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

doi:10.1016/j.biopsych.2012.10.021

Biological Psychiatry

Volume 73, Issue 11, 1 June 2013, Pages 1071-1077

https://doi.org/10.1016/j.biopsych.2012.10.021 Get rights and content

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.

Section snippets

Animals

Male Sprague-Dawley rats (Charles River, Wilmington, Massachusetts) weighing 250 g to 300 g on arrival were housed in a standard animal care facility on a 12-hour light/dark cycle (lights on at 7:00 am) with access to food and water ad libitum. All procedures were approved by the Institutional Animal Care and Use Committee, University of Texas at Dallas.

Surgery

The VNS surgical procedure has been described in detail elsewhere (11). Briefly, platinum-iridium wire electrodes and biocompatible

Vagus Nerve Stimulation Enhances Extinction Memory

Vagus nerve stimulation during a single paired-extinction treatment session significantly reduced the percent of CFR on the following day (Figure 1B). A statistically significant main effect was seen across auditory fear conditioning and extinction trials (F = 6.881, p<.05), and a post hoc analysis revealed no significant group differences in CFR on the day before VNS or sham treatment (Fisher's PLSD, p>.05). A significant reduction of percent of CFR was seen 1 day after extinction paired with

Discussion

The present findings demonstrate that VNS administered during exposure to conditioned cues both enhances and accelerates extinction of conditioned fear. The significant reduction in freezing is not likely to be the result of a performance effect of VNS that is carried over to testing 24 hours later because the group given unpaired VNS and extinction showed no enhancement of extinction of conditioned fear. Neither group demonstrated spontaneous increases in fear responding 2 weeks after

References (53)

M.E. Bouton
Context, ambiguity, and unlearning: Sources of relapse after behavioral extinction
Biol Psychiatry
(2002)
C.B. Nemeroff et al.
Posttraumatic stress disorder: A state-of-the-science review
J Psychiatr Res
(2006)
M.R. Milad et al.
Presence and acquired origin of reduced recall for fear extinction in PTSD: Results of a twin study
J Psychiatr Res
(2008)
M.R. Milad et al.
Neurobiological basis of failure to recall extinction memory in posttraumatic stress disorder
Biol Psychiatry
(2009)
T. Miyashita et al.
Epinephrine administration increases neural impulses propagated along the vagus nerve: Role of peripheral beta-adrenergic receptors
Neurobiol Learn Mem
(2006)
T. Miyashita et al.
Peripheral arousal-related hormones modulate norepinephrine release in the hippocampus via influences on brainstem nuclei
Behav Brain Res
(2004)
P. Follesa et al.
Vagus nerve stimulation increases norepinephrine concentration and the gene expression of BDNF and bFGF in the rat brain
Brain Res
(2007)
K.B. Clark et al.
Posttraining electrical stimulation of vagal afferents with concomitant vagal efferent inactivation enhances memory storage processes in the rat
Neurobiol Learn Mem
(1998)
M.B. Powers et al.
A meta-analytic review of prolonged exposure for posttraumatic stress disorder
Clin Psychol Rev
(2010)
M.S. George et al.
A pilot study of vagus nerve stimulation (VNS) for treatment-resistant anxiety disorders
Brain Stimul
(2008)

H. Furmaga et al.

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)

K.B. Clark et al.

Post-training unilateral vagal stimulation enhances retention performance in the rat

Neurobiol Learn Mem

(1995)

M.H. Milekic et al.

Temporally graded requirement for protein synthesis following memory reactivation

Neuron

(2002)

C.L. Williams et al.

Reversible inactivation of the nucleus of the solitary tract impairs retention performance in an inhibitory avoidance task

Behav Neural Biol

(1992)

K.K. Sumal et al.

Synaptic interaction of vagal afferents and catecholaminergic neurons in the rat nucleus tractus solitarius

Brain Res

(1983)

K.C. Liang et al.

Modulating effects of posttraining epinephrine on memory: Involvement of the amygdala noradrenergic system

Brain Res

(1986)

G.L. Quirarte et al.

Norepinephrine release in the amygdala in response to footshock and opioid peptidergic drugs

Brain Res

(1998)

D.J. Berlau et al.

Enhancement of extinction memory consolidation: The role of the noradrenergic and GABAergic systems within the basolateral amygdala

Neurobiol Learn Mem

(2006)

M.J. Kim et al.

The structural and functional connectivity of the amygdala: From normal emotion to pathological anxiety

Behav Brain Res

(2011)

V. O'Keane et al.

Changes in hypothalamic-pituitary-adrenal axis measures after vagus nerve stimulation therapy in chronic depression

Biol Psychiatry

(2005)

T. Sahar et al.

Vagal modulation of responses to mental challenge in posttraumatic stress disorder

Biol Psychiatry

(2001)

M. Sack et al.

Low respiratory sinus arrhythmia and prolonged psychophysiological arousal in posttraumatic stress disorder: Heart rate dynamics and individual differences in arousal regulation

Biol Psychiatry

(2004)

B.H. Friedman

An autonomic flexibility-neurovisceral integration model of anxiety and cardiac vagal tone

Biol Psychol

(2007)

D.L. Hassert et al.

The effects of peripheral vagal nerve stimulation at a memory-modulating intensity on norepinephrine output in the basolateral amygdala

Behav Neurosci

(2004)

K.B. Clark et al.

Enhanced recognition memory following vagus nerve stimulation in human subjects

Nat Neurosci

(1999)

N.D. Engineer et al.

Reversing pathological neural activity using targeted plasticity

Nature

(2011)

Cited by (110)

Dorsal motor vagal neurons can elicit bradycardia and reduce anxiety-like behavior
2024, iScience
Cardiovagal neurons (CVNs) innervate cardiac ganglia through the vagus nerve to control cardiac function. Although the cardioinhibitory role of CVNs in nucleus ambiguus (CVN^NA) is well established, the nature and functionality of CVNs in dorsal motor nucleus of the vagus (CVN^DMV) is less clear. We therefore aimed to characterize CVN^DMV anatomically, physiologically, and functionally. Optogenetically activating cholinergic DMV neurons resulted in robust bradycardia through peripheral muscarinic (parasympathetic) and nicotinic (ganglionic) acetylcholine receptors, but not beta-1-adrenergic (sympathetic) receptors. Retrograde tracing from the cardiac fat pad labeled CVN^NA and CVN^DMV through the vagus nerve. Using whole-cell patch-clamp, CVN^DMV demonstrated greater hyperexcitability and spontaneous action potential firing ex vivo despite similar resting membrane potentials, compared to CVN^NA. Chemogenetically activating DMV also caused significant bradycardia with a correlated reduction in anxiety-like behavior. Thus, DMV contains uniquely hyperexcitable CVNs and is capable of cardioinhibition and robust anxiolysis.
The gut-brain axis and cognitive control: A role for the vagus nerve
2024, Seminars in Cell and Developmental Biology
Survival requires the integration of external information and interoceptive cues to effectively guide advantageous behaviors, particularly foraging and other behaviors that promote energy acquisition and consumption. The vagus nerve acts as a critical relay between the abdominal viscera and the brain to convey metabolic signals. This review synthesizes recent findings from rodent models and humans revealing the impact of vagus nerve signaling from the gut on the control of higher-order neurocognitive domains, including anxiety, depression, reward motivation, and learning and memory. We propose a framework where meal consumption engages gastrointestinal tract-originating vagal afferent signaling that functions to alleviate anxiety and depressive-like states, while also promoting motivational and memory functions. These concurrent processes serve to favor the encoding of meal-relevant information into memory storage, thus facilitating future foraging behaviors. Modulation of these neurocognitive domains by vagal tone is also discussed in the context of pathological conditions, including the use of transcutaneous vagus nerve stimulation for the treatment of anxiety disorders, major depressive disorder, and dementia-associated memory impairments. Collectively, these findings highlight the contributions of gastrointestinal vagus nerve signaling to the regulation of neurocognitive processes that shape various adaptive behavioral responses.
Vagus Nerve Stimulation Must Occur During Tactile Rehabilitation to Enhance Somatosensory Recovery
2023, Neuroscience
Chronic sensory loss is a common and undertreated consequence of many forms of neurological injury. Emerging evidence indicates that vagus nerve stimulation (VNS) delivered during tactile rehabilitation promotes recovery of somatosensation. Here, we systematically varied the timing of VNS relative to tactile rehabilitation to determine the paradigm that yields the greatest degree of somatosensory recovery after peripheral nerve injury (PNI). The medial and ulnar nerves in rats were transected, causing chronic sensory loss. Eight weeks after injury, rats were given a VNS implant followed by four weeks of tactile rehabilitation sessions consisting of repeated mechanical stimuli to the previously denervated forepaw. Rats received VNS before, during, or after tactile rehabilitation. Delivery of VNS during rehabilitative training generates robust, significant recovery compared to rehabilitative training without stimulation (56 ± 14% improvement over sham stimulation). A matched amount of VNS before training, immediately after training, or two hours after training is significantly less effective than VNS during rehabilitative training and fails to improve recovery compared to rehabilitative training alone (5 ± 10%, 4 ± 11%, and −7 ± 22% improvement over sham stimulation, respectively). These findings indicate that concurrent delivery of VNS during rehabilitative training is most effective and illustrate the importance of considering stimulation timing for clinical implementation of VNS therapy.
Effect of transcutaneous cervical vagus nerve stimulation on declarative and working memory in patients with Posttraumatic Stress Disorder (PTSD): A pilot study
2023, Journal of Affective Disorders
Posttraumatic stress disorder (PTSD) is associated with changes in multiple neurophysiological systems, including verbal declarative memory deficits. Vagus Nerve Stimulation (VNS) has been shown in preliminary studies to enhance function when paired with cognitive and motor tasks. The purpose of this study was to analyze the effect of transcutaneous cervical VNS (tcVNS) on attention, declarative and working memory in PTSD patients.
Fifteen PTSD patients were randomly assigned to active tcVNS (N = 8) or sham (N = 7) stimulation in a double-blinded fashion. Memory assessment tests including paragraph recall and N-back tests were performed to assess declarative and working memory function when paired with active/sham tcVNS once per month in a longitudinal study during which patients self-administered tcVNS/sham twice daily.
Active tcVNS stimulation resulted in a significant improvement in paragraph recall performance following pairing with paragraph encoding for PTSD patients at two months (p < 0.05). It resulted in a 91 % increase in paragraph recall performance within group (p = 0.03), while sham tcVNS exhibited no such trend in performance improvement. In the N-back study, positive deviations in accuracy, precision and recall measures on different day visits (7,34,64,94) of patients with respect to day 1 revealed a pattern of better performance of the active tcVNS population compared to sham VNS which did not reach statistical significance.
Our sample size was small.
These preliminary results suggest that tcVNS improves attention, declarative and working memory, which may improve quality of life and productivity for patients with PTSD. Future studies are required to confirm these results.
How to fail with paired VNS therapy
2023, Brain Stimulation
Vagus nerve stimulation (VNS) has gained enormous traction as a promising bioelectronic therapy. In particular, the delivery of VNS paired with training to promote neural changes has demonstrated clinical success for stroke recovery and found far-reaching application in other domains, from autism to psychiatric disorders to normal learning. The success of paired VNS has been extensively documented. Here, we consider a more unusual question: why does VNS have such broad utility, and perhaps more importantly, when does VNS not work? We present a discussion of the concepts that underlie VNS therapy and an anthology of studies that describe conditions in which these concepts are violated and VNS fails. We focus specifically on the mechanisms engaged by implanted VNS, and how the parameters of stimulation, stimulation method, pharmacological manipulations, accompanying comorbidities, and specifics of concurrent training interact with these mechanisms to impact the efficacy of VNS therapy. As paired VNS therapy is increasing translated to clinical implementation, a clear understanding of the conditions in which it does, and critically, does not work is fundamental to the success of this approach.
Attenuated interoceptive processing in individuals with major depressive disorder and high repetitive negative thinking
2022, Journal of Psychiatric Research
Repetitive negative thinking (RNT) is a transdiagnostic symptom associated with poor outcomes in major depressive disorder (MDD). MDD is characterized by altered interoception, which has also been associated with poor outcomes. The present study investigated whether RNT is directly associated with altered interoceptive processing. Interoceptive awareness toward the heart and stomach was probed on the Visceral Interoceptive Attention (VIA) task with fMRI in MDD individuals who were propensity-matched on the severity of depression and anxiety symptoms and relevant demographics but different in RNT intensity (High RNT [H-RNT, n = 48] & Low RNT [L-RNT, n = 49]), and in matched healthy volunteers (HC, n = 27). Both H-RNT and L-RNT MDD individuals revealed reduced stomach interoceptive processing compared to HC in the left medial frontal region and insular cortex (H-RNT: β = −1.04, L-RNT: β = −0.97), perirhinal cortex (H-RNT: β = −0.99, L-RNT: β = −1.03), and caudate nucleus (H-RNT: β = −1.06, L-RNT: β = −0.89). However, H-RNT was associated with decreased right medial temporal lobe activity including the hippocampus and amygdala during stomach interoceptive trials (β = −0.61) compared to L-RNT. Insular interoceptive processing was similar in H-RNT and L-RNT participants (β = −0.07, p = 0.92). MDD individuals with high RNT exhibited altered gastric interoceptive responses in brain areas that are important for associating the information with specific contexts and emotions. Attenuated interoceptive processing may contribute to RNT generation, non-adaptive information processing, action selection, and thus poor treatment outcome.

View all citing articles on Scopus

View full text

Published by Elsevier Inc.

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

Background

Methods

Results

Conclusions

Section snippets

Animals

Surgery

Vagus Nerve Stimulation Enhances Extinction Memory

Discussion

Biol Psychiatry

J Psychiatr Res

J Psychiatr Res

Biol Psychiatry

Neurobiol Learn Mem

Behav Brain Res

Brain Res

Neurobiol Learn Mem

Clin Psychol Rev

Brain Stimul

Biol Psychiatry

Neurobiol Learn Mem

Neuron

Behav Neural Biol

Brain Res

Brain Res

Brain Res

Neurobiol Learn Mem

Behav Brain Res

Biol Psychiatry

Biol Psychiatry

Biol Psychiatry

Biol Psychol

The effects of peripheral vagal nerve stimulation at a memory-modulating intensity on norepinephrine output in the basolateral amygdala

Behav Neurosci

Enhanced recognition memory following vagus nerve stimulation in human subjects

Nat Neurosci

Reversing pathological neural activity using targeted plasticity

Nature

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