Higher Dose Noninvasive Transcutaneous Auricular Vagus Nerve Stimulation Increases Feeding Volumes and White Matter Microstructural Complexity in Open-Label Study of Infants Slated for Gastrostomy Tube

Jenkins, Dorothea; Moss, Hunter G.; Adams, Lauren E.; Hunt, Sally; Dancy, Morgan; Huffman, Sarah; Cook, Daniel; Jensen, Jens H.; Summers, Philipp M.; Thompson, Sean; George, Mark S.; Badran, Bashar W.

doi:10.1016/j.jpeds.2023.113563

Cited by 5 publications

(9 citation statements)

References 79 publications

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“…There is strong evidence in animal and adult rehabilitation literature that vagus nerve stimulation paired with active rehabilitation treatment promotes beneficial neuroplasticity leading to improved motor outcomes ( 36 , 37 ). Our data and others suggest that taVNS may have similar benefits and is safe in vulnerable infant populations ( 12 , 21 , 31 , 38 – 38 ). If future studies demonstrate motor improvements at lower doses of 40 h when taVNS is combined with CIMT in young infants, then these burdens will be lessened considerably, and the therapy can be made more widely available to families regardless of resources.…”

Section: Discussionsupporting

confidence: 77%

“…We paired taVNS at 0.1 mA less than the PT with CIMT after ensuring that the infant was not reacting to the stimulation at this level. This infant taVNS protocol was developed and used safely in over 700 stimulation sessions in infants enrolled in a feeding failure study ( 12 , 13 , 31 ). The EPG device displays the quality of the electrode connection (good, moderate, or poor), allowing adjustments to electrodes to be made in real-time to ensure stimulation is being delivered.…”

Section: Methodsmentioning

confidence: 99%

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Pairing taVNS and CIMT is feasible and may improve upper extremity function in infants

McGloon,

Humanitzki,

Brennan

et al. 2024

Front. Pediatr.

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In this study we combined non-invasive transcutaneous auricular vagal nerve stimulation (taVNS) with 40 h of constraint induced movement therapy (CIMT) in infants. All infants completed the full intervention with no adverse events. Therapists were able to maintain high treatment fidelity and reported high ratings for ease of use and child tolerance. Preliminary results show promising gains on motor outcomes: Mean QUEST increase 19.17 (minimal clinically important difference, MCID 4.89); Mean GMFM increase 13.33 (MCID 1%–3%). Infants also exceeded expectations on Goal Attainment Scores (+1). Early data is promising that taVNS paired with intensive motor CIMT is feasible, reliable, and safe in young infants with hemiplegia, and may help harness activity-dependent plasticity to enhance functional movement.

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Section: Discussionsupporting

confidence: 77%

Section: Methodsmentioning

confidence: 99%

Pairing taVNS and CIMT is feasible and may improve upper extremity function in infants

McGloon,

Humanitzki,

Brennan

et al. 2024

Front. Pediatr.

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“…taVNS may have similar effects as implanted vagus nerve stimulation when paired with an activity, modulating neurotransmitter activity and inducing cortical and white matter neuroplasticity, boosting long-term potentiation and motor learning ( Khodaparast et al, 2013 ; Capone et al, 2017 ; Dawson et al, 2021 ). In our first-in-infants trial, we enrolled 35 infants with feeding failure whose parents were in discussions about G-tube placement and paired transcutaneous auricular vagus nerve stimulation (taVNS) with the motor activity of bottle feeding ( Badran et al, 2020 ; Jenkins et al, 2023 ). Over 50% of these infants attained full oral feeds within 2 weeks.…”

Section: Introductionmentioning

confidence: 99%

“…With known impairment of synaptic plasticity, exposure to intrauterine hyperglycemia carries the potential for delays in developing motor skills, such as coordination of more than 30 muscles required for effective feeding ( Ornoy et al, 2001 ; Matsuo and Palmer, 2008 ; Camprubi Robles et al, 2015 ; Satrom et al, 2018 ). With magnetic resonance spectroscopy (MRS) obtained before and after the taVNS treatment period, we showed that reduced glutathione (GSH) concentrations in the basal ganglia, a measure of CNS oxidative stress, predicted response to taVNS-paired feeding only in the IDMs ( Jenkins et al, 2023 ). Neuroplastic changes were evidenced by increased complexity and microstructure of specific white matter (WM) tracts in diffusion kurtosis imaging (DKI) and were significantly greater in infants who attained full oral feeds during taVNS-paired feeding than in those who needed a G-tube for feeds ( Jenkins et al, 2023 ).…”

Section: Introductionmentioning

confidence: 99%

“…With magnetic resonance spectroscopy (MRS) obtained before and after the taVNS treatment period, we showed that reduced glutathione (GSH) concentrations in the basal ganglia, a measure of CNS oxidative stress, predicted response to taVNS-paired feeding only in the IDMs ( Jenkins et al, 2023 ). Neuroplastic changes were evidenced by increased complexity and microstructure of specific white matter (WM) tracts in diffusion kurtosis imaging (DKI) and were significantly greater in infants who attained full oral feeds during taVNS-paired feeding than in those who needed a G-tube for feeds ( Jenkins et al, 2023 ). Taken together, these data suggest that there were blocks to neuroplasticity in those who did not improve, half of whom were IDMs.…”

Section: Introductionmentioning

confidence: 99%

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Transcutaneous auricular vagus nerve stimulation may benefit from the addition of N-acetylcysteine to facilitate motor learning in infants of diabetic mothers failing oral feeds

Jenkins,

Garner,

Brennan

et al. 2024

Front. Hum. Neurosci.

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ObjectiveThis study aims to determine if pretreating with enteral N-acetylcysteine (NAC) improves CNS oxidative stress and facilitates improvement in oromotor skills during transcutaneous auricular nerve stimulation (taVNS) paired with oral feedings in infants of diabetic mothers (IDMs) who are failing oral feeds.MethodsWe treated 10 IDMs who were gastrostomy tube candidates in an open-label trial of NAC and taVNS paired with oral feeding. NAC (75 or 100 mg/kg/dose) was given by nasogastric (NG) administration every 6 h for 4 days, then combined with taVNS paired with 2 daily feeds for another 14 days. NAC pharmacokinetic (PK) parameters were determined from plasma concentrations at baseline and at steady state on day 4 of treatment in conjunction with magnetic resonance spectroscopic (MRS) quantification of CNS glutathione (GSH) as a marker of oxidative stress. We compared increases in oral feeding volumes before and during taVNS treatment and with a prior cohort of 12 IDMs who largely failed to achieve full oral feeds with taVNS alone.ResultsNAC 100 mg/kg/dose every 6 h NG resulted in plasma [NAC] that increased [GSH] in the basal ganglia with a mean of 0.13 ± 0.08 mM (p = 0.01, compared to baseline). Mean daily feeding volumes increased over 14 days of NAC + taVNS compared to the 14 days before treatment and compared to the prior cohort of 12 IDMs treated with taVNS alone. Seven IDMs reached full oral feeds sufficient for discharge, while three continued to have inadequate intake.ConclusionIn IDM failing oral feeds, NAC 100 mg/kg/dose every 6 h NG for 4 days before and during taVNS paired with oral feeding increased CNS GSH, potentially mitigating oxidative stress, and was associated with improving functional feeding outcomes compared to taVNS alone in a prior cohort. This represents a novel approach to neuromodulation and supports the concept that mitigation of ongoing oxidative stress may increase response to taVNS paired with a motor task.

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Transcutaneous Vagus Nerve Stimulation Boosts Post-Error Accuracy During Perceptual Decision-Making

Su,

Vanvoorden,

Le Denmat

et al. 2024

Preprint

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The locus coeruleus-norepinephrine (LC-NE) system is a well-established regulator of behavior, yet its precise role remains unclear. Animal studies predominantly support a ''gai'' hypothesis, suggesting that the LC-NE system enhances sensory processing, while human studies have proposed an alternative ''urgenc'' hypothesis, postulating that LC-NE primarily accelerates responses. To address this discrepancy, we administered transcutaneous vagus nerve stimulation (tVNS) in two experiments involving 43 participants. In the first experiment, we showed that 4-second tVNS trains reliably induced greater pupil dilation compared to SHAM condition, indicating increased LC-NE activity. In the second experiment, we applied tVNS during a random dot motion task to assess its impact on perceptual decision-making. Notably, tVNS improved accuracy without affecting reaction times, which appears inconsistent with the ''urgenc'' hypothesis. Drift-diffusion model analyses further supported the ''gai'' hypothesis, revealing that tVNS increased the drift rate, indicative of enhanced evidence accumulation. Accuracy and drift-rate improvements were especially pronounced following errors and in less proficient participants, who otherwise exhibited post-error declines in these measures under SHAM condition. Our findings suggest that the influence of the LC-NE system adapts to task demands, becoming especially beneficial in challenging contexts. Overall, this study underscores the potential of tVNS as a non-invasive tool to investigate the causal role of the LC-NE system in human behavior.

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Higher Dose Noninvasive Transcutaneous Auricular Vagus Nerve Stimulation Increases Feeding Volumes and White Matter Microstructural Complexity in Open-Label Study of Infants Slated for Gastrostomy Tube

Cited by 5 publications

References 79 publications

Pairing taVNS and CIMT is feasible and may improve upper extremity function in infants

Pairing taVNS and CIMT is feasible and may improve upper extremity function in infants

Transcutaneous auricular vagus nerve stimulation may benefit from the addition of N-acetylcysteine to facilitate motor learning in infants of diabetic mothers failing oral feeds

Transcutaneous Vagus Nerve Stimulation Boosts Post-Error Accuracy During Perceptual Decision-Making

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