The Effects of Combined Respiratory-Gated Auricular Vagal Afferent Nerve Stimulation and Mindfulness Meditation for Chronic Low Back Pain: A Pilot Study.

OBJECTIVE: Respiratory-gated Auricular Vagal Afferent Nerve stimulation (RAVANS) is a safe nonpharmacological approach to managing chronic pain. The purpose of the current study was to examine (1) the feasibility and acceptability of RAVANS, combined with mindful meditation (MM) for chronic low back pain (CLBP), (2) the potential synergy of MM+RAVANS on improving pain, and (3) possible moderators of the influence of MM+RAVANS on pain. DESIGN: Pilot feasibility and acceptability study. SETTING: Pain management center at large academic medical center. SUBJECTS: Nineteen adults with CLBP and previous MM training. METHODS: Participants attended two sessions during which they completed quantitative sensory testing (QST), rated pain severity, and completed a MM+stimulation session. Participants received RAVANS during one visit and sham stimulation during the other, randomized in order. Following intervention, participants repeated QST. RESULTS: MM+RAVANS was well tolerated, acceptable, and feasible to provide relief for CLBP. Both MM+stimulation sessions resulted in improved back pain severity, punctate pain ratings, and pressure pain threshold. Individuals with greater negative affect showed greater back pain improvement from MM+RAVANS while those with greater mindfulness showed greater back pain improvement from MM+sham. CONCLUSIONS: Results suggest that for CLBP patients with prior MM training, the analgesic effects of MM may have overshadowed effects of RAVANS given the brief single session MM+RAVANS intervention. However, those with greater negative affect may benefit from combined MM+RAVANS.

Effectiveness of HIIT compared to moderate continuous training in improving vascular parameters in inactive adults.

BACKGROUND: Strong evidence shows that physical inactivity increases the risk of many adverse health conditions, including major non-communicable diseases, such as cardiovascular disease (CVD), metabolic syndrome, and breast and colon cancers, and shortens life expectancy. We aimed to determine the effects of moderate (MCT)- versus high-intensity interval training (HIT) on vascular function parameters in physically inactive adults. We hypothesized that individualized HIT prescription would improve the vascular function parameters more than the MCT in a greater proportion of individuals. METHODS: Twenty-one inactive adults were randomly allocated to receive either MCT group (60-75% of their heart rate reserve, [HRR] or HIT group (4 min at 85-95% of peak HRR), 3 days a week for 12 weeks. Vascular function (brachial artery flow-mediated dilation, FMD [%], normalized brachial artery flow-mediated dilation, FMDn [%], aortic pulse wave velocity, PWV [m·s- 1], AIx, augmentation index: aortic and brachial [%]), were measured at baseline and over 12 weeks of training. In order for a participant to be considered a responder to improvements in vascular function parameters (FMDn and PWV), the typical error was calculated in a favorable direction. RESULTS: FMD changed by - 1.0% (SE 2.1, d = 0.388) in the MCT group, and + 1.8% (SE 1.8, d = 0.699) in the HIT group (no significant difference between groups: 2.9% [95% CI, - 3.0 to 8.8]. PWV changed by + 0.1 m·s- 1 (SE 0.2, d = 0.087) in the MCT group but decreased by - 0.4 m·s- 1 in the HIT group (SE 0.2, d = 0.497), with significant difference between groups: - 0.4 [95% CI, - 0.2 to - 0.7]. There was not a significant difference in the prevalence of no-responder for FMD (%) between the MCT and HIT groups (66% versus 36%, P = 0.157). Regarding PWV (m·s- 1), an analysis showed that the prevalence of no-responder was 77% (7 cases) in the MCT group and 45% (5 cases) in the HIT group (P = 0.114). CONCLUSIONS: Under the conditions of the present study, both groups experienced changed in vascular function parameters. Compared to MCT group, HIT is more efficacious for improving FMD and decreasing PWV, in physically inactive adults. TRIAL REGISTRATION: ClinicalTrials.gov NCT02738385 registered on 23 March 2016.

Reduced insula habituation associated with amplification of trigeminal brainstem input in migraine.

Background Impaired sensory processing in migraine can reflect diminished habituation, increased activation, or even increased gain or amplification of activity from the primary synapse in the brainstem to higher cortical/subcortical brain regions. Methods We scanned 16 episodic migraine (interictal) and 16 healthy controls (cross-sectional study), and evaluated brain response to innocuous air-puff stimulation over the right forehead in the ophthalmic nerve (V1) trigeminal territory. We further evaluated habituation, and cortical/subcortical amplification relative to spinal trigeminal nucleus (Sp5) activation. Results Migraine subjects showed greater amplification from Sp5 to the posterior insula and hypothalamus. In addition, while controls showed habituation to repetitive sensory stimulation in all activated cortical regions (e.g. the bilateral posterior insula and secondary somatosensory cortices), for migraine subjects, habituation was not found in the posterior insula. Moreover, in migraine, the habituation slope was correlated with the amplification ratio in the posterior insula and secondary somatosensory cortex, i.e. greater amplification was associated with reduced habituation in these regions. Conclusions These findings suggest that in episodic migraine, amplified information processing from spinal trigeminal relay nuclei is linked to an impaired habituation response. This phenomenon was localized in the posterior insula, highlighting the important role of this structure in mechanisms supporting altered sensory processing in episodic migraine.

Brain Circuitry Supporting Multi-Organ Autonomic Outflow in Response to Nausea.

While autonomic outflow is an important co-factor of nausea physiology, central control of this outflow is poorly understood. We evaluated sympathetic (skin conductance level) and cardiovagal (high-frequency heart rate variability) modulation, collected synchronously with functional MRI (fMRI) data during nauseogenic visual stimulation aimed to induce vection in susceptible individuals. Autonomic data guided analysis of neuroimaging data, using a stimulus-based (analysis windows set by visual stimulation protocol) and percept-based (windows set by subjects' ratings) approach. Increased sympathetic and decreased parasympathetic modulation was associated with robust and anti-correlated brain activity in response to nausea. Specifically, greater autonomic response was associated with reduced fMRI signal in brain regions such as the insula, suggesting an inhibitory relationship with premotor brainstem nuclei. Interestingly, some sympathetic/parasympathetic specificity was noted. Activity in default mode network and visual motion areas was anti-correlated with parasympathetic outflow at peak nausea. In contrast, lateral prefrontal cortical activity was anti-correlated with sympathetic outflow during recovery, soon after cessation of nauseogenic stimulation. These results suggest divergent central autonomic control for sympathetic and parasympathetic response to nausea. Autonomic outflow and the central autonomic network underlying ANS response to nausea may be an important determinant of overall nausea intensity and, ultimately, a potential therapeutic target.

Causal influence of brainstem response to transcutaneous vagus nerve stimulation on cardiovagal outflow.

BACKGROUND: The autonomic response to transcutaneous auricular vagus nerve stimulation (taVNS) has been linked to the engagement of brainstem circuitry modulating autonomic outflow. However, the physiological mechanisms supporting such efferent vagal responses are not well understood, particularly in humans. HYPOTHESIS: We present a paradigm for estimating directional brain-heart interactions in response to taVNS. We propose that our approach is able to identify causal links between the activity of brainstem nuclei involved in autonomic control and cardiovagal outflow. METHODS: We adopt an approach based on a recent reformulation of Granger causality that includes permutation-based, nonparametric statistics. The method is applied to ultrahigh field (7T) functional magnetic resonance imaging (fMRI) data collected on healthy subjects during taVNS. RESULTS: Our framework identified taVNS-evoked functional brainstem responses with superior sensitivity compared to prior conventional approaches, confirming causal links between taVNS stimulation and fMRI response in the nucleus tractus solitarii (NTS). Furthermore, our causal approach elucidated potential mechanisms by which information is relayed between brainstem nuclei and cardiovagal, i.e., high-frequency heart rate variability, in response to taVNS. Our findings revealed that key brainstem nuclei, known from animal models to be involved in cardiovascular control, exert a causal influence on taVNS-induced cardiovagal outflow in humans. CONCLUSION: Our causal approach allowed us to noninvasively evaluate directional interactions between fMRI BOLD signals from brainstem nuclei and cardiovagal outflow.

Efficacy and Safety of Vagus Nerve Stimulation on Upper Limb Motor Recovery After Stroke. A Systematic Review and Meta-Analysis.

Background: Upper limb motor impairment is one of the main complications of stroke, affecting quality of life both for the patient and their family. The aim of this systematic review was to summarize the scientific evidence on the safety and efficacy of Vagus Nerve Stimulation (VNS) on upper limb motor recovery after stroke. Methods: A systematic review and meta-analysis of studies that have evaluated the efficacy or safety of VNS in stroke patients was performed. The primary outcome was upper limb motor recovery. A search of articles published on MEDLINE, CENTRAL, EBSCO and LILACS up to December 2021 was performed, and a meta-analysis was developed to calculate the overall effects. Results: Eight studies evaluating VNS effects on motor function in stroke patients were included, of which 4 used implanted and 4 transcutaneous VNS. It was demonstrated that VNS, together with physical rehabilitation, increased upper limb motor function on average 7.06 points (95%CI 4.96; 9.16) as assessed by the Fugl-Meyer scale. Likewise, this improvement was significantly greater when compared to a control intervention (mean difference 2.48, 95%CI 0.98; 3.98). No deaths or serious adverse events related to the intervention were reported. The most frequent adverse events were dysphonia, dysphagia, nausea, skin redness, dysgeusia and pain related to device implantation. Conclusion: VNS, together with physical rehabilitation, improves upper limb motor function in stroke patients. Additionally, VNS is a safe intervention.

Optimization of respiratory-gated auricular vagus afferent nerve stimulation for the modulation of blood pressure in hypertension.

Background: The objective of this pilot study was to identify frequency-dependent effects of respiratory-gated auricular vagus afferent nerve stimulation (RAVANS) on the regulation of blood pressure and heart rate variability in hypertensive subjects and examine potential differential effects by sex/gender or race. Methods: Twenty hypertensive subjects (54.55 ± 6.23 years of age; 12 females and 8 males) were included in a within-person experimental design and underwent five stimulation sessions where they received RAVANS at different frequencies (i.e., 2 Hz, 10 Hz, 25 Hz, 100 Hz, or sham stimulation) in a randomized order. EKG and continuous blood pressure signals were collected during a 10-min baseline, 30-min stimulation, and 10-min post-stimulation periods. Generalized estimating equations (GEE) adjusted for baseline measures were used to evaluate frequency-dependent effects of RAVANS on heart rate, high frequency power, and blood pressure measures, including analyses stratified by sex and race. Results: Administration of RAVANS at 100 Hz had significant overall effects on the reduction of heart rate (ß = -2.03, p = 0.002). It was also associated with a significant reduction of diastolic (ß = -1.90, p = 0.01) and mean arterial blood pressure (ß = -2.23, p = 0.002) in Black hypertensive participants and heart rate in female subjects (ß = -2.83, p = 0.01) during the post-stimulation period when compared to sham. Conclusion: Respiratory-gated auricular vagus afferent nerve stimulation exhibits frequency-dependent rapid effects on the modulation of heart rate and blood pressure in hypertensive patients that may further differ by race and sex. Our findings highlight the need for the development of optimized stimulation protocols that achieve the greatest effects on the modulation of physiological and clinical outcomes in this population.

Plasma nitrate levels and flow-mediated vasodilation in untreated major depression.

OBJECTIVE: Findings from several studies have revealed that major depression is associated with an increased cardiovascular risk. The physiopathologic mechanisms of this association remain unclear, although recently, it has been hypothesized that a decreased production of nitric oxide could be a potential contributor to vascular dysfunction in depressive patients. The objective of this study was to evaluate nitric oxide production and vascular endothelial function in treatment-naive young healthy adults with a first episode of major depression. METHODS: A case-control study in 50 treatment-naive young adults with a first episode of major depression and 50 healthy control subjects was conducted. Plasma levels of nitric oxide metabolites (nitrates/nitrites) were determined using a colorimetric assay based on Griess reaction. Endothelial function was assessed by flow-mediated vasodilation measurements after reactive hyperemia. RESULTS: The mean age of the depressed patients was 22.6 (standard deviation [SD], 4.6) years, whereas the controls were 23.4 (SD, 4.8) years. Sixteen men (32%) and 34 women (68%) were included in each group. The plasma nitrite/nitrate concentrations were significantly lower in depressive subjects compared with healthy controls (17.5 [SD, 4.9] µmol/L versus 21.6 [SD, 7.0] µmol/L, p < .001); however, flow-mediated vasodilation values were similar in both groups (13.1% [SD, 4.3%] versus 12.1% [SD, 5.0%], p = .10). CONCLUSIONS: Decreased plasma concentrations of nitric oxide metabolites are not associated with vascular endothelial dysfunction in young subjects with a first episode of major depression. Reduced nitrate/nitrite levels could reflect a decreased nitric oxide production in the central nervous system of depressed subjects. Further studies are needed to confirm this hypothesis.

Respiratory-gated auricular vagal afferent nerve stimulation (RAVANS) modulates brain response to stress in major depression.

BACKGROUND: Negative stress significantly impacts major depressive disorder (MDD), given the shared brain circuitry between the stress response and mood. Thus, interventions that target this circuitry will have an important impact on MDD. The aim of this study was to evaluate the acute effects of a novel respiratory-gated auricular vagal afferent nerve stimulation (RAVANS) technique in the modulation of brain activity and connectivity in women with MDD in response to negative stressful stimuli. METHODS: Twenty premenopausal women with recurrent MDD in an active episode were included in a cross-over experimental study that included two functional MRI visits within one week, randomized to receive exhalatory- (e-RAVANS) or inhalatory-gated (i-RAVANS) at each visit. Subjects were exposed to a visual stress challenge that preceded and followed RAVANS. A Factorial analysis was used to evaluate the effects of RAVANS on brain activity and connectivity and changes in depressive and anxiety symptomatology post-stress. RESULTS: Compared with i-RAVANS, e-RAVANS was significantly associated with increased activation of subgenual anterior cingulate, orbitofrontal and ventromedial prefrontal cortices and increased connectivity between hypothalamus and dorsolateral prefrontal cortex, and from nucleus tractus solitarii to locus coeruleus and ventromedial prefrontal cortex. Changes in brain activity and connectivity after e-RAVANS were significantly associated with a reduction in depressive and anxiety symptoms. CONCLUSIONS: Our study suggests exhalatory-gated RAVANS effectively modulates brain circuitries regulating response to negative stress and is associated with significant acute reduction of depressive and anxiety symptomatology in women with recurrent MDD. Findings suggest a potential non-pharmacologic intervention for acute relief of depressive symptomatology in MDD.

Modulatory Effects of Respiratory-Gated Auricular Vagal Nerve Stimulation on Cardiovagal Activity in Hypertension.

The objective of this study was to determine potential effects of Respiratory-gated Auricular Vagal Afferent Nerve Stimulation (RAVANS) on cardiac autonomic activity in hypertensive patients.20 hypertensive subjects (57.3±6.2 years; 11 females, 9 males) were randomized to receive either active RAVANS at 25 Hz or sham stimulation for 5 consecutive days and were assessed 5 and 10 days later. Continuous electrocardiogram, pulse rate, and blood pressure signals were collected during 10-minute baseline, 30-minute stimulation, and 10-minute recovery periods for each session. LabChart was used to acquire and process heart rate variability and blood pressure indices. Percent changes of mean values during the recovery period were calculated comparing the final stimulation session and follow-up sessions to the first stimulation session. General linear models were applied to assess the effects of RAVANS on the variables evaluated, considering baseline values and sex as covariates in the models.We found that RAVANS increased high frequency (HF-HRV) power during recovery of the final stimulation session and both follow-up sessions in comparison to sham. RAVANS also lowered heart rate and increased average RR and root mean square of successive RR interval differences (RMSSD) during recovery on the final day of stimulation. No significant effects on blood pressure values were observed during these periods.These results suggest that RAVANS effectively stimulates cardiovagal activity in hypertension, with effects lasting up to 10 days. Future research incorporating larger sample sizes is needed to replicate the effects of RAVANS.Clinical Relevance- This research has implications for potential therapeutic effects of respiratory-gated tVNS on cardiovagal modulation in hypertensive patients.

Impact of sex and depressed mood on the central regulation of cardiac autonomic function.

Cardiac autonomic dysregulation has been implicated in the comorbidity of major psychiatric disorders and cardiovascular disease, potentially through dysregulation of physiological responses to negative stressful stimuli (here, shortened to stress response). Further, sex differences in these comorbidities are substantial. Here, we tested the hypothesis that mood- and sex-dependent alterations in brain circuitry implicated in the regulation of the stress response are associated with reduced peripheral parasympathetic activity during negative emotional arousal. Fifty subjects (28 females) including healthy controls and individuals with major depression, bipolar psychosis and schizophrenia were evaluated. Functional magnetic resonance imaging and physiology (cardiac pulse) data were acquired during a mild visual stress reactivity challenge. Associations between changes in activity and functional connectivity of the stress response circuitry and variations in cardiovagal activity [normalized high frequency power of heart rate variability (HFn)] were evaluated using GLM analyses, including interactions with depressed mood and sex across disorders. Our results revealed that in women with high depressed mood, lower cardiovagal activity in response to negative affective stimuli was associated with greater activation of hypothalamus and right amygdala and reduced connectivity between hypothalamus and right orbitofrontal cortex, amygdala, and hippocampus. No significant associations were observed in women with low levels of depressed mood or men. Our results revealed mood- and sex-dependent interactions in the central regulation of cardiac autonomic activity in response to negative affective stimuli. These findings provide a potential pathophysiological mechanism for previously observed sex differences in the comorbidity of major depression and cardiovascular disease.

Stimulus frequency modulates brainstem response to respiratory-gated transcutaneous auricular vagus nerve stimulation.

BACKGROUND: The therapeutic potential of transcutaneous auricular VNS (taVNS) is currently being explored for numerous clinical applications. However, optimized response for different clinical indications may depend on specific neuromodulation parameters, and systematic assessments of their influence are still needed to optimize this promising approach. HYPOTHESIS: We proposed that stimulation frequency would have a significant effect on nucleus tractus solitarii (NTS) functional MRI (fMRI) response to respiratory-gated taVNS (RAVANS). METHODS: Brainstem fMRI response to auricular RAVANS (cymba conchae) was assessed for four different stimulation frequencies (2, 10, 25, 100 Hz). Sham (no current) stimulation was used to control for respiration effects on fMRI signal. RESULTS: Our findings demonstrated that RAVANS delivered at 100 Hz evoked the strongest brainstem response, localized to a cluster in the left (ipsilateral) medulla and consistent with purported NTS. A co-localized, although weaker, response was found for 2 Hz RAVANS. Furthermore, RAVANS delivered at 100 Hz also evoked stronger fMRI responses for important monoamine neurotransmitter source nuclei (LC, noradrenergic; MR, DR, serotonergic) and pain/homeostatic regulation nuclei (i.e. PAG). CONCLUSION: Our fMRI results support previous localization of taVNS afference to pontomedullary aspect of NTS in the human brainstem, and demonstrate the significant influence of the stimulation frequency on brainstem fMRI response.

The influence of respiration on brainstem and cardiovagal response to auricular vagus nerve stimulation: A multimodal ultrahigh-field (7T) fMRI study.

BACKGROUND: Brainstem-focused mechanisms supporting transcutaneous auricular VNS (taVNS) effects are not well understood, particularly in humans. We employed ultrahigh field (7T) fMRI and evaluated the influence of respiratory phase for optimal targeting, applying our respiratory-gated auricular vagal afferent nerve stimulation (RAVANS) technique. HYPOTHESIS: We proposed that targeting of nucleus tractus solitarii (NTS) and cardiovagal modulation in response to taVNS stimuli would be enhanced when stimulation is delivered during a more receptive state, i.e. exhalation. METHODS: Brainstem fMRI response to auricular taVNS (cymba conchae) was assessed for stimulation delivered during exhalation (eRAVANS) or inhalation (iRAVANS), while exhalation-gated stimulation over the greater auricular nerve (GANctrl, i.e. earlobe) was included as control. Furthermore, we evaluated cardiovagal response to stimulation by calculating instantaneous HF-HRV from cardiac data recorded during fMRI. RESULTS: Our findings demonstrated that eRAVANS evoked fMRI signal increase in ipsilateral pontomedullary junction in a cluster including purported NTS. Brainstem response to GANctrl localized a partially-overlapping cluster, more ventrolateral, consistent with spinal trigeminal nucleus. A region-of-interest analysis also found eRAVANS activation in monoaminergic source nuclei including locus coeruleus (LC, noradrenergic) and both dorsal and median raphe (serotonergic) nuclei. Response to eRAVANS was significantly greater than iRAVANS for all nuclei, and greater than GANctrl in LC and raphe nuclei. Furthermore, eRAVANS, but not iRAVANS, enhanced cardiovagal modulation, confirming enhanced eRAVANS response on both central and peripheral neurophysiological levels. CONCLUSION: 7T fMRI localized brainstem response to taVNS, linked such response with autonomic outflow, and demonstrated that taVNS applied during exhalation enhanced NTS targeting.

Inter-relationships between body mass index, C-reactive protein and blood pressure in a Hispanic pediatric population.

BACKGROUND: The link between inflammation, obesity, and cardiovascular disease (CVD) has been described in adult populations but few data are available with respect to children. The aim of this study was to describe the inter-relationships between adiposity, C-reactive protein (CRP) plasma concentrations, and blood pressure levels in a Hispanic pediatric population. METHODS: We included 325 schoolchildren (mean age, 10.0 years) selected from the school population of Bucaramanga, Colombia. Blood pressure, lipid profile, glucose, and CRP plasma concentration were measured using standard procedures. Body mass index (BMI) was used for evaluating the children's nutritional condition. Correlation coefficients were calculated for all the variables using Spearman's test. RESULTS: As expected, a positive correlation was found between BMI and systolic blood pressure (SBP) in both genders, and between CRP and SBP levels in boys. After a multivariate regression analysis, the association between adiposity and blood pressure remained significant, whereas the CRP concentrations were no longer associated with SBP. CONCLUSIONS: The results obtained in our study of Hispanic school-age children show that adiposity is correlated with CRP concentrations and SBP values as has been earlier described in Caucasian populations. However, we failed to find a significant relationship between low-grade inflammation and SBP levels. Further studies are needed in order to explore alternative pathophysiological mechanisms linking obesity and high blood pressure in children and to define the impact of these associations on the cardiovascular risk of our pediatric population.

Raised C-reactive protein and impaired flow-mediated vasodilation precede the development of preeclampsia.

BACKGROUND: The aim of this study was to investigate whether impaired flow mediated vasodilation precedes the clinical manifestations of preeclampsia and whether is associated with inflammation. METHODS: We conducted a nested case-control study in a prospective cohort of 506 normotensive women recruited before the 30th week of gestation (mean gestational age of 21.8 weeks). At enrollment, flow-mediated dilation was measured in the brachial artery using a 7.5-MHz transducer. C-reactive protein plasma concentrations and leukocyte count were also determined at study entry. Patients were followed until delivery, and medical records were reviewed for each patient to confirm the presence or absence of preeclampsia or gestational hypertension. RESULTS: Of the women studied, 14 developed preeclampsia, 18 developed gestational hypertension, and 474 remained normotensive. Two normotensive pregnant control subjects were randomly selected for each case, matched by maternal age, gestational age, and body mass index at enrollment. Women who subsequently developed preeclampsia had lower flow-mediated dilation (13.4% +/- 4.3% v 18.2% +/- 7.2, P = .026), higher C-reactive protein plasma concentrations (8.7 +/- 5.5 mg/dL v 5.3 +/- 4.3 mg/dL, P = .022) and leukocyte count (10.3 +/- 2.0 x 10(9)/L v 9.1 +/- 2.0 x 10(9)/L, P = .036) at study entry. CONCLUSIONS: Decreased flow-mediated vasodilation and higher levels of CRP are present in early stages of gestation in women who subsequently develop preeclampsia. These alterations occur before the onset of clinical symptoms of PE. Further studies are needed to confirm that flow-mediated dilation and C-reactive protein could be useful methods to screen women at risk of developing preeclampsia.

Determination of insulin resistance using the homeostatic model assessment (HOMA) and its relation with the risk of developing pregnancy-induced hypertension.

OBJECTIVE: To assess whether increased insulin resistance determined by homeostatic model assessment (HOMA) early in pregnancy is associated with the subsequent development of pregnancy-induced hypertension (PIH) in Colombian women with known risk factors. METHODS: We conducted a nested case control study in a prospective cohort of 572 normotensive pregnant women, with gestational age < or = 30 weeks, recruited in Bucaramanga and Floridablanca, Colombia. Fasting plasma glucose and insulin concentrations were determined at enrollment, and HOMA index was calculated. Log-transformed HOMA (log-HOMA) was used in the statistical analysis. Thirty nine PIH cases (18 preeclampsia [PE], 21 gestational hypertension [GH]) were compared to 78 controls, matched by body mass index, gestational and maternal age at enrollment. RESULTS: Women who subsequently developed PIH had higher levels of log-HOMA at enrollment (-0.13 +/- 0.54 v 0.21 +/- 0.60; P = .002), which was significantly associated with the development of PIH (odds ratio 3.13, 95% confidence interval 1.41-6.94; P = .005). Higher log-HOMA was found in women who subsequently developed PE (0.28 +/- 0.58; P = .003), and in those who presented with GH (0.15 +/- 0.62; P = .026). CONCLUSIONS: Women who subsequently develop PIH have a higher degree of insulin resistance determined by log-HOMA early in pregnancy, before the onset of clinical manifestations of the disease. The HOMA seems to be a useful method to evaluate women at risk of developing PIH. More studies are required to confirm its usefulness as a screening tool to identify pregnant women at risk of developing PIH.

Complexity Variability Assessment of Nonlinear Time-Varying Cardiovascular Control.

The application of complex systems theory to physiology and medicine has provided meaningful information about the nonlinear aspects underlying the dynamics of a wide range of biological processes and their disease-related aberrations. However, no studies have investigated whether meaningful information can be extracted by quantifying second-order moments of time-varying cardiovascular complexity. To this extent, we introduce a novel mathematical framework termed complexity variability, in which the variance of instantaneous Lyapunov spectra estimated over time serves as a reference quantifier. We apply the proposed methodology to four exemplary studies involving disorders which stem from cardiology, neurology and psychiatry: Congestive Heart Failure (CHF), Major Depression Disorder (MDD), Parkinson's Disease (PD), and Post-Traumatic Stress Disorder (PTSD) patients with insomnia under a yoga training regime. We show that complexity assessments derived from simple time-averaging are not able to discern pathology-related changes in autonomic control, and we demonstrate that between-group differences in measures of complexity variability are consistent across pathologies. Pathological states such as CHF, MDD, and PD are associated with an increased complexity variability when compared to healthy controls, whereas wellbeing derived from yoga in PTSD is associated with lower time-variance of complexity.

Respiratory-gated Auricular Vagal Afferent Nerve Stimulation (RAVANS) effects on autonomic outflow in hypertension.

Transcutaneous stimulation of the auricular branch of the vagus nerve (ABVN) has been proposed as a non-invasive alternative to vagus nerve stimulation (VNS). However, its cardiovagal effects are inconsistent across studies, likely due to inhomogeneity in the stimulation parameters. Here, we evaluate respiratory-gated ABVN stimulation (Respiratory-gated Auricular Vagal Afferent Nerve Stimulation, RAVANS), where the stimuli are delivered in 1 s bursts during the exhalation phase of respiration, thus mimicking the breathing-induced modulation of cardiac vagal activity. In this study, we present preliminary results from an ongoing single-arm, open label trial investigating the effects of different intensities of RAVANS in hypertensive subjects. We found that a mid-intensity RAVANS stimulation (rated as a 5 on a 0-10 scale) increases the cardiovagal tone and reduces the sympathetic tone during a paced breathing task. The present results could contribute to optimize RAVANS as a non-invasive, low-cost therapeutic intervention for hypertension.

Modulation of brainstem activity and connectivity by respiratory-gated auricular vagal afferent nerve stimulation in migraine patients.

Migraine pathophysiology includes altered brainstem excitability, and recent neuromodulatory approaches aimed at controlling migraine episodes have targeted key brainstem relay and modulatory nuclei. In this study, we evaluated the impact of respiratory-gated auricular vagal afferent nerve stimulation (RAVANS), a novel neuromodulatory intervention based on an existing transcutaneous vagus nerve stimulation approach, in the modulation of brainstem activity and connectivity in migraine patients. We applied 3T-functional magnetic resonance imaging with improved in-plane spatial resolution (2.62 × 2.62 mm) in episodic migraine (interictal) and age- and sex-matched healthy controls to evaluate brain response to RAVANS (gated to either inhalation or exhalation) and sham stimulation. We further investigated RAVANS modulation of tactile trigeminal sensory afference response in the brainstem using air-puff stimulation directed to the forehead during functional magnetic resonance imaging. Compared with sham and inhalatory-gated RAVANS (iRAVANS), exhalatory-gated RAVANS (eRAVANS) activated an ipsilateral pontomedullary region consistent with nucleus tractus solitarii (NTS). During eRAVANS, NTS connectivity was increased to anterior insula and anterior midcingulate cortex, compared with both sham and iRAVANS, in migraine patients. Increased connectivity was inversely correlated with relative time to the next migraine attack, suggesting clinical relevance to this change in connectivity. Poststimulation effects were also noted immediately after eRAVANS, as we found increased activation in putative pontine serotonergic (ie, nucleus raphe centralis) and noradrenergic (ie, locus coeruleus) nuclei in response to trigeminal sensory afference. Regulation of activity and connectivity of brainstem and cortical regions involved in serotonergic and noradrenergic regulation and pain modulation may constitute an underlying mechanism supporting beneficial clinical outcomes for eRAVANS applied for episodic migraine.

Calcium and conjugated linoleic acid reduces pregnancy-induced hypertension and decreases intracellular calcium in lymphocytes.

BACKGROUND: The aim of the present study was to determine whether the beneficial effect of oral supplementation with calcium and conjugated linoleic acid (CLA) in the reduction of the incidence of pregnancy-induced hypertension (PIH) is related with changes in plasma levels of prostanoids, renin, angiotensin II, calciotropic hormones, and plasma and intracellular ionized free calcium. METHODS: These mediators were determined using the blood samples obtained from a randomized, double-blind, placebo-controlled trial that included 48 healthy primigravidas with a family history of preeclampsia and with diastolic notch, recruited from four outpatient clinics from two developing countries. Participants were randomized to daily oral doses of elemental calcium and CLA or lactose-starch placebo from week 18 to week 22 of gestation until delivery. RESULTS: The incidence of PIH was significantly reduced in women receiving the supplement (2 women [8.3%]) compared with placebo (10 women [41.7%]) (relative risk = 0.20, 95% confidence interval 0.05-0.82, P = .01). There were no significant differences in the plasma concentrations of ionized calcium, prostaglandin E(2), renin, angiotensin II, parathormone,and calcitonine. The concentration of intracellular ionized free calcium presented a significant reduction after interventions (92.0 nmol/L [range 62.5 to 220 nmol/L] v 62.5 nmol/L [range 28 to 200 nmol/L; P = .01) in the supplemented group but not in the placebo group. The women who developed PIH (n = 12) presented a significant increase in the concentrations of intracellular calcium after interventions (120 nmol/L [range 89.2 to 240 nmol/L] v 137.5 nmol/L [range 89.2 to 138 nmol/L; P = .02). CONCLUSIONS: Calcium and CLA supplementation during pregnancy reduces the incidence of PIH, and decreases the intracellular concentration of ionized free calcium in peripheral blood lymphocytes.