Impact of Stimulation Duration in taVNS—Exploring Multiple Physiological and Cognitive Outcomes
Abstract
:1. Introduction
2. Materials and Methods
2.1. Sample
2.2. Procedure
2.3. Stimulation
2.4. Main Outcome Parameters
2.4.1. Saliva
2.4.2. Pupil
2.4.3. EEG
2.4.4. Cognitive Tasks
2.5. Statistical Analysis
Additional Analyses
3. Results
3.1. Saliva
3.2. Pupil
3.3. EEG
3.4. Cognition
4. Discussion
4.1. Effect of the taVNS on Saliva Marker
4.2. Effect of the taVNS on Pupil Size
4.3. Effect of taVNS on EEG
4.4. Effect of the taVNS on Cognition
4.5. Differences between Invasive and Non-Invasive VNS
4.6. Limitations and Future Directions
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Appendix A
Parameter | Unit | Description | Phase of PLR | Controlled by | Effect of LC-NE Activation on Pupil Size |
---|---|---|---|---|---|
D1 | mm | Output variable (mean value 1 s before annotation) | 1 | P | larger |
D2 | mm | Minimal pupil size | 1 | P | larger |
AMP | mm | Constriction amplitude: Difference between initial width and max. constriction (D1-D2) | 1 | P | smaller |
VCmax | mm/s | Maximum constriction speed | 1 | P | smaller |
ACmax | mm/s2 | Maximum constriction acceleration | 1 | P | smaller |
T1 | s | Latency from light annotation to maximum acceleration (ACmax) | 1 | P | larger |
T2 | s | Latency from light annotation to maximum speed (VCmax) | 1 | P | larger |
T3 | s | Latency from light annotation to maximum constriction (D2) | 1 | P | larger |
Rel_AMP | % | Constriction amplitude in relation to the output width (AMP/D1) | 1 | P/S | smaller |
Redil_25 | s | Time after max. constriction until pupil size reaches 25% of initial value | 2 | P/S | smaller |
Redil_50 | s | Time after max. constriction until pupil size reaches 50% of the initial value | 2 | P/S | smaller |
Redil_75 | s | Time after max. constriction until pupil size reaches 75% of the initial value | 3 | S | smaller |
Light Stimulus Sequence | Width in Height Units 1 | Height in Height Units | Brightness in Lux |
---|---|---|---|
1 | 0.1 | 0.1 | 0.0 2 |
2 | 0.15 | 0.15 | 1.8 |
3 | 0.25 | 0.25 | 5.0 |
4 | 5.00 | 5.00 | 130.0 |
Appendix B
Condition | Contrast | Estimated Value (ß) | Standard Error | Degrees of Freedom | t-Value | p-Value | Adjusted p-Value |
---|---|---|---|---|---|---|---|
3.4 s | morning vs. afternoon | −13.96 | 22.33 | 52.47 | −0.62 | 0.535 | 0.802 |
morning vs. noon | 6.66 | 25.07 | 54.68 | 0.27 | 0.792 | 0.847 | |
noon vs. afternoon | −20.61 | 26.50 | 52.33 | −0.78 | 0.440 | 0.802 | |
30 s | morning vs. afternoon | −4.73 | 24.44 | 53.51 | −0.29 | 0.847 | 0.847 |
morning vs. noon | −59.98 | 26.13 | 53.62 | −2.30 | 0.026 | 0.154 | |
noon vs. afternoon | 55.25 | 28.20 | 52.29 | 1.96 | 0.055 | 0.166 |
3.4 s Real | 3.4 s Sham | 30 s Real | 30 s Sham | |
---|---|---|---|---|
Sample (n) | 21 | 22 | 21 | 16 |
Mean (U/mL) | 19.12 | 21.84 | 24.61 | 7.37 |
Standard deviation | 41.38 | 40.51 | 44.30 | 26.52 |
Shapiro-wilk (p-value) | 0.00005 | 0.00018 | 0.00006 | 0.006 |
Correlation coefficient (r) | −0.03 | −0.03 | −0.42 | 0.17 |
p-value | 0.897 | 0.909 | 0.057 | 0.517 |
Appendix C
Stimulation Duration | Eye | Number of Subjects | Threshold | Number of Clusters | p-Values |
---|---|---|---|---|---|
30 s | left | 19 | 2.100922 | 0 | - |
right | 25 | 2.063899 | 4 | 0.101; 0.357; 0.214; 0.396 | |
3.4 s | left | 25 | 2.063899 | 0 | - |
right | 21 | 2.085963 | 0 | - |
Parameter | 3.4 s Real | 3.4 s Sham | 30 s Real | 30 s Sham |
---|---|---|---|---|
D1 | −0.323 (0.339) | −0.425 (0.164) | −0.312 (1.934) | 0.541 (2.358) |
D2 | −0.216 (0.190) | −0.332 (0.117) | −0.268 (0.098) | −0.229 (0.147) |
AMP | −0.107 (0.167) | −0.094 (0.120) | −0.092 (0.095) | −0.007 (0.086) |
VCmax | 0.383 (1.649) | −0.677 (0.842) | −0.722 (0.660) | 0.326 (0.656) |
ACmax | 15.054 (31.004) | −8.031 (11.917) | −12.584 (14.293) | 4.463 (11.757) |
T1 | −0.003 (0.060) | −0.042 (0.054) | −0.027 (0.046) | −0.008 (0.048) |
T2 | 0.073 (0.181) | 0.323 (0.386) | −0.155 (0.165) | 0.000 0.283 |
T3 | 0.074 (0.174) | −0.021 (0.065) | −0.224 (0.264) | −0.006 (0.188) |
rel_AMP | 0.001 (0.018) | 0.010 (0.022) | 0.001 (0.018) | 0.008 (0.014) |
redil_75 | −0.214 (0.544) | −0.080 (0.343) | 0.015 (0.458) | 0.038 (0.251) |
redil_50 | −0.079 (0.164) | −0.001 (0.060) | −0.033 (0.094) | 0.010 (0.089) |
redil_25 | −0.039 (0.037) | −0.010 (0.030) | −0.007 (0.037) | 0.012 (0.057) |
Independent Variables | Parameter | Estimated Value (ß) | Standard Error | Degrees of Freedom | t-Value | p-Value | Adjusted p-Value |
---|---|---|---|---|---|---|---|
ACmax | (Intercept) | −7.65 | 6.86 | 35.65 | −1.11 | 0.272 | 0.272 |
3.4 s real vs. sham | 20.358 | 8.372 | 508.897 | 2.432 | 0.015 | 0.038 | |
30 s real vs. sham | −15.72 | 8.23 | 517.33 | −1.91 | 0.057 | 0.094 | |
Light strength (Lux) | −0.08 | 0.05 | 502.07 | −1.46 | 0.145 | 0.181 | |
AMP | (Intercept) | −0.10 | 0.06 | 27.34 | −1.80 | 0.082 | 0.335 |
3.4 s real vs. sham | −0.03 | 0.06 | 507.42 | −0.45 | 0.656 | 0.656 | |
30 s real vs. sham | −0.05 | 0.06 | 517.80 | −0.82 | 0.414 | 0.518 | |
Light strength (Lux) | −0.0005 | 0.0004 | 500.56 | −1.25 | 0.210 | 0.351 | |
rel_AMP | (Intercept) | 0.002 | 0.01 | 42.50 | 0.21 | 0.832 | 0.832 |
3.4 s real vs. sham | −0.01 | 0.01 | 514.15 | −1.07 | 0.286 | 0.715 | |
30 s real vs. sham | −0.01 | 0.01 | 521.71 | −0.73 | 0.466 | 0.716 | |
Light strength (Lux) | −0.00004 | 0.00007 | 506.07 | −0.56 | 0.573 | 0.716 | |
D1 | (Intercept) | −0.89 | 0.44 | 70.17 | −2.01 | 0.048 | 0.102 |
3.4 s real vs. sham | 0.14 | 0.72 | 519.32 | 0.19 | 0.848 | 0.851 | |
30 s real vs. sham | −0.13 | 0.71 | 523.91 | −0.19 | 0.851 | 0.851 | |
Light strength (Lux) | 0.01 | 0.005 | 510.57 | 2.37 | 0.018 | 0.090 | |
D2 | (Intercept) | −0.44 | 0.14 | 19.70 | −3.04 | 0.007 | 0.033 |
3.4 s real vs. sham | 0.13 | 0.09 | 501.39 | 1.434 | 0.152 | 0.379 | |
30 s real vs. sham | 0.08 | 0.09 | 508.47 | 0.93 | 0.355 | 0.592 | |
Light strength (Lux) | 0.00003 | 0.0006 | 499.07 | 0.05 | 0.964 | 0.964 | |
VCmax | (Intercept) | −0.58 | 0.38 | 37.08 | −1.52 | 0.137 | 0.172 |
3.4 s real vs. sham | 0.95 | 0.47 | 511.55 | 2.04 | 0.042 | 0.069 | |
30 s real vs. sham | −0.94 | 0.46 | 519.68 | −2.05 | 0.041 | 0.069 | |
Light strength (Lux) | −0.002 | 0.003 | 504.94 | −0.72 | 0.469 | 0.469 | |
Redil_25 | (Intercept) | 0.001 | 0.02 | 35.22 | 0.06 | 0.954 | 0.954 |
3.4 s real vs. sham | −0.03 | 0.02 | 509.68 | −1.45 | 0.147 | 0.367 | |
30 s real vs. sham | −0.01 | 0.02 | 518.35 | −0.62 | 0.533 | 0.781 | |
Light strength (Lux) | 0.00006 | 0.0001 | 502.70 | 0.49 | 0.625 | 0.781 | |
Redil_50 | (Intercept) | 0.06 | 0.05 | 32.13 | 1.004 | 0.323 | 0.404 |
3.4 s real vs. sham | −0.09 | 0.06 | 510.40 | −1.39 | 0.164 | 0.379 | |
30 s real vs. sham | −0.01 | 0.06 | 519.23 | −0.25 | 0.805 | 0.805 | |
Light strength (Lux) | −0.00045 | 0.0004 | 504.52 | −1.21 | 0.228 | 0.379 | |
Redil_75 | (Intercept) | 0.07 | 0.15 | 41.16 | 0.44 | 0.661 | 0.964 |
3.4 s real vs. sham | −0.15 | 0.21 | 513.67 | −0.70 | 0.481 | 0.964 | |
30 s real vs. sham | 0.01 | 0.21 | 521.54 | 0.045 | 0.964 | 0.964 | |
Light strength (Lux) | −0.003 | 0.001 | 504.89 | −2.43 | 0.02 | 0.08 | |
T1 | (Intercept) | 0.01 | 0.02 | 37.61 | 0.59 | 0.556 | 0.556 |
3.4 s real vs. sham | 0.04 | 0.02 | 511.60 | 1.62 | 0.106 | 0.177 | |
30 s real vs. sham | −0.01 | 0.02 | 519.70 | −0.66 | 0.511 | 0.556 | |
Light strength (Lux) | −0.0003 | 0.0001 | 504.22 | −1.84 | 0.0677 | 0.167 | |
T2 | (Intercept) | 0.008 | 0.08 | 515.00 | 0.10 | 0.924 | 0.924 |
3.4 s real vs. sham | −0.28 | 0.16 | 515.00 | −1.79 | 0.073 | 0.249 | |
30 s real vs. sham | −0.16 | 0.15 | 515.00 | −1.08 | 0.279 | 0.348 | |
Light strength (Lux) | −0.001 | 0.001 | 515.00 | −1.12 | 0.263 | 0.348 | |
T3 | (Intercept) | −0.06 | 0.09 | 37.53 | −0.61 | 0.547 | 0.571 |
3.4 s real vs. sham | 0.07 | 0.11 | 502.80 | 0.65 | 0.515 | 0.571 | |
30 s real vs. sham | −0.22 | 0.11 | 510.76 | −2.01 | 0.045 | 0.224 | |
Light strength (Lux) | 0.0008 | 0.0007 | 496.83 | 1.11 | 0.270 | 0.571 |
Study | iVNS | nVNS |
---|---|---|
Alpha Amylase | ||
Doerr et al., 2023 [99] 10.1002/epi4.12774 (Patients with epilepsy) | - | No effect of tVNS on sAA activity |
Warren et al., 2019 * 10.1016/j.brs.2018.12.224 (Healthy individuals) | - | taVNS increased sAA |
Venutra-Bort et al., 2018 * 10.3389/fnhum.2018.00202 (Healthy individuals) | - | taVNS increased sAA levels after stimulation |
D’Agostini et al., 2021 * 10.1111/psyp.13885 (Healthy individuals) | - | taVNS did not increase sAA |
D’Agostini 2023 * 10.1016/j.biopsycho.2023.108646 (Healthy individuals) | - | TaVNS did not increase sAA |
D’Agostini et al., 2022 * 10.1111/psyp.13984 (Healthy individuals) | - | No effect on sAA secretion with taVNS |
Giraudier et al., 2020 [100] 10.3389/fpsyg.2020.01276 (Healthy individuals) | - | No tVNS effects on sAA level changes |
Koenig et al., 2019 [101] 10.1017/S0033291719003490 (Adolescents with depression) | - | No effect of tVNS on sAA |
Pupil Response | ||
Vespa et al., 2022 [102] 10.1016/j.brs.2022.11.002 (Patients with epilepsy) | iVNS induced late PDR | - |
Desbaumes Jodoin et al., 2015 * 10.1016/j.ijpsycho.2015.10.001 (Patients with epilepsy and depression) | iVNS induced PDR | - |
Skora et al., 2024 * 10.1101/2023.09.20.558607 (healthy controls) | - | taVNS induced early PDR |
D’Agostini et al., 2023 [103] 10.1016/j.cortex.2022.11.012 (Healthy individuals) | - | Increase in event-related pupil dilation with taVNS |
Lloyd et al., 2023 * 10.1016/j.brs.2023.06.010 (Healthy individuals) | - | taVNS induced early PDR |
Sharon et al., 2021 * 10.1523/JNEUROSCI.1361-20.2020 (Healthy individuals) | - | taVNS induced early PDR |
Urbin et al., 2021 [104] 10.1016/j.brs.2021.06.002 (Healthy individuals) | - | taVNS induced early PDR |
Villani et al., 2023 [105] 10.1016/j.psyneuen.2022.105719 (Healthy individuals) | - | Event-related taVNS decreased pupil dilation in response to target stimuli |
Borges et al., 2021 * 10.1016/j.ijpsycho.2021.01.003 (Healthy individuals) | - | No effect on pupillary responses |
Burger et al., 2020 * j.biopsycho.2020.107863 (Healthy individuals) | - | tVNS did not affect pupil dilation |
Capone et al., 2021 * 10.1016/j.clinph.2021.05.014 (Healthy individuals) | - | taVNS induced pupil dilation under specific luminance and stimulation intensity |
D’Agostini et al., 2021 * 10.1111/psyp.13885 (Healthy individuals) | - | taVNS did not increase pupil size |
D’Agostini et al., 2022 * 10.1111/psyp.13984 (Healthy individuals) | - | taVNS did not impact event-related pupil dilation |
Keute et al., 2019 * 10.1038/s41598-019-47961-4 (Healthy individuals) | - | No modulation of pupil size or event-related pupil response with taVNS |
Warren et al., 2019 * 10.1016/j.brs.2018.12.224 (Healthy individuals) | - | Pupil size not affected by tVNS |
Wienke et al., 2023 * 10.1523/JNEUROSCI.0452-23.2023 (Healthy individuals) | Increased pupil dilation with taVNS | |
EEG | ||
Sharon et al., 2021 * 10.1523/JNEUROSCI.1361-20.2020 (Healthy individuals) | - | Attenuation of occipital alpha with taVNS |
Lloyd et al., 2023 * 10.1016/j.brs.2023.06.010 (Healthy individuals) | - | No attenuation of occipital alpha |
Wienke et al., 2023 * 10.1523/JNEUROSCI.0452-23.2023 (Healthy individuals) | - | Increase in midfrontal theta with taVNS |
Pan et al., 2024 * 10.1111/cns.14395 (Patients with epilepsy) | - | Decrease in midfrontal theta with taVNS |
Li et al., 2023 [106] 10.1089/brain.2022.0011 (Patients with epilepsy) | Patients showed reductions in functional connectivity in theta and alpha bands | - |
Neuhaus et al., 2007 [107] 10.1016/j.jad.2006.10.005 (Patients with depression) | P300 was significantly increased in responders | - |
De Taeye et al., 2014 [108] 10.1007/s13311-014-0272-3 (Patients with epilepsy) | Increase of P300 amplitude in VNS responders | - |
D’Agostini 2023 * 10.1016/j.biopsycho.2023.108646 (Healthy individuals) | - | taVNS did not increase P3b |
Ventura-Bort 2018 * 10.3389/fnhum.2018.00202 (Healthy individuals) | - | Larger P3b amplitudes during tVNS |
Warren 2019 * 10.1016/j.brs.2018.12.224 (Healthy individuals) | - | P3 amplitude not affected by tVNS |
Fischer 2018 * 10.3758/s13415-018-0596-2 (Healthy individuals) | - | No effect of tVNS on P3 |
Pihlaja 2020 * 10.3389/fnhum.2020.561780 (Healthy individuals) | - | No effect on P3 with tVNS |
Gadeyne 2022 * 10.1016/j.clinph.2021.11.079 (Healthy individuals) | - | No differences in P3b amplitude or latency with tVNS |
Response Inhibition | ||
Schevernels et al., 2016 [109] 10.1016/j.yebeh.2016.09.014 (Patients with epilepsy) | iVNS induced inhibitory benefit | - |
Zhu 2023 * 10.1101/2023.09.14.23295532 (Healthy individuals) | - | Improved No-Go response accuracy with taVNS |
Beste et al., 2016 * 10.1016/j.brs.2016.07.004 (Healthy individuals) | - | Better response inhibition performance with taVNS |
Koenig et al., 2019 [101] 10.1017/S0033291719003490 (Adolescents with depression) | - | Altered response inhibition in emotional Go/NoGo task |
Beste et al., 2016 * [60] 10.1016/j.brs.2016.07.004 (Healthy individuals) | - | Improved response inhibition performance with taVNS |
Van Bochove et al., 2016 [110] 10.1016/j.ijpsycho.2018.03.015 (Patients with epilepsy) | Improved ability to suppress distractor interference with VNS |
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3.4 s Real Stimulation (Baseline) | 3.4 s Real Stimulation | 3.4 s Sham Stimulation (Baseline) | 3.4 s Sham Stimulation | 30 s Real Stimulation (Baseline) | 30 s Real Stimulation | 30 s Sham Stimulation (Baseline) | 30 s Sham Stimulation | |
---|---|---|---|---|---|---|---|---|
sAA concentration (U/mL) | 130.43 (160.05) | 160.96 (142.26) | 90.95 (76.10) | 142.52 (91.31) | 95.46 (73.90) | 151.93 (125.30) | 98.43 (56.24) | 123.92 (112.17) |
sAA secretion (U/min) | 20.00 (31.74) | 39.12 (55.30) | 21.37 (39.87) | 43.21 (50.95) | 25.38 (40.47) | 47.06 (67.35) | 24.96 (33.64) | 28.92 (45.24) |
Cortisol concentration (nmol/L) | 4.03 (1.72) | 2.20 (0.78) | 4.17 (2.06) | 2.48 (1.14) | 4.10 (2.06) | 2.37 (1.08) | 4.40 (2.23) | 2.17 (1.13) |
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Bömmer, T.; Schmidt, L.M.; Meier, K.; Kricheldorff, J.; Stecher, H.; Herrmann, C.S.; Thiel, C.M.; Janitzky, K.; Witt, K. Impact of Stimulation Duration in taVNS—Exploring Multiple Physiological and Cognitive Outcomes. Brain Sci. 2024, 14, 875. https://doi.org/10.3390/brainsci14090875
Bömmer T, Schmidt LM, Meier K, Kricheldorff J, Stecher H, Herrmann CS, Thiel CM, Janitzky K, Witt K. Impact of Stimulation Duration in taVNS—Exploring Multiple Physiological and Cognitive Outcomes. Brain Sciences. 2024; 14(9):875. https://doi.org/10.3390/brainsci14090875
Chicago/Turabian StyleBömmer, Till, Luisa M. Schmidt, Katharina Meier, Julius Kricheldorff, Heiko Stecher, Christoph S. Herrmann, Christiane M. Thiel, Kathrin Janitzky, and Karsten Witt. 2024. "Impact of Stimulation Duration in taVNS—Exploring Multiple Physiological and Cognitive Outcomes" Brain Sciences 14, no. 9: 875. https://doi.org/10.3390/brainsci14090875