Highlights
- •Vagus nerve stimulation (VNS) promotes generalization of fear extinction.
- •VNS induced generalization is only present for memories of co-occurring stimuli.
- •Acute amounts of VNS reduce innate anxiety.
- •VNS can promote extinction, generalize extinction, and reduce anxiety to improve therapy.
Abstract
Background
Exposure-based therapies are used to treat a variety of trauma- and anxiety-related
disorders by generating successful extinction following cue exposure during treatment.
The development of adjuvant strategies that accelerate extinction learning, improve
tolerability, and increase efficiency of treatment could increase the efficacy of
exposure-based therapies. Vagus nerve stimulation (VNS) paired with exposure can enhance
fear extinction, in rat models of psychiatric disorders, and chronic administration
of VNS reduces anxiety in rats and humans. Objective: We tested whether VNS, like
other cognitive enhancers, could produce generalization of extinction for stimuli
that are not presented during the extinction sessions, but are associated with the
fear event.
Methods
Male Sprague Dawley rats underwent auditory fear conditioning with two easily discriminable
auditory stimuli. Following fear conditioning, extinction training consisted of exposure
to only one of the conditioned sounds. Half of the rats received VNS and half received
sham stimulation during with sound presentations. VNS effects on anxiety were examined
in a separate study where VNS was administered prior to testing on the elevated plus
maze.
Results
Sham stimulated rats given 20 presentations of a conditioned stimulus (CS) during
the extinction session showed performance that was matched to VNS-treated rats given
only 4 presentations of the CS. Despite comparable levels of freezing to the presented
CS, only the VNS-treated rats showed a significant decrease in freezing to the CS
that was not presented. VNS-induced generalization of extinction was observed only
when the two sounds were paired with footshock within the same fear conditioning session;
VNS did not promote generalization of extinction when the two sounds were conditioned
on different days or in different contexts. On the anxiety test, VNS administration
significantly increased time spent in the open arms of the elevated plus maze.
Conclusion
These results provide evidence that VNS can promote generalization of extinction to
other stimuli associated with a specific fear experience. Furthermore, non-contingent
VNS appears to reduce anxiety. The ability to generalize extinction and reduce anxiety
makes VNS a potential candidate for use as an adjunctive strategy to improve the efficacy
and tolerability of exposure-based therapies.
Keywords
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References
- Emotional processing theory (EPT) and exposure therapy for PTSD.J Contemp Psychother. 2006; 36: 1-7
- VA practice patterns and practice guidelines for treating posttraumatic stress disorder.J Trauma Stress. 2004; 17: 213-222
- Virtual reality exposure therapy for PTSD Vietnam veterans: a case study.Behav Res Ther. 1999; 34: 477-481
- D-cycloserine augmented exposure therapy for obsessive-compulsive disorder.Biol Psychiatr. 2007; 62: 835-838
- Randomized, placebo-controlled trial of exposure and ritual prevention, clomipramine, and their combination in the treatment of obsessive-compulsive disorder.Am J Psychiatr. 2005; 162: 151-161
- Obsessive-compulsive disorder.in: Barlow D.H. Clinical handbook of psychological disorders. Guilford Press, New York1993: 189-239
- Virtual reality exposure therapy in the treatment of fear of flying: a case report.Behav Res Ther. 1996; 34: 477-481
- The treatment of fear of flying: a controlled study of imaginal and virtual reality graded exposure therapy.IEEE Transactions on Information. 2002; 6: 1-10
- Context and behavioral processes in extinction.Learn Mem. 2004; 11: 485-494
- Brain mechanisms of fear extinction: historical perspectives on the contribution of prefrontal cortex.Biol Psychiatr. 2006; 60: 329-336
- Neural mechanisms of extinction learning and retrieval.Neuropsychopharmacology. 2008; 33: 56-72
- Nonresponse and dropout rates in outcome studies on PTSD: review and methodological considerations.Psychiatry. 2008; 71: 134-168
- A meta-analytic review of prolonged exposure for posttraumatic stress disorder.Clin Psychol Rev. 2010; 30: 635-641
- Pharmacological treatments that facilitate extinction of fear: relevance to psychotherapy.NeuroRx. 2006; 3: 82-96
- Presence and acquired origin of reduced recall for fear extinction in PTSD: results of a twin study.J Psychiatr Res. 2008; 42: 515-520
- Neurobiological basis of failure to recall extinction memory in posttraumatic stress disorder.Biol Psychiatr. 2009; 66: 1075-1082
- Applying learning principles to the treatment of post-trauma reactions.Ann N Y Acad Sci. 2003; 1008: 112-121
- Deficits in conditioned fear extinction in obsessive-compulsive disorder and neurobiological changes in the fear circuit.JAMA Psychiatr. 2013; 70: 608-618
- Facilitation of fear extinction in phobic participants with a novel cognitive enhancer: a randomized placebo controlled trial of yohimbine augmentation.J Anxiety Disord. 2009; 23: 350-356
- Perceptual implicit memory for trauma-related information in posttraumatic stress disorder.Cognit Emot. 1996; 10: 551-556
- Implicit and explicit memory for trauma-related information in PTSD.Ann Acad Sci. 1997; 821: 219-224
- D-cycloserine enhances generalization of fear extinction in children.Depress Anxiety. 2015; 32: 408-414
- Stress before extinction learning enhances and generalizes extinction memory in a predictive learning task.Neurobiol Learn Mem. 2017; 141: 143-149
- D-cycloserine augmentation of exposure-based cognitive behavior therapy for anxiety, obsessive-compulsive, and posttraumatic stress disorders. A systematic review and meta-analysis of individual patient data.JAMA Psychiatr. 2017; 74: 501-510
- A randomized placebo-controlled trial of d-cycloserine and exposure therapy for post-traumatic stress disorder.J Psychiatr Res. 2012; 46: 1184-1190
- Post-training unilateral vagal stimulation enhances retention performance in the rat.Neurobiol Learn Mem. 1995; 63: 213-216
- Enhanced recognition memory following vagus nerve stimulation in human subjects.Nat Neurosci. 1999; 2: 94-98
- Vagus nerve stimulation enhances extinction of conditioned fear in rats and modulates Arc protein, CaMKII, and GluN2B-containing NMDA receptors in the basolateral amygdala.Neural Plast. 2016; : 1-11
- Rapid remission of conditioned fear expression with extinction training paired with vagus nerve stimulation.Biol Psychiatr. 2013; 73: 1071-1077
- Vagus nerve stimulation enhances extinction of conditioned fear and modulates plasticity in the pathway from the ventromedial prefrontal cortex to the amygdala.Front Behav Neurosci. 2014; 8: 327
- Effects of vagus nerve stimulation on extinction of conditioned fear and post-traumatic stress disorder symptoms in rats.Transl Psychiatry. 2017; 7: 1-8
- Role of TrkB in the anxiolytic-like and antidepressant-like effects of vagal nerve stimulation: comparison with desipramine.Neuroscience. 2016; 322: 273-286
- Vagus nerve stimulation therapy in depression and epilepsy: therapeutic parameter settings.Acta Neurol Scand. 2007; 115: 23-33
- A pilot study of vagus nerve stimulation (VNS) for treatment-resistant anxiety disorders.Brain Stimul. 2008; 1: 112-121
- Vagus nerve stimulation as a tool to induce plasticity in pathways relevant for extinction learning.J Vis Explor. 2015; : 53032
- Vagus nerve stimulation: a new tool for brain research and therapy.Biol Psychiatr. 2000; 47: 287-295
- Cortical activity patterns predict speech discrimination ability.Nat Neurosci. 2008; 11: 603-608
- Similarity of cortical activity patterns predicts generalization behavior.PLoS One. 2013; 8e78607
- Validation of open:closed arm entries in an elevated plus-maze as a measure of anxiety in the rat.J Neurosci Meth. 1985; 14: 149-187
- From normal fear to pathological anxiety.Psychol Rev. 1998; 105: 325-350
- Optogenetic stimulation of a hippocampal engram activates fear memory recall.Nature. 2012; 484: 381-385
- A shared neural ensemble links distinct contextual memories encoded close in time.Nature. 2016; 534: 115-118
- Environment-specific expression of the immediate-early gene Arc in hippocampal neuronal ensembles.Nature. 1999; 2: 1120-1124
- Histone deacetylase inhibition via RGFP966 releases the brakes on sensory cortical plasticity and the specificity of memory formation.J Neurosci. 2015; 35: 13124-13132
- Reversing pathological neural activity using targeted plasticity.Nature. 2011; 470: 101-106
- 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
- The bradykinesia assessment task: an automated method to measure forelimb speed in rodents.J Neurosci. 2013; 214: 52-61
- Parametric characterization of neural activity in the locus coeruleus in response to vagus nerve stimulation.Exp Neurol. 2016; 289: 21-30
- Vagus nerve stimulation during rehabilitative training improves forelimb strength following ischemic stroke.Neurobiol Dis. 2013; 60: 80-88
- Harnessing plasticity to understand learning and treat disease.Trends Neurosci. 2012; 35: 715-722
- Enhancement of the function of rat serotonin and norepinephrine neurons by sustained vagus nerve stimulation.J Psychiatry Neurosci. 2009; 34: 272-280
- Repeatedly pairing vagus nerve stimulation with a movement reorganizes primary motor cortex.Cerebr Cortex. 2012; 22: 2365-2374
- Increased extracellular concentrations of norepinephrine in cortex and hippocampus following vagus nerve stimulation in the rat.Brain Res. 2006; 1119: 124-132
- Pairing tone trains with vagus nerve stimulation induces temporal plasticity in auditory cortex.Exp Neurol. 2012; 233: 342-349
- Enhancement of extinction memory consolidation: the role of noradrenergic and GABAergic systems within the basolateral amygdala.Neurobiol Learn Mem. 2006; 86: 123-132
- Vagus nerve stimulation increases norepinephrine concentration and the gene expression of BDNF and bFGF in the rat brain.Brain Res. 2007; 1179: 28-34
- BDNF function in adult synaptic plasticity: the synaptic consolidation hypothesis.Prog Neurobiol. 2005; 76: 99-125
- Amygdala BDNF signaling is required for consolidation but not encoding of extinction.Nat Neurosci. 2006; 9: 870-872
- Brain-derived neurotrophic factor induces long-term potentiation in intact adult hippocampus: requirement for ERK activation coupled to CREB and upregulation of Arc synthesis.J Neurosci. 2002; 22: 1532-1540
- Vagal nerve stimulation rapidly activates brain-derived neurotrophic factor receptor TrkB in rat brain.PLoS One. 2012; 7: 1-10
- Induction of fear extinction with hippocampal-infralimbic BDNF.Science. 2010; 328: 1288-1290
- Hippocampal-prefrontal BDNF and memory for fear extinction.Neuropsychopharmacology. 2014; 39: 2161-2169
- Vagus nerve stimulation for epilepsy: a meta-analysis of efficacy and predictors of response.J Neurosurg. 2011; 115: 1248-1255
Article info
Publication history
Published online: September 21, 2018
Accepted:
September 19,
2018
Received in revised form:
September 17,
2018
Received:
June 8,
2018
Identification
Copyright
© 2018 Elsevier Inc. All rights reserved.
