Optimized microburst VNS elicits fMRI responses beyond thalamic-specific response from standard VNS.

OBJECTIVE: In parallel to standard vagus nerve stimulation (VNS), microburst stimulation delivery has been developed. We evaluated the fMRI-related signal changes associated with standard and optimized microburst stimulation in a proof-of-concept study (NCT03446664). METHODS: Twenty-nine drug-resistant epilepsy patients were prospectively implanted with VNS. Three 3T fMRI scans were collected 2 weeks postimplantation. The maximum tolerated VNS intensity was determined prior to each scan starting at 0.125 mA with 0.125 mA increments. FMRI scans were block-design with alternating 30 sec stimulation [ON] and 30 sec no stimulation [OFF]: Scan 1 utilized standard VNS and Scan 3 optimized microburst parameters to determine target settings. Semi-automated on-site fMRI data processing utilized ON-OFF block modeling to determine VNS-related fMRI activation per stimulation setting. Anatomical thalamic mask was used to derive highest mean thalamic t-value for determination of microburst stimulation parameters. Paired t-tests corrected at P < 0.05 examined differences in fMRI responses to each stimulation type. RESULTS: Standard and microburst stimulation intensities at Scans 1 and 3 were similar (P = 0.16). Thalamic fMRI responses were obtained in 28 participants (19 with focal; 9 with generalized seizures). Group activation maps showed standard VNS elicited thalamic activation while optimized microburst VNS showed widespread activation patterns including thalamus. Comparison of stimulation types revealed significantly greater cerebellar, midbrain, and parietal fMRI signal changes in microburst compared to standard VNS. These differences were not associated with seizure responses. INTERPRETATION: While standard and optimized microburst VNS elicited thalamic activation, microburst also engaged other brain regions. Relationship between these fMRI activation patterns and clinical response warrants further investigation. CLINICAL TRIAL REGISTRATION: The study was registered with clinicaltrials.gov (NCT03446664).

Design and rationale for the treating Obstructive Sleep Apnea using Targeted Hypoglossal Nerve Stimulation (OSPREY) trial.

Obstructive sleep apnea (OSA) affects nearly 1 billion people worldwide, including approximately 35 million US residents. OSA has detrimental cardiovascular and neurocognitive consequences. Positive airway pressure corrects sleep disordered breathing but is not always tolerated or used sufficiently. Oral appliances and surgery provide alternatives in select populations but are variably effective. Hypoglossal nerve stimulation can effectively treat obstructive sleep apnea. Targeted hypoglossal nerve stimulation (THN) is simpler than incumbent technology with no sensor and an easier, proximal electrode implantation. The third clinical study of THN, THN3, was the first randomized, controlled trial of hypoglossal nerve stimulation to demonstrate significant improvement of sleep disordered breathing in OSA. The present investigation reports the design of a novel trial of targeted stimulation to provide additional Level 1 evidence in moderate to severe obstructive apnea. OSPREY is a randomized, parallel-arm, 13-month trial wherein all subjects are implanted, 2/3 are activated at Month 1 ("Treatment") and 1/3 are activated at Month 7 ("Control"). The primary endpoint is the difference in apnea-hypopnea index response rates between Treatment and Control groups at Month 7. Secondary endpoints include quality of life and oximetry metrics. OSPREY follows an adaptive "Goldilocks" design which optimizes the number of subjects with the need for high-confidence results. A maximum of 150 subjects is allowed, at which study power of >95% is predicted. Interim analyses begin once 50 patients are randomized and recur after each 20 additional randomizations to detect early success or futility. OSPREY is a unique, efficient trial that should provide high-confidence confirmation of the safety and efficacy of targeted hypoglossal nerve stimulation for moderate to severe obstructive sleep apnea.

Association between autonomic control indexes and mortality in subjects admitted to intensive care unit.

This study checks whether autonomic markers derived from spontaneous fluctuations of heart period (HP) and systolic arterial pressure (SAP) and from their interactions with spontaneous or mechanical respiration (R) are associated with mortality in patients admitted to intensive care unit (ICU). Three-hundred consecutive HP, SAP and R values were recorded during the first day in ICU in 123 patients. Population was divided into survivors (SURVs, n = 83) and non-survivors (NonSURVs, n = 40) according to the outcome. SURVs and NonSURVs were aged- and gender-matched. All subjects underwent modified head-up tilt (MHUT) by tilting the bed back rest segment to 60°. Autonomic control indexes were computed using time-domain, spectral, cross-spectral, complexity, symbolic and causality techniques via univariate, bivariate and conditional approaches. SAP indexes derived from time-domain, model-free complexity and symbolic approaches were associated with the endpoint, while none of HP variability markers was. The association was more powerful during MHUT. Linear cross-spectral and causality indexes were useless to separate SURVs from NonSURVs, while nonlinear bivariate symbolic markers were successful. When indexes were combined with clinical scores, only SAP variance provided complementary information. Cardiovascular control variability indexes, especially when derived after an autonomic challenge such as MHUT, can improve mortality risk stratification in ICU.

Separating arterial pressure increases and decreases in assessing cardiac baroreflex sensitivity via sequence and bivariate phase-rectified signal averaging techniques.

Cardiac baroreflex (cBR) is activated by both arterial pressure (AP) increases and decreases. Sequence method, a widely utilized tool assessing cBR sensitivity (cBRS) from spontaneous heart period (HP) and systolic AP (SAP) variations, allows the separated computation of cBRS from positive and negative SAP variations. The recently proposed phase-rectified signal averaging (PRSA) method has the same feature but it has been applied so far solely to positive SAP variations. We adapted the PRSA method to compute cBRS over negative SAP variations and we compared the results with those derived from sequence method over two protocols: (i) graded head-up tilt (HUT) at 15, 30, 45, 60, and 75° in 19 healthy subjects and (ii) general anesthesia induction in 118 patients undergoing coronary artery bypass graft surgery. Regardless of the sign of SAP changes and method, cBRS moved toward 0 during HUT. Only sequence method detected the cBRS decrease after general anesthesia induction. In both protocols, the correlation between the PRSA-based cBRSs derived from positive and negative SAP changes was higher than that obtained from analogous sequence-based cBRSs and correlation between equivalent cBRSs derived from different methods might be absent. We conclude that the two methods are not interchangeable in assessing cBRS. Graphical abstract Graphical representation of the baroreflex sensitivity (BRS) estimation procedures carried out using sequence (SEQ) and phase-rectified signal averaging (PRSA) techniques over spontaneous fluctuations of heart period (HP) and systolic arterial pressure (SAP). BRSSEQ and BRSPRSA was separately computed over positive (+) and negative (-) SAP variations.

Evaluating the association between cardiac and peripheral resistance arms of the baroreflex.

The study proposes an extension of cardiac baroreflex (cBR) sequence analysis, traditionally performed over spontaneous fluctuations of heart period and systolic arterial pressure, to typify peripheral resistance baroreflex (prBR) from spontaneous variations of peripheral resistances and diastolic arterial pressure. The prBR baroreflex sensitivity (BRSprBR) and percentage of prBR sequences (SEQ%prBR) were computed along with analogous quantities assessed over cBR (i.e. BRScBR and SEQ%cBR). The cBR and prBR were typified in healthy subjects at rest (REST) and during light bicycle ergometer exercise at 10 percent of the maximal effort (EXE). Both cBR and prBR were affected by EXE: indeed, BRScBR and SEQ%prBR were significantly reduced. Moreover, while BRScBR and BRSprBR were not significantly associated, SEQ%cBR and SEQ%prBR were, and the correlation coefficient was positive. This study suggests that prBR can be typified from spontaneous variabilities along with the more traditional cBR, thus enlarging the possibility of monitoring human cardiovascular control mechanisms.

Towards the identification of subjects prone to develop atrial fibrillation after coronary artery bypass graft surgery via univariate and multivariate complexity analysis of heart period variability.

The assessment of cardiovascular control complexity as derived from spontaneous heart period (HP) fluctuations can be improved by exploiting a multivariate (MV) approach. This work proposes the assessment of a normalized complexity index (NCI) of HP variability according to a k-nearest-neighbor approach based on local predictability performed in a MV nonuniform embedding space. The method allows the selection of the past components of HP, systolic arterial pressure (SAP) and respiration (R) most useful for the prediction of HP fluctuations. The NCI derived from the MV approach (NCIMV) was compared to a NCI computed via the same technique applied in a univariate (UV) embedding space (NCIUV) formed exclusively by HP past samples. Indexes were computed in 130 patients undergoing coronary artery bypass graft (CABG) surgery before and after the induction of general anesthesia. Thirty-eight subjects developed atrial fibrillation (AF) after surgery, while the remaining ones did not (noAF, n=92). Both NCIUV and NCIMV could separate AF from noAF patients and revealed a larger complexity of the AF subjects. However, the statistical power of the NCIMV was superior given that the probability of type I error was smaller than that of NCIUV. The assessment of cardiac control complexity could improve risk stratification of patients at risk of developing AF after CABG surgery.

Assessing multiscale complexity of short heart rate variability series through a model-based linear approach.

We propose a multiscale complexity (MSC) method assessing irregularity in assigned frequency bands and being appropriate for analyzing the short time series. It is grounded on the identification of the coefficients of an autoregressive model, on the computation of the mean position of the poles generating the components of the power spectral density in an assigned frequency band, and on the assessment of its distance from the unit circle in the complex plane. The MSC method was tested on simulations and applied to the short heart period (HP) variability series recorded during graded head-up tilt in 17 subjects (age from 21 to 54 years, median = 28 years, 7 females) and during paced breathing protocols in 19 subjects (age from 27 to 35 years, median = 31 years, 11 females) to assess the contribution of time scales typical of the cardiac autonomic control, namely in low frequency (LF, from 0.04 to 0.15 Hz) and high frequency (HF, from 0.15 to 0.5 Hz) bands to the complexity of the cardiac regulation. The proposed MSC technique was compared to a traditional model-free multiscale method grounded on information theory, i.e., multiscale entropy (MSE). The approach suggests that the reduction of HP variability complexity observed during graded head-up tilt is due to a regularization of the HP fluctuations in LF band via a possible intervention of sympathetic control and the decrement of HP variability complexity observed during slow breathing is the result of the regularization of the HP variations in both LF and HF bands, thus implying the action of physiological mechanisms working at time scales even different from that of respiration. MSE did not distinguish experimental conditions at time scales larger than 1. Over a short time series MSC allows a more insightful association between cardiac control complexity and physiological mechanisms modulating cardiac rhythm compared to a more traditional tool such as MSE.