Efficient parameters of vagus nerve stimulation to enhance extinction learning in an extinction-resistant rat model of PTSD

Souza, Rimenez R.; Robertson, Nicole; Mathew, Ezek; Tabet, Michel N.; Bucksot, Jesse E; Pruitt, David; Rennaker, Robert L.; McIntyre, Christa K.; Kilgard, Michael P.

doi:10.1016/j.pnpbp.2019.109848

Cited by 14 publications

(20 citation statements)

References 75 publications

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“…All rats were submitted to a model of PTSD that produces extinction-resistant fear (Fig. 1 A), as we previously described 38 . In Phase 1, rats were submitted to the Single Prolonged Stress (SPS) 51 procedure followed by the Protracted Aversive Conditioning (PAC) protocol seven days later 36 , 52 .…”

Section: Methodsmentioning

confidence: 99%

“…In Phase 2, 4 days after the PAC procedure all rats were implanted with a VNS cuff, as we previously described 38 . This was performed to prevent any effect of the surgical procedures or anesthesia on the fear acquisition and to have an experimental design that parallels the clinical application of VNS surgery after the trauma (Fig.…”

Section: Methodsmentioning

confidence: 99%

“…We have demonstrated in a number of recent studies that delivering VNS paired with the presentation of conditioned acoustic or olfactory cues during extinction training enhances extinction learning and reverses extinction impairments in rodent models for PTSD 22 , 25 , 33 – 37 . Importantly, studies indicate that choosing adequate stimulation parameters, including duration and intensity of stimulation, is critical in maximizing recovery after VNS-paired extinction 38 , 39 . In the same way that electrical stimulation parameters determine VNS efficacy 28 , 40 – 45 , the timing of VNS with respect to the concordant training regimens also critically determines efficacy 46 – 49 .…”

Section: Introductionmentioning

confidence: 99%

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Timing of vagus nerve stimulation during fear extinction determines efficacy in a rat model of PTSD

Souza

Powers

Rennaker

et al. 2022

Sci Rep

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Studies have indicated that vagus nerve stimulation (VNS) enhances extinction learning in rodent models. Here, we investigated if pairing VNS with the conditioned stimulus is required for the enhancing effects of VNS. Adult Sprague–Dawley rats were exposed to intense stress followed by fear conditioning training to produce resistant fear. Rats were then implanted with a cuff electrode around the left vagus. After recovery, rats underwent extinction training paired with VNS (0.5 s, 0.8 mA, 100 µs, and 30 Hz) or with Sham VNS (0 mA). VNS rats were randomized into the following subgroups: During VNS (delivered during presentations of the conditioned stimulus, CS), Between VNS (delivered between CS presentations), Continuous VNS (delivered during the entire extinction session), and Dispersed VNS (delivered at longer inter-stimulation intervals across the extinction session). Sham VNS rats failed to extinguish the conditioned fear response over 5 days of repeated exposure to the CS. Rats that received Between or Dispersed VNS showed modest improvement in conditioned fear at the retention test. During and Continuous VNS groups displayed the greatest reduction in conditioned fear. These findings indicate that delivering VNS paired precisely with CS presentations or continuously throughout extinction promotes the maximum enhancement in extinction learning.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Timing of vagus nerve stimulation during fear extinction determines efficacy in a rat model of PTSD

Souza

Powers

Rennaker

et al. 2022

Sci Rep

Self Cite

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“…Fear extinction, a removal of conditioned response, is a gold standard therapy for PTSD ( Genheimer et al, 2017 ), yet for many it remains not entirely effective, calling for its enhancement, potentially with VNS or tVNS. So far, however, the results are mixed, with promising results of VNS on fear extinction in rats ( Peña et al, 2013 , 2014 ; Noble et al, 2017 ; Souza et al, 2019 , 2020 ), and with varied success of tVNS in humans ( Burger et al, 2016 , 2017 ; Genheimer et al, 2017 ; Szeska et al, 2020 ), which may depend on particular stimulation parameters ( Hansen, 2019 ).…”

Section: Preconscious Impacts On Cognitive Processesmentioning

confidence: 99%

Vagus Nerve Stimulation as a Gateway to Interoception

Paciorek

Skora

2020

Front. Psychol.

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The last two decades have seen a growing interest in the study of interoception. Interoception can be understood as a hierarchical phenomenon, referring to the bodyto-brain communication of internal signals, their sensing, encoding, and representation in the brain, influence on other cognitive and affective processes, and their conscious perception. Interoceptive signals have been notoriously challenging to manipulate in experimental settings. Here, we propose that this can be achieved through electrical stimulation of the vagus nerve (either in an invasive or non-invasive fashion). The vagus nerve is the main pathway for conveying information about the internal condition of the body to the brain. Despite its intrinsic involvement in interoception, surprisingly little research in the field has used Vagus Nerve Stimulation to explicitly modulate bodily signals. Here, we review a range of cognitive, affective and clinical research using Vagus Nerve Stimulation, showing that it can be applied to the study of interoception at each level of its hierarchy. This could have considerable implications for our understanding of the interoceptive dimension of cognition and affect in both health and disease, and lead to development of new therapeutic tools.

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“…Vagus nerve stimulation (VNS) paired with rehabilitation has emerged as a therapeutic strategy to enhance recovery in a range of neurological disorders, including stroke ( Khodaparast et al, 2013 , 2014 ; Hays et al, 2014b , 2016 ; Dawson et al, 2016 , 2021 ; Kilgard et al, 2018 ; Kimberley et al, 2018 ; Meyers et al, 2018 ; Pruitt et al, 2021 ), traumatic brain injury ( Pruitt et al, 2016b ), neuropathy ( Meyers et al, 2019 ; Darrow et al, 2020a , 2021 ), spinal cord injury (SCI; Ganzer et al, 2018 ; Darrow et al, 2020b ; Kilgard et al, 2021 ), and post-traumatic stress disorder (PTSD; George et al, 2008 ; Pena et al, 2014 ; Noble et al, 2017 ; Kilgard et al, 2020 ; Souza et al, 2020 ). Following a recently completed pivotal study, VNS paired with rehabilitation has received United States FDA approval as the first neuromodulation therapy for chronic stroke ( Dawson et al, 2021 ; FDA, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Common Cholinergic, Noradrenergic, and Serotonergic Drugs Do Not Block VNS-Mediated Plasticity

et al. 2022

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Vagus nerve stimulation (VNS) delivered during motor rehabilitation enhances recovery from a wide array of neurological injuries and was recently approved by the U.S. FDA for chronic stroke. The benefits of VNS result from precisely timed engagement of neuromodulatory networks during rehabilitative training, which promotes synaptic plasticity in networks activated by rehabilitation. Previous studies demonstrate that lesions that deplete these neuromodulatory networks block VNS-mediated plasticity and accompanying enhancement of recovery. There is a great deal of interest in determining whether commonly prescribed pharmacological interventions that influence these neuromodulatory networks would similarly impair VNS effects. Here, we sought to directly test the effects of three common pharmaceuticals at clinically relevant doses that target neuromodulatory pathways on VNS-mediated plasticity in rats. To do so, rats were trained on a behavioral task in which jaw movement during chewing was paired with VNS and received daily injections of either oxybutynin, a cholinergic antagonist, prazosin, an adrenergic antagonist, duloxetine, a serotonin-norepinephrine reuptake inhibitor, or saline. After the final behavioral session, intracortical microstimulation (ICMS) was used to evaluate reorganization of motor cortex representations, with area of cortex eliciting jaw movement as the primary outcome. In animals that received control saline injections, VNS paired with training significantly increased the movement representation of the jaw compared to naïve animals, consistent with previous studies. Similarly, none of the drugs tested blocked this VNS-dependent reorganization of motor cortex. The present results provide direct evidence that these common pharmaceuticals, when used at clinically relevant doses, are unlikely to adversely impact the efficacy of VNS therapy.

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Efficient parameters of vagus nerve stimulation to enhance extinction learning in an extinction-resistant rat model of PTSD

Cited by 14 publications

References 75 publications

Timing of vagus nerve stimulation during fear extinction determines efficacy in a rat model of PTSD

Timing of vagus nerve stimulation during fear extinction determines efficacy in a rat model of PTSD

Vagus Nerve Stimulation as a Gateway to Interoception

Common Cholinergic, Noradrenergic, and Serotonergic Drugs Do Not Block VNS-Mediated Plasticity

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