The efficacy and safety of transcutaneous auricular vagus nerve stimulation in patients with mild cognitive impairment: A double blinded randomized clinical trial

BackgroundThere are 9.9 million new cases of dementia in the world every year. Short-term conversion rate from mild cognitive impairment (MCI) to dementia is between 20% and 40%, but long-term in 5–10 years ranges from 60% to 100%. It is particularly important to prevent or prolong the development of MCI into dementia. Both auriculotherapy and vagus nerve stimulation are effective on improving cognitive functions. However, there is no double blinded randomized clinical trial to support the effectiveness of transcutaneous electrical stimulation of auricular acupoints in patients with MCI.MethodsThis randomized controlled trial involved patients with MCI, aged from 55 to 75 years old. Patients were randomly allocated to transcutaneous auricular vagus nerve stimulation (taVNS) group or sham taVNS group. In the taVNS group, two auricular acupoints were stimulated, including heart (concha, CO₁₅) and kidney (CO₁₀), which are in the distribution of vagus nerve. While in the sham taVNS group, two other auricular acupoints were stimulated, including elbow (scaphoid fossa, SF₃) and shoulder (SF_4,5), which are out of the distribution of vagus nerve. The primary outcome was the Montreal cognitive assessment-basic, MOCA-B. The secondary outcomes included auditory verbal learning test-HuaShan version (AVLT-H), shape trails test A&B (STT-A&B), animal fluence test (AFT), Boston naming test (BNT), Pittsburgh sleep quality index (PSQI), rapid eye movement sleep behavior disorder screening questionnaire (RBDSQ), Epworth sleepiness scale (ESS) and functional activities questionnaire (FAQ). These outcome measures were taken at baseline, 24 weeks later.ResultsAfter 24 weeks of intervention, the data of 52 patients were intended for analysis. After intervention, there was significant difference in the overall scores of MoCA-B between taVNS group and sham taVNS group (p = 0.033 < 0.05). In taVNS group, compared with before intervention, the overall scores of MOCA-B increased significantly after intervention (p < 0.001). As for N5 and N7, the two sub-indicators of AVLT-H, in taVNS group, compared with before intervention, both N5 and N7 increased significantly after intervention (both ps < 0.001). As for STTB, in taVNS group, compared with before intervention, STTB was significantly reduced after intervention (p = 0.016). For BNT, in taVNS group, compared with before intervention, BNT increased significantly after intervention (p < 0.001). In taVNS group, compared with before intervention, PSQI, RBDSQ, ESS and FAQ decreased significantly after intervention (p = 0.002, 0.025, <0.001, 0.006 respectively). 1 patient with a history of tympanic membrane perforation in taVNS group was reported with mild adverse reactions which disappeared a week after termination of taVNS. The intervention of taVNS is effective on increasing the overall scores of MoCA-B, N5 and N7.ConclusionThe clinical trial demonstrated that taVNS can improve cognitive performance in patients with MCI. This inexpensive, effective and innovative method can be recommended as a therapy for more patients with MCI in the prevention or prolonging of its development into dementia, but it is still required to be further investigated.Trial registrationhttp://www.chictr.org.cn. (ID: ChiCTR2000038868)     

Auricular transcutaneous electrical nerve stimulation in depressed patients: a randomized controlled pilot study

Invasive vagus nerve stimulation has been demonstrated to be an effective treatment in major depressive episodes. Recently, a novel non-invasive method of stimulating the vagus nerve on the outer canal of the ear has been proposed. In healthy subjects, a prominent fMRI BOLD signal deactivation in the limbic system was found. The present pilot study investigates the effects of this novel technique of auricular transcutaneous electric nerve stimulation in depressed patients for the first time. A total of 37 patients suffering from major depression were included in two randomized sham controlled add-on studies. Patients were stimulated five times a week on a daily basis for the duration of 2 weeks. On days 0 and 14, the Hamilton Depression Rating Scale (HAMD) and the Beck Depression Inventory (BDI) were assessed. In contrast to sham-treated patients, electrically stimulated persons showed a significantly better outcome in the BDI. Mean decrease in the active treatment group was 12.6 (SD 6.0) points compared to 4.4 (SD 9.9) points in the sham group. HAMD score did not change significantly in the two groups. An antidepressant effect of a new transcutaneous auricular nerve stimulation technique has been shown for the first time in this controlled pilot study. Regarding the limitations of psychometric testing, the risk of unblinding for technical reasons, and the small sample size, further studies are necessary to confirm the present results and verify the practicability of tVNS in clinical fields.     

Transcutaneous auricular vagus nerve stimulation influences gastric motility: A randomized,double-blind trial in healthy individuals

BackgroundTranscutaneous auricular vagus nerve stimulation (taVNS) has been investigated regarding its therapeutic properties in several several conditions such as epilepsy, migraine and major depressive disorder and was shown to access similar neural pathways as invasive vagus nerve stimulation. While the vagus nerve's role in gut motility is physiologically established, the effect of taVNS has scarcely been investigated in humans and yielded conflicting results. Real-time gastric magnetic resonance imaging (rtMRI) is an established reproducible method to investigate gastric motility non-invasively.ObjectiveTo investigate the influence of taVNS on gastric motility of healthy participants using rtMRI.MethodsWe conducted a randomized, double-blind study using high-frequency (HF) stimulation at 25Hz or low-frequency (LF) taVNS at 1Hz after ingestions of a standardized meal in 57 healthy participants. The gastric motility index (GMI) was determined by measuring the amplitude and velocity of the peristaltic waves using rtMRI.ResultsAfter HF taVNS, GMI was significantly higher than after LF stimulation (p = 0.005), which was mainly attributable to a higher amplitude of the peristaltic waves (p = 0.003).ConclusionWe provide evidence that 4-h of taVNS influences gastric motility in healthy human participants for the first time using rtMRI. HF stimulation is associated with higher amplitudes of peristaltic waves in the gastric antrum compared to LF stimulation. Further studies are needed to investigate the effect of different frequencies of taVNS and its therapeutic properties in conditions with impaired gastric motility.     

Four-week training involving ankle mobilization with movement versus static muscle stretching in patients with chronic stroke: a randomized controlled trial

Background: Patients with stroke generally have diminished balance and gait. Mobilization with movement (MWM) can be used with manual force applied by a therapist to enhance talus gliding movement. Furthermore, the weight-bearing position during the lunge may enhance the stretch force.

Objectives: This study aimed to compare the effects of a 4-week program of MWM training with those of static muscle stretching (SMS). Ankle dorsiflexion passive range of motion (DF-PROM), static balance ability (SBA), the Berg balance scale (BBS), and gait parameters (gait speed and cadence) were measured in patients with chronic stroke.

Methods: Twenty patients with chronic stroke participated in this study. Participants were randomized to either the MWM (n = 10) or the SMS (n = 10) group. Patients in both groups underwent standard rehabilitation therapy for 30 min per session. In addition, MWM and SMS techniques were performed three times per week for 4 weeks. Ankle DF-PROM, SBA, BBS score, and gait parameters were measured after 4 weeks of training.

Results: After 4 weeks of training, the MWM group showed significant improvement in all outcome measures compared with baseline (p < 0.05). Furthermore, SBA, BBS, and cadence showed greater improvement in the MWM group compared to the SMS group (p < 0.05).

Conclusions: This study demonstrated that MWM training, combined with standard rehabilitation, improved ankle DF-PROM, SBA, BBS scores, and gait speed and cadence. Thus, MWM may be an effective treatment for patients with chronic stroke.     

经皮电刺激联合功能训练治疗卒中后吞咽功能障碍的疗效比较

目的本研究旨在探讨经皮神经电刺激（TENS）联合吞咽功能训练治疗急性期、恢复期脑卒中后吞咽功能障碍的疗效评价,对比急、慢性期患者治疗的效果差异;以及对比急性期患者TENS联合治疗与单纯吞咽功能训练的疗效差异。方法118例脑卒中后吞咽功能障碍的患者分为急性期治疗组和恢复期TENS联合功能训练治疗组（简称：恢复期联合治疗组）;其中急性期治疗组随机分为急性期TENS联合吞咽功能训练治疗组（简称：急性期联合治疗组）和急性期吞咽功能训练组（急性期功能训练组）两个亚组。三组均使用常规药物治疗和吞咽功能训练,除急性期吞咽功能训练组外其他两组在此基础上加用TENS治疗,疗程两周。在治疗前、治疗1周、治疗2周后采用吞咽x线电视透视检查吞咽功能进行评价。急性期联合治疗组、急性期吞咽功能训练组分别与恢复期联合治疗组比较;以及急性期两亚组间进行比较。结果治疗后2周急性期联合治疗组有效35例,有效率87．5％;急性期功能训练组有效32例,有效率82％;恢复期联合治疗组有效24例,有效率61．5％。急性期联合治疗组和急性期功能训练组均与恢复期联合治疗组比较,差异有统计学意义（P〈0．05）;但急性期两亚组间差异无统计学意义（P〉0．05）。结论脑卒中后吞咽功能障碍患者采用吞咽功能训练联合TENS治疗和单纯吞咽功能训练均有效改善脑卒中后的吞咽功能,急性期明显高于慢性期患者的疗效。但是急性期采用吞咽功能训练联合TENS与单纯吞咽功能训练的效果相当。     

Vagus nerve stimulation for treatment-resistant depression: a randomized, controlled acute phase trial.

BACKGROUND: Vagus nerve stimulation (VNS) alters both concentrations of neurotransmitters or their metabolites and functional activity of central nervous system regions dysregulated in mood disorders. An open trial has suggested efficacy. METHODS: This 10-week, acute, randomized, controlled, masked trial compared adjunctive VNS with sham treatment in 235 outpatients with nonpsychotic major depressive disorder (n = 210) or nonpsychotic, depressed phase, bipolar disorder (n = 25). In the current episode, participants had not responded adequately to between two and six research-qualified medication trials. A two-week, single-blind recovery period (no stimulation) and then 10 weeks of masked active or sham VNS followed implantation. Medications were kept stable. Primary efficacy outcome among 222 evaluable participants was based on response rates (>/=50% reduction from baseline on the 24-item Hamilton Rating Scale for Depression [HRSD(24)]). RESULTS: At 10-weeks, HRSD(24) response rates were 15.2% for the active (n = 112) and 10.0% for the sham (n = 110) groups (p = .251, last observation carried forward [LOCF]). Response rates with a secondary outcome, the Inventory of Depressive Symptomatology - Self-Report (IDS-SR(30)), were 17.0% (active) and 7.3% (sham) (p = .032, LOCF). VNS was well tolerated; 1% (3/235) left the study because of adverse events. CONCLUSIONS: This study did not yield definitive evidence of short-term efficacy for adjunctive VNS in treatment-resistant depression.     

Mirror therapy and treadmill training for patients with chronic stroke: a pilot randomized controlled trial

Background: Previous lower-limb mirror therapy research has focused on non-weight bearing interventions.

Objectives: The primary aim of this study was to investigate the effect and feasibility of a combination of mirror therapy and treadmill training on post-stroke lower-limb recovery compared to a placebo intervention.

Methods: All patients (N = 30) walked on a treadmill for 30 min per day, 3 days per week, for 4 weeks. The mirror therapy and treadmill training group (n = 15) walked on the treadmill while viewing a reflection of their non-paretic limb in a mirror positioned in their mid-sagittal plane. The placebo group (n = 15) received no mirror visual feedback due to an altered mirror position. Primary outcome measures: Ten Metre Walk Test (10MWT) and Six Minute Walk Test (6MWT). Secondary outcome measures: Modified Ashworth Scale (MAS) and Fugl-Meyer Assessment-Lower Extremity (FMA-LE). Feasibility was appraised by examining participant compliance and any adverse events.

Results: No significant between group differences were demonstrated for the 10MWT, 6MWT or FMA-LE at post-training or 3-month follow-up assessment. A significant between group difference on the MAS was demonstrated in the reduction of ankle dorsiflexion muscle tone (p = 0.006) and ankle plantarflexion muscle tone (p = 0.01) in the mirror therapy group compared to the placebo group at post-training assessment but not at 3-month follow-up.

Conclusion: Our study reveals that in our group of patients with chronic stroke, mirror therapy combined with treadmill training facilitated significant reductions in ankle muscle tone (p < 0.05) compared to a placebo intervention.     

Vagus nerve stimulation in children with intractable epilepsy: a randomized controlled trial

Aim The aim of this study was to evaluate the effects of vagus nerve stimulation (VNS) in children with intractable epilepsy on seizure frequency and severity and in terms of tolerability and safety. Method In this study, the first randomized active controlled trial of its kind in children, 41 children (23 males; 18 females; mean age at implantation 11y 2mo, SD 4y 2mo, range 3y 10mo–17y 8mo) were included. Thirty‐five participants had localization‐related epilepsy (25 symptomatic; 10 cryptogenic), while six participants had generalized epilepsy (four symptomatic; two idiopathic). During a baseline period of 12 weeks, seizure frequency and severity were recorded using seizure diaries and the adapted Chalfont Seizure Severity Scale (NHS3), after which the participants entered a blinded active controlled phase of 20 weeks. During this phase, half of the participants received high‐output VNS (maximally 1.75mA) and the other half received low‐output stimulation (0.25mA). Finally, all participants received high‐output stimulation for 19 weeks. For both phases, seizure frequency and severity were assessed as during the baseline period. Overall satisfaction and adverse events were assessed by semi‐structured interviews. Results At the end of the randomized controlled blinded phase, seizure frequency reduction of 50% or more occurred in 16% of the high‐output stimulation group and in 21% of the low‐output stimulation group (p=1.00). There was no significant difference in the decrease in seizure severity between participants in the stimulation groups. Overall, VNS reduced seizure frequency by 50% or more in 26% of participants at the end of the add‐on phase The overall seizure severity also improved (p<0.001). Interpretation VNS is a safe and well‐tolerated adjunctive treatment of epilepsy in children. Our results suggest that the effect of VNS on seizure frequency in children is limited. However, the possible reduction in seizure severity and improvement in well‐being makes this treatment worth considering in individual children with intractable epilepsy.     

Efficacy and safety of transcranial magnetic stimulation in the acute treatment of major depression: a multisite randomized controlled trial.

BACKGROUND: We tested whether transcranial magnetic stimulation (TMS) over the left dorsolateral prefrontal cortex (DLPFC) is effective and safe in the acute treatment of major depression. METHODS: In a double-blind, multisite study, 301 medication-free patients with major depression who had not benefited from prior treatment were randomized to active (n = 155) or sham TMS (n = 146) conditions. Sessions were conducted five times per week with TMS at 10 pulses/sec, 120% of motor threshold, 3000 pulses/session, for 4-6 weeks. Primary outcome was the symptom score change as assessed at week 4 with the Montgomery-Asberg Depression Rating Scale (MADRS). Secondary outcomes included changes on the 17- and 24-item Hamilton Depression Rating Scale (HAMD) and response and remission rates with the MADRS and HAMD. RESULTS: Active TMS was significantly superior to sham TMS on the MADRS at week 4 (with a post hoc correction for inequality in symptom severity between groups at baseline), as well as on the HAMD17 and HAMD24 scales at weeks 4 and 6. Response rates were significantly higher with active TMS on all three scales at weeks 4 and 6. Remission rates were approximately twofold higher with active TMS at week 6 and significant on the MADRS and HAMD24 scales (but not the HAMD17 scale). Active TMS was well tolerated with a low dropout rate for adverse events (4.5%) that were generally mild and limited to transient scalp discomfort or pain. CONCLUSIONS: Transcranial magnetic stimulation was effective in treating major depression with minimal side effects reported. It offers clinicians a novel alternative for the treatment of this disorder.     

迷走神经刺激术治疗5例难治性抑郁症患者的疗效及安全性分析

目的 开展小样本探索性研究,通过对难治性抑郁症(TRD)患者附加迷走神经刺激术(VNS)治疗,验证其有效性及安全性.方法 于2018年2月至2020年12月在北京安定医院门诊筛选并纳入符合纳入及排除标准的5例TRD患者进行VNS治疗,并在术后2周(开机调试参数)以及开机后1、6、12个月随访,采用17项汉密尔顿抑郁量表...     

Four-week training involving self-ankle mobilization with movement versus calf muscle stretching in patients with chronic stroke: a randomized controlled study

ABSTRACT

Background

In self-ankle mobilization with movement (S-MWM) therapy, a strap can be utilized to stabilize the posterior glide of the talus during ankle dorsiflexion movements.