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• Research Paper Volume 11, Issue 14 pp 4836-4857

  Effects of transcutaneous vagus nerve stimulation in individuals aged 55 years or above: potential benefits of daily stimulation

  Relevance score: 5.91703

  Beatrice Bretherton, Lucy Atkinson, Aaron Murray, Jennifer Clancy, Susan Deuchars, Jim Deuchars

  Keywords: vagus nerve stimulation, autonomic nervous system, neuromodulation, quality of life, mood

  Published in Aging on July 30, 2019

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  Ageing is associated with attenuated autonomic function. Transcutaneous vagal nerve stimulation (tVNS) improved autonomic function in healthy young participants. We therefore investigated the effects of a single session of tVNS (studies 1 and 2) and tVNS administered daily for two weeks (study 3) in volunteers aged ≥ 55 years. tVNS was performed using modified surface electrodes on the tragus and connected to a transcutaneous electrical nerve stimulation (TENS) machine. Study 1: participants (n=14) received a single session of tVNS and sham. Study 2: all participants (n=51) underwent a single session of tVNS. Study 3: participants (n=29) received daily tVNS for two weeks. Heart rate variability and baroreflex sensitivity were derived. Quality of life (QoL), mood and sleep were assessed in study 3. tVNS promoted increases in measures of vagal tone and was associated with greater increases in baroreflex sensitivity than sham. Two weeks of daily tVNS improved measures of autonomic function, and some aspects of QoL, mood and sleep. Importantly, findings showed that improvements in measures of autonomic balance were more pronounced in participants with greater baseline sympathetic prevalence. This suggests it may be possible to identify individuals who are likely to encounter significant benefits from tVNS.

  

  Baseline LF/HF ratio significantly predicted response (change) to tVNS.

  
  
  

  

  Baseline LF/HF ratio significantly predicted change in LF/HF during tVNS (Δ LF/HF ratio).

  
  
  

  

  Visit 1 baseline Δ RR (A) and BRS (B) significantly predicted change at visit 2 baseline, where lower baseline Δ RR (A) and BRS (B) in visit 1 were associated with greater increases in baseline Δ RR (A) and BRS (B) in visit 2. In A, Δ Δ RR reflects the difference between maximum and minimum RR intervals (Δ RR) between visit 1 baseline and visit 2 baseline. In B, Δ BRS reflects the difference in BRS between visit 1 baseline and visit 2 baseline.

  
  
  

  

  Δ RR significantly differed both within and between the two visits (p = 0.036); * = significantly different to visit 2 recovery.

  
  
  

  

  Baseline LF/HF ratio in visits 1 (A) and 2 (B) significantly predicted change in LF/HF ratio between baseline and tVNS. Δ refers to the differences between baseline and tVNS.

  
  
  

  

  Baseline LF/HF ratio reduced after 2 weeks of daily tVNS in six responders with three showing an increase in baseline LF/HF ratio following the daily tVNS (indicated by the blue boxes).

  
  
  

  

  LF/HF ratio values during visit 1 (A) and visit 2 (B) for each responder during baseline, tVNS and recovery. Dashed black line indicates the group mean.

  
  
  

  

  Baseline LF/HF ratio reduced after 2 weeks of daily tVNS in seven non-responders with ten showing an increase in baseline LF/HF ratio following the daily tVNS (indicated by the blue boxes).

  
  
  

  

  LF/HF ratio values during visit 1 (A) and visit 2 (B) for each non-responder during baseline, tVNS and recovery. Dashed black line indicates the group mean.

  
  
  

  

  Visit 1 SF-36 energy score significantly predicted change at visit 2.

  
  
  

  

  Visit 1 tension (A), depression (B), anger (C) and confusion (D) scores significantly predicted change at visit 2.

  
  
  

  

  Visit 1 ease of falling asleep (A), time taken to fall sleep (B), sleep quality (C) and ease of waking up (D) significantly predicted change at visit 2.

  
  
  

  

  Procedure for study 1.

  
  
  

  

  Procedure for study 2.

  
  
  

  

  Procedure for study 3.

  
  
  

• Research Paper Volume 11, Issue 1 pp 174-184

  Loss of the interaction between estradiol and insulin-like growth factor I in brain endothelial cells associates to changes in mood homeostasis during peri-menopause in mice

  Relevance score: 6.1726947

  Victor Munive, Jonathan A. Zegarra-Valdivia, Raquel Herrero-Labrador, Ana M. Fernandez, Ignacio Torres Aleman

  Keywords: reproductive aging, mood, exercise, insulin-like growth factor 1, estrogen

  Published in Aging on January 11, 2019

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  We recently reported that exercise increases resilience to stress in young female mice. Underlying mechanisms include an interaction of the ovarian hormone estradiol (E2) with insulin-like growth factor I (IGF-I), and an increase in the hippocampal levels of the latter. Since changes in mood regulation during aging may contribute to increasing incidence of affective disorders at older age, we determined whether the protective actions of exercise are maintained at later ages. We found that during peri-menopause, exercise no longer improves resilience to stress and even becomes anxiogenic. Furthermore, the interaction seen in young females between the E2 α receptor (ERα) and the IGF-I receptor (IGF-IR) is lost at middle-age. In addition, E2 no longer induces IGF-I uptake by brain endothelial cells, and consequently, hippocampal IGF-I levels do not increase. Treatment of middle-aged females with an ERα agonist did not recover the positive actions of exercise. Collectively, these data indicate that the loss of action of exercise during peri-menopause may be related to a loss of the interaction of IGF-IR with ERα in brain endothelial cells that cannot be ameliorated by estrogen therapy. Changes in regulation of mood by physical activity may contribute to increased appearance of affective disorders along age.

  

  Exercise actions in anxiety-like behavior and resilience to stress in middle-aged female mice at peri-menopause. (A) Over 60% of middle age female mice were in constant estrous. E2 levels were significantly decreased in middle-age females as compared to young females. ***p<0.001 vs young (n=8-9). (B) Middle-aged female mice (9 months old) showed reduced immobility time in the forced swim test compared to young females (2 months old), indicating a lower “depressive-like” state (n=17 per group). (C) Anxiety-like levels measured in the elevated plus maze showed a profound anxiogenic effect of exercise in middle-aged female mice as compared to young mice (n= 5-10). Values of young females were taken from reference 7. (D) Exercise does not modify resilience to stress (measured by the tail suspension test delivered after the forced swim test) in middle-aged females (n=5-6). Exe: exercised mice; Sed: sedentary mice (in this and following figures).

  
  
  

  

  Effects of exercise on IGF-I in middle-aged females. (A) Hippocampal levels of IGF-I did not change after exercise in middle-aged female mice (n=9-10). (B) Serum IGF-I increased in middle-aged females after exercise (n= 6-7). **p<0.01 and ***p<0.001 vs respective control in this and following figures.

  
  
  

  

  Effects of exercise on clusterin and its receptor in middle-aged females. (A) Hippocampal levels of clusterin (Clu) changed in an age-dependent manner in response to exercise (n=5-10, p<0.05). (B) Hippocampal levels of the Clu receptor Plxna4 did not change with age, nor with exercise (n=7-12). *p<0.05 vs respective control in this and following figures.

  
  
  

  

  Interactions between E2 and IGF-I. (A) Uptake of biotinylated IGF-I (bIGF-I) by brain endothelial cells obtained from young female mice (2 months-old) is increased by estradiol (E2) acting through E2Rα. Note that only the ERα agonist PPT, but not the ERβ agonist DPN, mimics the actions of E2. Representative blots are shown at the right. β-actin was measured as a loading control (n=6). (B) Estradiol does not stimulate uptake of bIGF-I in brain endothelial cells obtained from middle-aged female mice (n= 4). (C) Levels of ERα mRNA were reduced in brain endothelia from middle-aged female mice (n=4). (D) Levels of IGF-IR mRNA remain unaltered in brain endothelia in middle-aged female mice compared to young mice (n=9-10). (E) Co-immunoprecipitation of ERα with IGF-IR showed a significantly decreased interaction in response to E2 in brain endothelial cells obtained from middle-aged female mice (n=4). Representative blot of an immunoprecipitation using anti-ERα is shown. NIS: non-immune serum. *p<0.05 vs respective control.

  
  
  

  

  Exercise modulation of anxiety and resilience to stress in middle-aged female mice after treatment with an ERα agonist. (A) Administration of the ERα agonist PPT resulted in marked anxiolysis in middle-aged females, but exercise did not modify anxiety-like behavior, as measured in the EPM test (n=7-9). (B) PPT treatment increased resilience to stress, as indicated by reduced immobility in the tail suspension test, while exercise abrogated its effects (n=8-9). (C) PPT did not affect hippocampal IGF-I levels and did not significantly affect responses to exercise (n=3-4).