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Biomedical subjects

Philippe van de Borne

Publications and source records attributed to Philippe van de Borne.

At least 19 recordsLinked to original sources
PubMed2006

Acute cardiovascular and sympathetic effects of nicotine replacement therapy.

Sympathetic overactivity is implicated in the increased cardiovascular risk of cigarette smokers. Excitatory nicotinic receptors are present on peripheral chemoreceptor cells. Chemoreceptors located in the carotid and aortic bodies increase ventilation (Ve), blood pressure (BP), heart rate (HR), and sympathetic nerve activity to muscle circulation (MSNA) in response to hypoxia. We tested the hypothesis that nicotine replacement therapy (NRT) increases MSNA and chemoreceptor sensitivity to hypoxia. Sixteen young healthy smokers were included in the study (8 women). After a randomized and blinded sublingual administration of a 4-mg tablet of nicotine or placebo, we measured minute Ve, HR, mean BP, and MSNA during normoxia and 5 minutes of isocapnic hypoxia. Maximal voluntary end-expiratory apneas were performed at baseline and at the end of the fifth minute of hypoxia. Nicotine increased HR by 7+/-3 bpm, mean BP by 5+/-2 mm Hg, and MSNA by 4+/-1 bursts/min, whereas subjects breathed room air (all P<0.05). During hypoxia, nicotine also raised HR by 8+/-2 bpm, mean BP by 2+/-1 mm Hg, and MSNA by 7+/-2 bursts/min (all P<0.05). Nicotine increased MSNA during the apneas performed in normoxia and hypoxia (P<0.05). Nicotine also raised the product of systolic BP and HR, a marker of cardiac oxygen consumption, during normoxia, hypoxia, and the apneas (P<0.05). Ve, apnea duration, and O2 saturation during hypoxia and the apneas remained unaffected. In conclusion, sympathoexcitatory effects of NRT are not because of an increased chemoreflex sensitivity to hypoxia. NRT increases myocardial oxygen consumption in periods of reduced oxygen availability.

Adult↗
PubMed2006

Increased peripheral chemoreceptors sensitivity and exercise ventilation in heart transplant recipients.

BACKGROUND: Heart failure is characterized by increased ventilation during exercise, which is positively related to increased peripheral and central chemoreceptor sensitivity. Heart transplantation does not normalize the ventilatory response to exercise, and its effects on the chemoreflex control of ventilation remain unknown. We tested the hypothesis that chemoreceptor sensitivity is increased in heart transplant recipients (HTRs) and linked to exercise hyperpnea. METHODS AND RESULTS: We determined the ventilatory, muscle sympathetic nerve activity (MSNA), and circulatory responses to isocapnic hypoxia and hyperoxic hypercapnia 7+/-1 years after transplantation in 19 HTRs with a normal left ventricular ejection fraction of 60+/-2%. Results were compared with those of 11 closely matched referent subjects. Sixteen patients and 10 referent subjects also underwent cycle ergometer exercise tests. HTRs compared with referent subjects presented higher MSNA (52+/-4 versus 34+/-3 bursts/min; P<0.01) and heart rates (83+/-3 versus 68+/-3 bpm; P<0.01) during room air breathing. The ventilatory response to hypoxia was higher in HTRs than in referent subjects (P<0.01, ANOVA). The increase in MSNA also was more marked during hypoxia in the HTRs than in the referent group (P<0.05, ANOVA). Responses to hyperoxic hypercapnia did not differ between the HTRs and the referent group. The ventilatory response to exercise, characterized by the regression slope relating minute ventilation to CO2 output, was steeper in HTRs than in referent subjects (38+/-2 versus 29+/-1 L/mm Hg; P<0.01). Exercise ventilation in HTRs was related to the ventilatory response to isocapnic hypoxia (r=0.57; n=16; P<0.05) and to the ventilatory response to hyperoxic hypercapnia (r=0.50; n=16; P<0.05). CONCLUSIONS: Peripheral chemoreceptor sensitivity is increased in HTRs and is related to exercise hyperpnea after heart transplantation.

Case-Control Studies↗
PubMed2006

Ethnic differences in arterial stiffness and wave reflections after cigarette smoking.

BACKGROUND: Smoking increases plasma nicotine. Nicotine releases catecholamines and alters arterial distensibility. The nicotine intake per cigarette is greater and serum cotinine levels, the proximate metabolite of nicotine, are higher in Blacks than in Whites. We tested the hypothesis that cigarette smoking increases the pulse wave velocity (PWV), a marker of arterial stiffness, and the augmentation index (AI), a measure of wave reflection, more in Blacks than in Whites. METHODS: We matched Black (n = 30) and White (n = 30) smokers for age, gender, body mass index and height. We determined carotid-femoral PWV (PWVCF) and carotid-radial PWV (PWVCR) (Complior), the AI derived from the aortic pressure waveform (applanation tonometry, Sphygmocor), blood pressure, heart rate (HR) and cotinine levels before and after cigarette smoking. We also performed measurements in 16 participants after sham smoking. RESULTS: Smoking increased the AI, PWVCF and PWVCR in the whole population (all P < 0.05, n = 60). Increases in the AI and PWV were positively related to serum cotinine levels (all P < 0.05). Smoking increased serum cotinine (P = 0.01) and mean blood pressure (P = 0.03) more, but raised the HR to a lesser extent, in Blacks [+8 +/- 4 versus +13 +/- 6 beats/min in Whites (mean +/- SD), P = 0.01]. Blacks disclosed larger increases in AI adjusted for HR (Blacks, +7.2 +/- 8 versus Whites, +4.4 +/- 8%; P = 0.03), PWVCF (Blacks, +1.1 +/- 0.2 versus Whites, +0.6 +/- 0.3 m/s; P < 0.01) and PWVCR (Blacks, +1.4 +/- 0.1 versus Whites, +0.7 +/- 0.4 m/s; P < 0.01) normalized for the mean blood pressure. No changes were observed with sham smoking. CONCLUSIONS: Smoking acutely increases the PWV and AI in Blacks more than in Whites. Differences in nicotine metabolism and beta-adrenergic sensitivity could explain these findings.

Adult↗
PubMed2005

Sympathetic neural outflow and chemoreflex sensitivity are related to spontaneous breathing rate in normal men.

Respiration contributes importantly to short-term modulation of sympathetic nerve activity. However, the relationship between spontaneous breathing rate, chemoreflex function, and direct measures of sympathetic traffic in healthy humans has not been studied previously. We tested the hypothesis that muscle sympathetic nerve activity and chemoreflex sensitivity are linked independently to respiratory rate in normal subjects. We studied 69 normal male subjects aged 29.6+/-8.1 years. Subjects were subdivided according to the tertiles of respiratory rate distributions. Mean respiration rate was 10.6 breaths/min in the first tertile, 14.8 breaths/min in the second tertile, and 18.0 breaths/min in the third tertile. Subjects from the third tertile (faster respiratory rate) had greater sympathetic activity than subjects from the first tertile (slower respiratory rate; 29+/-3 versus 17+/-2 bursts/min; P<0.001). Stepwise multiple linear regression analysis revealed that only respiratory rate was linked independently to sympathetic activity (r=0.42; P<0.001). In comparison to subjects with slow respiratory rate, subjects with fast respiratory rate had greater increases in minute ventilation during both hypercapnia (7.3+/-0.8 versus 3.2+/-1.0 L/min; P=0.005) and hypoxia (5.7+/-0.8 versus 2.4+/-0.7 L/min; P=0.007). Muscle sympathetic nerve activity and chemoreflex sensitivity are linked to spontaneous respiratory rate in normal humans. Faster respiratory rate is associated with higher levels of sympathetic traffic and potentiated responses to hypoxia and hypercapnia. Spontaneous breathing frequency, central sympathetic outflow, and chemoreflex sensitivity exhibit significant and hitherto unrecognized interactions in the modulation of neural circulatory control.

Adult↗
PubMed2005

Respiratory-related heart rate variability in progressive experimental heart failure.

Heart failure is associated with autonomic imbalance, and this can be evaluated by a spectral analysis of heart rate variability. However, the time course of low-frequency (LF) and high-frequency (HF) heart rate variability changes, and their functional correlates during progression of the disease are not exactly known. Progressive heart failure was induced in 16 beagle dogs over a 7-wk period by rapid ventricular pacing. Spectral analysis of heart rate variability and respiration, echocardiography, hemodynamic measurements, plasma atrial natriuretic factor, and norepinephrine was obtained at baseline and every week, 30 min after pacing interruption. Progressive heart failure increased heart rate (from 91 +/- 4 to 136 +/- 5 beats/min; P < 0.001) and decreased absolute and normalized (percentage of total power) HF variability from week 1 and 2, respectively (P < 0.01). Absolute LF variability did not change during the study until it disappeared in two dogs at week 7 (P < 0.05). Normalized LF variability increased in moderate heart failure (P < 0.01), leading to an increased LF-to-HF ratio (P < 0.05), but decreased in severe heart failure (P < 0.044; week 7 vs. week 5). Stepwise regression analysis revealed that among heart rate variables, absolute HF variability was closely associated with wedge pressure, right atrial and pulmonary arterial pressure, left ventricular ejection fraction and volume, ratio of maximal velocity of early (E) and atrial (A) mitral flow waves, left atrial diameter, plasma norepinephrine, and atrial natriuretic peptide (0.45 < r < 0.65, all P < 0.001). In tachycardia-induced heart failure, absolute HF heart rate variability is a more reliable indicator of cardiac dysfunction and neurohumoral activation than LF heart rate variability.

Animals↗
PubMed2005

Effects of peripheral chemoreceptors deactivation on sympathetic activity in heart transplant recipients.

Heart transplantation initially normalizes sympathetic hyperactivity directed at the muscle circulation. However, sympathetic activity increases with time after transplantation and the exact mechanisms responsible for sympathetic control in heart transplant recipients remain unclear. We examined the effects of peripheral chemoreflex deactivation caused by breathing 100% oxygen on muscle sympathetic nerve activity (expressed as number of burst per minute and mean burst amplitude), heart rate, and mean blood pressure in 13 heart transplant recipients, 13 patients with essential hypertension, and 10 controls. Heart transplant recipients disclosed the highest sympathetic activity, whereas it did not differ between controls and patients with essential hypertension (51+/-16 versus 37+/-14 versus 39+/-12 burst/min, respectively; P<0.05). Breathing 100% oxygen, in comparison with 21% oxygen, reduced sympathetic activity (-4+/-4 versus -1+/-2 burst/min, P<0.01; 85+/-9 versus 101+/-8% of amplitude at baseline, P<0.001) and mean blood pressure (-4+/-5 versus +3+/-6 mm Hg; P<0.05) in heart transplant recipients, decreased sympathetic activity (-4+/-4 versus 0+/-3 burst/min, P<0.05; 90+/-16 versus 101+/-9% of amplitude at baseline, P<0.05) in patients with essential hypertension, but did not reduce sympathetic activity (2+/-4 versus 3+/-3 burst/min, P=NS; 95+/-11 versus 95+/-13% of amplitude at baseline, P=NS) in control subjects. The sympathetic response to hyperoxia was more marked in heart transplant recipients than in controls (85+/-9 versus 95+/-11% of baseline amplitude; P<0.05). The decrease in sympathetic activity was most evident in patients with the longest time after heart transplantation (r=-0.75, P<0.01). In conclusion, tonic chemoreflex activation increases resting muscle sympathetic nerve activity and favors blood pressure elevation after heart transplantation.

Administration, Inhalation↗
PubMed2005

Sympathetic nerve activity after thoracoscopic cardiac resynchronization therapy in congestive heart failure.

BACKGROUND: Sympathetic benefits of thoracoscopic cardiac resynchronization therapy (TCRT) in congestive heart failure (CHF) are unknown. We determined cardiac hemodynamics, functional status, and muscle sympathetic nerve activity (MSNA) in a group of TCRT patients. We aimed to compare these patients with CHF patients with cardiac asynchrony (ASY) to substantiate the beneficial effects of TCRT. METHODS AND RESULTS: Eleven patients resynchronized by TCRT 6 +/- 1 months before study inclusion (SYN) and 10 matched ASY patients underwent blood pressure, heart rate, and MSNA recordings. All underwent functional status, cardiac index, and left ventricular ejection fraction (LVEF) assessments. SYN patients had shorter QRS duration and interventricular mechanical delays, longer 6 minute walking distance and lower New York Heart Association class (all P < .05) than ASY patients. MSNA of 56 +/- 2 bursts/min in ASY patients was higher than in SYN patients (48 +/- 3 bursts/min, P < .05). Cardiac index was higher in SYN patients than in ASY patients (2.8 +/- 0.2 versus 1.9 +/- 0.2 L.min.m2, P < .05, respectively). MSNA was highest in the patients with the lowest LVEF (r = -0.49, P < .05), cardiac index (r = -0.48, P < .05) and 6-minute walking distance (r = -0.50, P < .05). CONCLUSION: Lower sympathetic nerve activities in TCRT patients are related to more favorable cardiac indexes and six minute walking distances suggesting a sympathetic, hemodynamic, and functional improvement by TCRT.

Aged↗
PubMed2005

Effects of right ventricular pacing on regional myocardial glucose metabolism.

AIMS: Permanent right ventricular apical pacing (RVP) is associated with a wide range of myocardial abnormalities. The purpose of this study was to determine the changes over time of RVP on myocardial blood flow (MBF) and glucose metabolism as assessed by positron emission tomography (PET). METHODS: In eight candidates for permanent pacemaker implantation PET imaging was performed with 13N-ammonia and 18F-Fluorodeoxyglucose (FDG) to assess MBF and glucose metabolism before (PET1) and repeated after 3 months of RVP (PET2). For the analysis, the left ventricle was divided into three parts (apex, mid-ventricular and base) and subdivided into six segments (inferior, posterior, lateral, anterior, antero-septal and infero-septal). RESULTS: After RVP, defects of FDG uptake were found in the left ventricle near the stimulation site, without corresponding changes in MBF. Changes over time in the mean FDG uptake were statistically significant between PET1 and PET2 in the apical inferior, apical-posterior, apical-anterior, apical antero-septal, apical infero-septal, mid-inferior and mid-infero-septal segments. CONCLUSIONS: This study shows that RVP induces major changes in the distribution of FDG uptake in the left ventricular myocardium. FDG uptake significantly decreases in the regions surrounding the pacing site.

Aged↗
PubMed2005

New evidence of baroreflex dysfunction in congenital central hypoventilation syndrome.

In this issue of Clinical Science, Trang and co-workers report the results of short-term blood pressure and heart rate variability measurements in patients with congenital central hypoventilation syndrome (CCHS). The results reveal that these young patients disclose signs of vagal withdrawal and baroreflex failure. Baroreflex sensitivity was reduced by one third compared with the matched control subjects; however, patients have a relative preservation of the cardiac and vascular sympathetic function. These findings are clearly new and improve our understanding of CCHS physiopathology. Nevertheless, more research is needed to better delineate the respective contribution of cardiac vagal and sympathetic dysregulation, and the extent to which these abnormalities relate to genetic mutations as well as to clinical status.

Baroreflex↗
PubMed2005

The effect of different intensity modalities of resistance training on beat-to-beat blood pressure in cardiac patients.

BACKGROUND: Resistance training has been introduced in cardiac rehabilitation to give more benefit than traditional training. Haemodynamic evaluation of cardiac patients to resistance training has generally consisted of continuous HR monitoring and discontinuous blood pressure measurements. DESIGN AND METHODS: Blood pressure (BP) and heart rate (HR) responses to resistance training were evaluated using continuous monitoring (Finapres) during low (four sets of 17 repetitions at 40% of the one-repetition maximum strength [1-RM]) and high intensity resistance training (four sets of 10 repetitions at 70% of 1-RM) on a leg extension machine in 14 patients who participated in a rehabilitation programme. Work volume was identical in the low- and high-level resistance training. RESULTS: The HR and systolic blood pressure (SBP) during low intensity resistance training were always larger than during high intensity (P<0.001). Peak SBP increased from set 1 to set 3 and 4 during both low and high intensity resistance training (P<0.05). Peak HR was larger in set 4 (95+/-11 bpm) than in set 1 only during low intensity resistance training (91+/-12 bpm) (P<0.05). One-minute recovery periods did not allow a return to baseline HR and SBP during both low and high intensity modalities. CONCLUSIONS: The SBP and HR responses to resistance training are related to the duration of exercise. Sets with < or =10 repetitions of high intensity should be preferred to longer sets with low intensity. Pauses between exercise sets should exceed 1 min. Blood pressure should be measured during the last repetitions of the exercise set.

Aged↗
PubMed2004

Chemoreflex and metaboreflex control during static hypoxic exercise.

To investigate the effects of muscle metaboreceptor activation during hypoxic static exercise, we recorded muscle sympathetic nerve activity (MSNA), heart rate, blood pressure, ventilation, and blood lactate in 13 healthy subjects (22 +/- 2 yr) during 3 min of three randomized interventions: isocapnic hypoxia (10% O(2)) (chemoreflex activation), isometric handgrip exercise in normoxia (metaboreflex activation), and isometric handgrip exercise during isocapnic hypoxia (concomitant metaboreflex and chemoreflex activation). Each intervention was followed by a forearm circulatory arrest to allow persistent metaboreflex activation in the absence of exercise and chemoreflex activation. Handgrip increased blood pressure, MSNA, heart rate, ventilation, and lactate (all P < 0.001). Hypoxia without handgrip increased MSNA, heart rate, and ventilation (all P < 0.001), but it did not change blood pressure and lactate. Handgrip enhanced blood pressure, heart rate, MSNA, and ventilation responses to hypoxia (all P < 0.05). During circulatory arrest after handgrip in hypoxia, heart rate returned promptly to baseline values, whereas ventilation decreased but remained elevated (P < 0.05). In contrast, MSNA, blood pressure, and lactate returned to baseline values during circulatory arrest after hypoxia without exercise but remained markedly increased after handgrip in hypoxia (P < 0.05). We conclude that metaboreceptors and chemoreceptors exert differential effects on the cardiorespiratory and sympathetic responses during exercise in hypoxia.

Adult↗
PubMed2004

Arterial stiffness and wave reflections in patients with sickle cell disease.

We tested the hypothesis that lower blood pressure and increased vasodilatation reported in sickle cell disease (SCD) patients with hemoglobin SS genotype (SS) are translated by lower arterial stiffness determined by pulse wave velocity (PWV) and wave reflections assessed by augmentation index (AI). We enrolled 20 SS (8 females; 12 male) patients closely matched for age, gender, height, and body mass index to 20 subjects with hemoglobin AA genotype (AA). Carotid-femoral PWV (PWV(CF)) and carotid-radial PWV (PWV(CR)) were recorded with the Complior device. Aortic AI was derived from pressure wave analysis (SphygmocoR). PWV(CF) and PWV(CR) were lower in SS than in AA (4.5+/-0.7 m/s versus 6.9+/-0.9 m/s, P<0.0001 and 6.6+/-1.2 m/s versus 9.5+/-1.4 m/s, P<0.0001, respectively). AI was lower in SS than in AA (2+/-14% versus 11+/-8%, P=0.02). Multivariate analysis revealed that both PWV(CF) and PWV(CR) were negatively associated with hemoglobin SS type and positively related to mean arterial pressure (MAP), whereas AI was positively associated with MAP and total cholesterol (all P<0.0001). Multivariate analysis restricted to SS indicated a positive association between PWV(CF) and PWV(CR) with age but a negative association with MAP (R2=0.57 and 0.51, respectively, both P<0.001), whereas MAP and heart rate were independently associated with AI (R2=0.65, P<0.001). This study provides the first evidence that SCD is associated with both lower arterial stiffness and wave reflections. SS patients have a paradoxical negative association between PWV and MAP, suggesting that low MAP does not protect them against arterial stiffness impairment.

Adult↗
PubMed2004

Increased sympathetic nerve activity in pulmonary artery hypertension.

BACKGROUND: This study tested the hypothesis that sympathetic nerve activity is increased in pulmonary artery hypertension (PAH), a rare disease of poor prognosis and incompletely understood pathophysiology. We subsequently explored whether chemoreflex activation contributes to sympathoexcitation in PAH. METHODS AND RESULTS: We measured muscle sympathetic nerve activity (MSNA) by microneurography, heart rate (HR), and arterial oxygen saturation (Sao(2)) in 17 patients with PAH and 12 control subjects. The patients also underwent cardiac echography, right heart catheterization, and a 6-minute walk test with dyspnea scoring. Circulating catecholamines were determined in 8 of the patients. Chemoreflex deactivation by 100% O(2) was assessed in 14 patients with the use of a randomized, double-blind, placebo-controlled, crossover study design. Compared with the controls, the PAH patients had increased MSNA (67+/-4 versus 40+/-3 bursts per minute; P<0.0001) and HR (82+/-4 versus 68+/-3 bpm; P=0.02). MSNA in the PAH patients was correlated with HR (r=0.64, P=0.006), Sao(2) (r=-0.53, P=0.03), the presence of pericardial effusion (r=0.51, P=0.046), and NYHA class (r=0.52, P=0.033). The PAH patients treated with prostacyclin derivatives had higher MSNA (P=0.009), lower Sao(2) (P=0.01), faster HR (P=0.003), and worse NYHA class (P=0.04). Plasma catecholamines were normal. Peripheral chemoreflex deactivation with hyperoxia increased Sao(2) (91.7+/-1% to 98.4+/-0.2%; P<0.0001) and decreased MSNA (67+/-5 to 60+/-4 bursts per minute; P=0.0015), thereby correcting approximately one fourth of the difference between PAH patients and controls. CONCLUSIONS: We report for the first time direct evidence of increased sympathetic nerve traffic in advanced PAH. Sympathetic hyperactivity in PAH is partially chemoreflex mediated and may be related to disease severity.

Calcium Channel Blockers↗
PubMed2004

Acute arterio-venous fistula occlusion decreases sympathetic activity and improves baroreflex control in kidney transplanted patients.

BACKGROUND: The acute bradycardia induced by the occlusion of an arteriovenous fistula (AVF), known as the Nicoladoni-Branham sign, is considerably larger than that which occurs during carotid sinus massage. This suggests increased arterial baroreflex sensitivity during acute AVF occlusion. Moreover, the influence of acute AVF occlusion on muscle sympathetic nerve traffic (MSNA, by microneurography) is unknown. We therefore assessed the effects of acute AVF occlusion on baroreflex sensitivity and on MSNA in patients with stable functional kidney grafts and patent AVF. METHODS: We measured blood pressure (BP), MSNA (n = 11), heart rate (HR), cardiac output (CO) and arterial baroreflex sensitivity (n = 18) at baseline and during acute, 30-s pneumatic AVF occlusions in 23 renal transplanted recipients. RESULTS: During the first 5 s of the AVF occlusion, mean BP increased from 98+/-4 to 112+/-4 mmHg (P<0.0001) while MSNA decreased to 28+/-5% of baseline values (P<0.0001) and HR decreased from 71+/-3 to 61+/-3 b.p.m. (P<0.0001). The largest increases in BP were accompanied by the most marked decreases in MSNA (r = -0.79, P = 0.003) and HR (r = -0.49; P = 0.01) during the first 5 s of the AVF occlusion. During AVF occlusion baseline CO of 6.9+/-0.3 decreased to 5.6+/-0.3 l/min (P<0.0001) while baroreflex sensitivity increased from 10+/-1 to 17+/-2 ms/mm Hg (P<0.001). CONCLUSIONS: Arterial baroreceptor activation and increased arterial baroreflex sensitivity decrease heart rate during AVF occlusion. In addition, our study is the first to demonstrate that arterial baroreflex activation decreases sympathetic nerve traffic during the Nicoladoni-Branham sign.

Arteriovenous Fistula↗
PubMed2004

Interdependency between heart rate variability and sleep EEG: linear/non-linear?

OBJECTIVE: To investigate whether the interdependency between heart rate variability (HRV) and sleep electroencephalogram (EEG) power spectra is linear or non-linear. METHODS: Heart rate and sleep EEG signals were recorded in 8 healthy young men. Spectral analysis was applied to electrocardiogram and EEG sleep recordings. Synchronization likelihood was computed over the first 3 non-rapid eye movement-rapid eye movement sleep cycles between normalized high frequency of RR intervals (RRI) and all electroencephalographic frequency bands. Comparison to surrogate data of different types was used to attest statistical significance of the coupling between RRI and EEG power bands and its linear or non-linear character. RESULTS: Synchronization likelihood values were statistically greater than univariate surrogate synchronization for all sleep bands both at the individual and the group levels. With reference to multivariate surrogates, synchronization values were statistically greater at the group level and, in a majority of cases, for individual comparison except for sigma and beta bands. CONCLUSIONS: While all electroencephalographic power bands are linked to normalized high frequency RRI band, this interdependency is non-linear for delta, theta and alpha bands. SIGNIFICANCE: Non-linear description is required to capture the full interdependent dynamics of HRV and sleep EEG power bands.

Adolescent↗