiatr Res. 2006; 40: 1-21
        • Milad M.R.
        • Orr S.P.
        • Lasko N.B.
        • Chang Y.
        • Rauch S.L.
        • Pitman R.K.
        Presence and acquired origin of reduced recall for fear extinction in PTSD: Results of a twin study.
        J Psychiatr Res. 2008; 42: 515-520
        • Milad M.R.
        • Pitman R.K.
        • Ellis C.B.
        • Gold A.L.
        • Shin L.M.
        • Lasko N.B.
        • et al.
        Neurobiological basis of failure to recall extinction memory in posttraumatic stress disorder.
        Biol Psychiatry. 2009; 66: 1075-1082
        • Miyashita T.
        • Williams C.L.
        Epinephrine administration increases neural impulses propagated along the vagus nerve: Role of peripheral beta-adrenergic receptors.
        Neurobiol Learn Mem. 2006; 85: 116-124
        • Miyashita T.
        • Williams C.L.
        Peripheral arousal-related hormones modulate norepinephrine release in the hippocampus via influences on brainstem nuclei.
        Behav Brain Res. 2004; 153: 87-95
        • Hassert D.L.
        • Miyashita T.
        • Williams C.L.
        The effects of peripheral vagal nerve stimulation at a memory-modulating intensity on norepinephrine output in the basolateral amygdala.
        Behav Neurosci. 2004; 118: 79-88
        • Follesa P.
        • Biggio F.
        • Gorini G.
        • Caria S.
        • Talani G.
        • Dazzi L.
        • et al.
        Vagus nerve stimulation increases norepinephrine concentration and the gene expression of BDNF and bFGF in the rat brain.
        Brain Res. 2007; 1179: 28-34
        • Clark K.B.
        • Naritoku D.K.
        • Smith D.C.
        • Browning R.A.
        • Jensen R.A.
        Enhanced recognition memory following vagus nerve stimulation in human subjects.
        Nat Neurosci. 1999; 2: 94-98
        • Clark K.B.
        • Smith D.C.
        • Hassert D.L.
        • Browning R.A.
        • Naritoku D.K.
        • Jensen R.A.
        Posttraining electrical stimulation of vagal afferents with concomitant vagal efferent inactivation enhances memory storage processes in the rat.
        Neurobiol Learn Mem. 1998; 70: 364-373
        • Engineer N.D.
        • Riley J.R.
        • Seale J.D.
        • Vrana W.A.
        • Shetake J.A.
        • Sudanagunta S.P.
        • et al.
        Reversing pathological neural activity using targeted plasticity.
        Nature. 2011; 470: 101-104
        • Porter B.A.
        • Khodaparast N.
        • Fayyaz T.
        • Cheung R.J.
        • Ahmed S.S.
        • Vrana W.A.
        • et al.
        Repeatedly pairing vagus nerve stimulation with a movement reorganizes primary motor cortex.
        Cereb Cortex. 2012; 22: 2365-2374
        • Powers M.B.
        • Halpern J.M.
        • Ferenschak M.P.
        • Gillihan S.J.
        • Foa E.B.
        A meta-analytic review of prolonged exposure for posttraumatic stress disorder.
        Clin Psychol Rev. 2010; 30: 635-641
        • Walker D.L.
        • Ressler K.J.
        • Lu K.T.
        • Davis M.
        Facilitation of conditioned fear extinction by systemic administration or intra-amygdala infusions of D-cycloserine as assessed with fear-potentiated startle in rats.
        J Neurosci. 2002; 22: 2343-2351
        • Davis M.
        • Barad M.
        • Otto M.
        • Southwick S.
        Combining pharmacotherapy with cognitive behavioral therapy: Traditional and new approaches.
        J Trauma Stress. 2006; 19: 571-581
        • Ressler K.J.
        • Rothbaum B.O.
        • Tannenbaum L.
        • Anderson P.
        • Graap K.
        • Zimand E.
        • et al.
        Cognitive enhancers as adjuncts to psychotherapy: Use of D-cycloserine in phobic individuals to facilitate extinction of fear.
        Arch Gen Psychiatry. 2004; 61: 1136-1144
        • Frumin M.J.
        • Herekar V.R.
        • Jarvik M.E.
        Amnesic actions of diazepam and scopolamine in man.
        Anesthesiology. 1976; 45: 406-412
        • Angus W.R.
        • Romney D.M.
        The effect of diazepam on patients' memory.
        J Clin Psychopharmacol. 1984; 4: 203-206
        • George M.S.
        • Ward H.E.
        • Ninan P.T.
        • Pollack M.
        • Nahas Z.
        • Anderson B.
        • et al.
        A pilot study of vagus nerve stimulation (VNS) for treatment-resistant anxiety disorders.
        Brain Stimul. 2008; 1: 112-121
        • Furmaga H.
        • Shah A.
        • Frazer A.
        Serotonergic and noradrenergic pathways are required for the anxiolytic-like and antidepressant-like behavioral effects of repeated vagal nerve stimulation in rats.
        Biol Psychiatry. 2011; 70: 937-945
        • Clark K.B.
        • Krahl S.E.
        • Smith D.C.
        • Jensen R.A.
        Post-training unilateral vagal stimulation enhances retention performance in the rat.
        Neurobiol Learn Mem. 1995; 63: 213-216
        • Izquierdo I.
        • Quillfeldt J.A.
        • Zanatta M.S.
        • Quevedo J.
        • Schaeffer E.
        • Schmitz P.K.
        • Medina J.H.
        Sequential role of hippocampus and amygdala, entorhinal cortex and parietal cortex in formation and retrieval of memory for inhibitory avoidance in rats.
        Eur J Neurosci. 1997; 9: 786-793
        • Frankland P.W.
        • Bontempi B.
        The organization of recent and remote memories.
        Nat Rev Neurosci. 2005; 6: 119-130
        • Milekic M.H.
        • Alberini C.M.
        Temporally graded requirement for protein synthesis following memory reactivation.
        Neuron. 2002; 36: 521-525
        • Urcelay G.P.
        • Wheeler D.S.
        • Miller R.R.
        Spacing extinction trials alleviates renewal and spontaneous recovery.
        Learn Behav. 2009; 37: 60-73
        • Quirk G.J.
        Memory for extinction of conditioned fear is long-lasting and persists following spontaneous recovery.
        Learn Mem. 2002; 9: 402-407
        • Monfils M.H.
        • Cowansage K.K.
        • Klann E.
        • LeDoux J.E.
        Extinction-reconsolidation boundaries: Key to persistent attenuation of fear memories.
        Science. 2009; 324: 951-955
        • Frankland P.W.
        • Bontempi B.
        • Talton L.E.
        • Kaczmarek L.
        • Silva A.J.
        The involvement of the anterior cingulate cortex in remote contextual fear memory.
        Science. 2004; 304: 881-883
        • Izquierdo J.A.
        • Insua J.A.
        • Biscardi A.M.
        • Izquierdo I.A.
        Some observations on the responses to the afferent stimulation of the vagus.
        Med Exp Int J Exp Med. 1959; 1: 325-332
        • Schreurs J.
        • Seelig T.
        • Schulman H.
        Beta 2-adrenergic receptors on peripheral nerves.
        J Neurochem. 1986; 46: 294-296
        • Lawrence A.J.
        • Watkins D.
        • Jarrott B.
        Visualization of beta-adrenoceptor binding sites on human inferior vagal ganglia and their axonal transport along the rat vagus nerve.
        J Hypertens. 1995; 13: 631-635
        • Williams C.L.
        • McGaugh J.L.
        Reversible inactivation of the nucleus of the solitary tract impairs retention performance in an inhibitory avoidance task.
        Behav Neural Biol. 1992; 58: 204-210
        • Kalia M.
        • Sullivan J.M.
        Brainstem projections of sensory and motor components of the vagus nerve in the rat.
        J Comp Neurol. 1982; 211: 248-265
        • Sumal K.K.
        • Blessing W.W.
        • Joh T.H.
        • Reis D.J.
        • Pickel V.M.
        Synaptic interaction of vagal afferents and catecholaminergic neurons in the rat nucleus tractus solitarius.
        Brain Res. 1983; 277: 31-40
        • Van Bockstaele E.J.
        • Peoples J.
        • Telegan P.
        Efferent projections of the nucleus of the solitary tract to peri-locus coeruleus dendrites in rat brain: Evidence for a monosynaptic pathway.
        J Comp Neurol. 1999; 412: 410-428
        • Liang K.C.
        • Juler R.G.
        • McGaugh J.L.
        Modulating effects of posttraining epinephrine on memory: Involvement of the amygdala noradrenergic system.
        Brain Res. 1986; 368: 125-133
        • McIntyre C.K.
        • Hatfield T.
        • McGaugh J.L.
        Amygdala norepinephrine levels after training predict inhibitory avoidance retention performance in rats.
        Eur J Neurosci. 2002; 16: 1223-1226
        • Quirarte G.L.
        • Galvez R.
        • Roozendaal B.
        • McGaugh J.L.
        Norepinephrine release in the amygdala in response to footshock and opioid peptidergic drugs.
        Brain Res. 1998; 808: 134-140
        • Williams C.L.
        • Men D.
        • Clayton E.C.
        • Gold P.E.
        Norepinephrine release in the amygdala after systemic injection of epinephrine or escapable footshock: Contribution of the nucleus of the solitary tract.
        Behav Neurosci. 1998; 112: 1414-1422
        • Vidal-Gonzalez I.
        • Vidal-Gonzalez B.
        • Rauch S.L.
        • Quirk G.J.
        Microstimulation reveals opposing influences of prelimbic and infralimbic cortex on the expression of conditioned fear.
        Learn Mem. 2006; 13: 728-733
        • Milad M.R.
        • Vidal-Gonzalez I.
        • Quirk G.J.
        Electrical stimulation of medial prefrontal cortex reduces conditioned fear in a temporally specific manner.
        Behav Neurosci. 2004; 118: 389-394
        • Berlau D.J.
        • McGaugh J.L.
        Enhancement of extinction memory consolidation: The role of the noradrenergic and GABAergic systems within the basolateral amygdala.
        Neurobiol Learn Mem. 2006; 86: 123-132
        • Kim M.J.
        • Loucks R.A.
        • Palmer A.L.
        • Brown A.C.
        • Solomon K.M.
        • Marchante A.N.
        • Whalen P.J.
        The structural and functional connectivity of the amygdala: From normal emotion to pathological anxiety.
        Behav Brain Res. 2011; 223: 403-410
        • Kim M.J.
        • Gee D.G.
        • Loucks R.A.
        • Davis F.C.
        • Whalen P.J.
        Anxiety dissociates dorsal and ventral medial prefrontal cortex functional connectivity with the amygdala at rest.
        Cereb Cortex. 2011; 21: 1667-1673
        • O'Keane V.
        • Dinan T.G.
        • Scott L.
        • Corcoran C.
        Changes in hypothalamic-pituitary-adrenal axis measures after vagus nerve stimulation therapy in chronic depression.
        Biol Psychiatry. 2005; 58: 963-968
        • Porges S.W.
        The polyvagal theory: New insights into adaptive reactions of the autonomic nervous system.
        Cleve Clin J Med. 2009; 76: S86-S90
        • Jennings J.R.
        • McKnight J.D.
        Inferring vagal tone from heart rate variability.
        Psychosom Med. 1994; 56: 194-196
        • Sahar T.
        • Shalev A.Y.
        • Porges S.W.
        Vagal modulation of responses to mental challenge in posttraumatic stress disorder.
        Biol Psychiatry. 2001; 49: 637-643
        • Sack M.
        • Hopper J.W.
        • Lamprecht F.
        Low respiratory sinus arrhythmia and prolonged psychophysiological arousal in posttraumatic stress disorder: Heart rate dynamics and individual differences in arousal regulation.
        Biol Psychiatry. 2004; 55: 284-290
        • Friedman B.H.
        An autonomic flexibility-neurovisceral integration model of anxiety and cardiac vagal tone.
        Biol Psychol. 2007; 74: 185-199
        • Waters A.M.
        • Henry J.
        • Neumann D.L.
        Aversive Pavlovian conditioning in childhood anxiety disorders: Impaired response inhibition and resistance to extinction.
        J Abnorm Psychol. 2009; 118: 311-321
        • Porges S.W.
        • Doussard-Roosevelt J.A.
        • Maiti A.K.
        Vagal tone and the physiological regulation of emotion.
        Monogr Soc Res Child Dev. 1994; 59: 167-186
        • Chen C.C.
        • Williams C.L.
        Interactions between epinephrine, ascending vagal fibers, and central noradrenergic systems in modulating memory for emotionally arousing events.
        Front Behav Neurosci. 2012; 6: 35