Metadata Framework to Support Deployment of Digital Health Technologies in Clinical Trials in Parkinson's Disease.

Sensor data from digital health technologies (DHTs) used in clinical trials provides a valuable source of information, because of the possibility to combine datasets from different studies, to combine it with other data types, and to reuse it multiple times for various purposes. To date, there exist no standards for capturing or storing DHT biosensor data applicable across modalities and disease areas, and which can also capture the clinical trial and environment-specific aspects, so-called metadata. In this perspectives paper, we propose a metadata framework that divides the DHT metadata into metadata that is independent of the therapeutic area or clinical trial design (concept of interest and context of use), and metadata that is dependent on these factors. We demonstrate how this framework can be applied to data collected with different types of DHTs deployed in the WATCH-PD clinical study of Parkinson's disease. This framework provides a means to pre-specify and therefore standardize aspects of the use of DHTs, promoting comparability of DHTs across future studies.

Use of a novel non-invasive respiratory monitor to study changes in pulmonary ventilation during labor epidural analgesia.

Measuring continuous changes in maternal ventilation during labor neuraxial analgesia is technically difficult. Consequently, the magnitude of pulmonary minute ventilation (MV) alterations following labor analgesia remains unknown. We hypothesized that a novel, bio-impedance based non-invasive respiratory monitor would provide this information. Furthermore, we sought to determine if an association between changes in MV and maternal temperature existed. Following calibration with a Haloscale Standard Wright Respirometer, the ExSpiron respiratory volume monitor (RVM) measured MV, respiratory rate (RR), and tidal volume (TV) in 41 term parturients receiving epidural analgesia. Simultaneously, maternal oral temperatures were recorded at pre-specified hourly intervals after epidural analgesia initiation until delivery. Cumulative MV changes were calculated as the integral of MV change over time: MV [Formula: see text], where T represents the time between epidural placement and variable measurement. The association between changes in MV and cumulative MV versus maternal temperature was determined by comparing patients whose temperature did or did not increase by ≥ 0.5 °C. After initiation of epidural analgesia, MV decreased by 11.1 ± 27.6% [mean ± SD] at 30 min, p = 0.006, and 19.8 ± 26.1% at 2 h compared to baseline (12.6 ± 7.3 L/min at baseline vs. 15.3 ± 6.3 L/min at 2 h, p < 0.001), Minute ventilation remained decreased at 4 h by 14.3 ± 31.4% (p = 0.013). The cumulative MV also decreased by 437 ± 852 L [mean ± SD], p = 0.009) at 2 h and by 795 ± 1431 L, p < 0.001) at 4 h following epidural analgesia initiation, compared to baseline. The association between changes in cumulative MV and maternal temperature following epidural placement was weak (R < 0.3); however, a decrease in MV at 30 min (p = 0.002) and cumulative MV at 2 h (p = 0.012) was observed in women whose temperature increased by at least 0.5 °C during labor. Our findings suggest that RVM can be a useful noninvasive technology to investigate pulmonary physiology during labor. The association between maternal MV and temperature change during labor analgesia deserves further investigation.Trial Registrationwww.clinicaltrials.gov (NCT02339389).

Assessment of perioperative minute ventilation in obese versus non-obese patients with a non-invasive respiratory volume monitor.

BACKGROUND: Monitoring the adequacy of spontaneous breathing is a major patient safety concern in the post-operative setting. Monitoring is particularly important for obese patients, who are at a higher risk for post-surgical respiratory complications and often have increased metabolic demand due to excess weight. Here we used a novel, noninvasive Respiratory Volume Monitor (RVM) to monitor ventilation in both obese and non-obese orthopedic patients throughout their perioperative course, in order to develop better monitoring strategies. METHODS: We collected respiratory data from 62 orthopedic patients undergoing elective joint replacement surgery under general anesthesia using a bio-impedance based RVM with an electrode PadSet placed on the thorax. Patients were stratified into obese (BMI ≥ 30) and non-obese cohorts and minute ventilation (MV) at various perioperative time points was compared against each patient's predicted minute ventilation (MVPRED) based on ideal body weight (IBW) and body surface area (BSA). The distributions of MV measurements were also compared across obese and non-obese cohorts. RESULTS: Obese patients had higher MV than the non-obese patients before, during, and after surgery. Measured MV of obese patients was significantly higher than their MVPRED from IBW formulas, with BSA-based MVPRED being a closer estimate. Obese patients also had greater variability in MV post-operatively when treated with standard opioid dosing. CONCLUSIONS: Our study demonstrated that obese patients have greater variability in ventilation post-operatively when treated with standard opioid doses, and despite overall higher ventilation, many of them are still at risk for hypoventilation. BSA-based MVPRED formulas may be more appropriate than IBW-based ones when estimating the respiratory demand of obese patients. The RVM allows for the continuous and non-invasive assessment of respiratory function in both obese and non-obese patients.

Anesthesia and Postoperative Respiratory Compromise Following Major Lower Extremity Surgery: Implications for Combat Casualties.

Care of military casualties requires not only assessment of patient, injury, and setting, but also the consequences of care decisions on other organ systems. In contemporary conflicts, pelviperineal and lower extremity trauma are common injuries, yet the optimal perioperative anesthetic and analgesic care remains unclear. Residual anesthesia and opioids can cause respiratory depression, specifically postoperative respiratory depression and opioid-induced respiratory depression. This observational study quantified and compared the incidences of respiratory depression following general anesthesia (GA) and spinal anesthesia (SA) for lower extremity surgery. Respiratory data were collected from 173 patients receiving either GA (n = 43) or SA (n = 130) via a bioimpedance-based respiratory volume monitor. Patients were further subdivided by postoperative opioid administration. The overall incidence of respiratory depression was significantly higher in the SA group (48/130 vs. 6/43, p = 0.004). These findings suggest that, while SA may be considered the safer alternative, it may in fact introduce confounding factors, which increase the risk of respiratory depression. Ensuring adequate respiratory status is particularly critical for the military population, as combat casualties are often monitored in understaffed environments following surgery. Using an SA strategy instead of GA may not prevent postoperative respiratory depression, and respiratory volume monitor monitoring may be useful to optimize care.

Quantification of respiratory depression during pre-operative administration of midazolam using a non-invasive respiratory volume monitor.

BACKGROUND: Pre-operative administration of benzodiazepines can cause hypoventilation-a decrease in minute ventilation (MV)-commonly referred to as "respiratory compromise or respiratory depression." Respiratory depression can lead to hypercarbia and / or hypoxemia, and may heighten the risk of other respiratory complications. Current anesthesia practice often places patients at risk for respiratory complications even before surgery, as respiratory monitoring is generally postponed until the patient is in the operating room. In the present study we examined and quantified the onset of respiratory depression following the administration of a single dose of midazolam in pre-operative patients, using a non-invasive respiratory volume monitor that reports MV, tidal volume (TV), and respiratory rate (RR). METHODS: Impedance-based Respiratory Volume Monitor (RVM) data were collected and analyzed from 30 patients prior to undergoing orthopedic or general surgical procedures. All patients received 2.0 mg of midazolam intravenously at least 20 minutes prior to the induction of anesthesia and the effects of midazolam on the patient's respiratory function were analyzed. RESULTS: Within 15 minutes of midazolam administration, we noted a significant decrease in both MV (average decrease of 14.3% ± 5.9%, p<0.05) and TV (22.3% ± 4.5%, p<0.001). Interestingly, the corresponding RR increased significantly by an average of 10.3% ± 4.7% (p<0.05). Further analysis revealed an age-dependent response, in which elderly patients (age≥65 years, n = 6) demonstrated greater reductions in MV and TV and a lack of compensatory RR increase. In fact, elderly patients experienced an average decrease in MV of 34% ± 6% (p<0.05) compared to an average decrease of 9% ± 6% (p<0.05) in younger patients. CONCLUSIONS: We were able to quantify the effects of pre-operative midazolam administration on clinically significant respiratory parameters (MV, TV and RR) using a non-invasive RVM, uncovering that the respiratory depressive effect of benzodiazepines affect primarily TV rather than RR. Such respiratory monitoring data provide the opportunity for individualizing dosing and adjustment of clinical interventions, especially important in elderly patients. With additional respiratory data, clinicians may be able to better identify and quantify respiratory depression, reduce adverse effects, and improve overall patient safety.

The evaluation of a non-invasive respiratory volume monitor in surgical patients undergoing elective surgery with general anesthesia.

Continuous respiratory assessment is especially important during post-operative care following extubation. Respiratory depression and subsequent adverse outcomes can arise due to opioid administration and/or residual anesthetics. A non-invasive respiratory volume monitor (RVM) has been developed that provides continuous, real-time, measurements of minute ventilation (MV), tidal volume (TV), and respiratory rate (RR) via a standardized set of thoracic electrodes. Previous work demonstrated accuracy of the RVM versus standard spirometry and its utility in demonstrating response to opioids in postoperative patients. This study evaluated the correlation between RVM measurements of MV, TV and RR to ventilator measurements during general anesthesia (GA). Continuous digital RVM and ventilator traces, as well as RVM measurements of MV, TV and RR, were analyzed from ten patients (mean 62.6±7.4 years; body mass index 28.6±5.2 kg/m2) undergoing surgery with GA. RVM data were compared to ventilator data and bias, precision and accuracy were calculated. The average MV difference between the RVM and ventilator was -0.10 L/min (bias: -1.3%, precision: 6.6%, accuracy: 9.0%. The average TV difference was 40 mL (bias: 0.4%, precision: 7.3%, accuracy: 9.1%). The average RR difference was -0.22 breaths/minute (bias: -1.8%, precision: 3.7% accuracy: 4.1%). Correlations between the RVM traces and the ventilator were compared at various points with correlations>0.90 throughout. Pairing the close correlation to ventilator measurements in intubated patients demonstrated by this study with previously described accuracy compared to spirometry in non-intubated patients, the RVM can be considered to have the capability to provide continuity of ventilation monitoring post-extubation This supports the use of real-time continuous RVM measurements to drive post-operative and post-extubation protocols, initiate therapeutic interventions and improve patient safety.

Special article: evaluation of a novel noninvasive respiration monitor providing continuous measurement of minute ventilation in ambulatory subjects in a variety of clinical scenarios.

BACKGROUND: Currently there is no technology that noninvasively measures the adequacy of ventilation in nonintubated patients. A novel, noninvasive Respiratory Volume Monitor (RVM) has been developed to continuously measure and display minute ventilation (MV), tidal volume (TV), and respiratory rate (RR) in a variety of clinical settings. We demonstrate the RVM's accuracy and precision as compared with a standard spirometer under a variety of clinically relevant breathing patterns in nonintubated subjects. METHODS: Thirty-one voluntary subjects completed the primary study. MV, TV, and RR measurements were collected from the RVM and spirometer simultaneously for each participant on day 1 and day 2 and analyzed to determine accuracy, precision, and bias for normal, fast, slow, irregular, and closed-glottis breathing. RESULTS: Data demonstrated that RVM and spirometer measurements of MV and TV are equivalent in a wide range of ambulatory subjects with an average error <10% (95% confidence interval for accuracy <16%, precision <12%, and bias <11%). Repeated measures analysis of variance found no significant difference between spirometry and RVM individual measurements of MV, TV, and RR (P > 0.7), whereas a paired-difference equivalent test demonstrated, with 99% power, that both MV and TV measurements from the 2 devices are equivalent within ±15%. CONCLUSIONS: This study demonstrates RVM's clinically relevant accuracy and precision in measuring MV, TV, and RR over a 24-hour period and during various breathing patterns.

The training schedule affects the stability, not the magnitude, of the interlimb transfer of learned dynamics.

The way that a motor adaptation is trained, for example, the manner in which it is introduced or the duration of the training period, can influence its internal representation. However, recent studies examining the gradual versus abrupt introduction of a novel environment have produced conflicting results. Here we examined how these effects determine the effector specificity of motor adaptation during visually guided reaching. After adaptation to velocity-dependent dynamics in the right arm, we estimated the amount of adaptation transferred to the left arm, using error-clamp measurement trials to directly measure changes in learned dynamics. We found that a small but significant amount of generalization to the untrained arm occurs under three different training schedules: a short-duration (15 trials) abrupt presentation, a long-duration (160 trials) abrupt presentation, and a long-duration gradual presentation of the novel dynamic environment. Remarkably, we found essentially no difference between the amount of interlimb generalization when comparing these schedules, with 9-12% transfer of the trained adaptation for all three. However, the duration of training had a pronounced effect on the stability of the interlimb transfer: The transfer elicited from short-duration training decayed rapidly, whereas the transfer from both long-duration training schedules was considerably more persistent (<50% vs. >90% retention over the first 20 trials). These results indicate that the amount of interlimb transfer is similar for gradual versus abrupt training and that interlimb transfer of learned dynamics can occur after even a brief training period but longer training is required for an enduring effect.

Motor memory is encoded as a gain-field combination of intrinsic and extrinsic action representations.

Actions can be planned in either an intrinsic (body-based) reference frame or an extrinsic (world-based) frame, and understanding how the internal representations associated with these frames contribute to the learning of motor actions is a key issue in motor control. We studied the internal representation of this learning in human subjects by analyzing generalization patterns across an array of different movement directions and workspaces after training a visuomotor rotation in a single movement direction in one workspace. This provided a dense sampling of the generalization function across intrinsic and extrinsic reference frames, which allowed us to dissociate intrinsic and extrinsic representations and determine the manner in which they contributed to the motor memory for a trained action. A first experiment showed that the generalization pattern reflected a memory that was intermediate between intrinsic and extrinsic representations. A second experiment showed that this intermediate representation could not arise from separate intrinsic and extrinsic learning. Instead, we find that the representation of learning is based on a gain-field combination of local representations in intrinsic and extrinsic coordinates. This gain-field representation generalizes between actions by effectively computing similarity based on the (Mahalanobis) distance across intrinsic and extrinsic coordinates and is in line with neural recordings showing mixed intrinsic-extrinsic representations in motor and parietal cortices.

Bayesian and "anti-Bayesian" biases in sensory integration for action and perception in the size-weight illusion.

Which is heavier: a pound of lead or a pound of feathers? This classic trick question belies a simple but surprising truth: when lifted, the pound of lead feels heavier--a phenomenon known as the size-weight illusion. To estimate the weight of an object, our CNS combines two imperfect sources of information: a prior expectation, based on the object's appearance, and direct sensory information from lifting it. Bayes' theorem (or Bayes' law) defines the statistically optimal way to combine multiple information sources for maximally accurate estimation. Here we asked whether the mechanisms for combining these information sources produce statistically optimal weight estimates for both perceptions and actions. We first studied the ability of subjects to hold one hand steady when the other removed an object from it, under conditions in which sensory information about the object's weight sometimes conflicted with prior expectations based on its size. Since the ability to steady the supporting hand depends on the generation of a motor command that accounts for lift timing and object weight, hand motion can be used to gauge biases in weight estimation by the motor system. We found that these motor system weight estimates reflected the integration of prior expectations with real-time proprioceptive information in a Bayesian, statistically optimal fashion that discounted unexpected sensory information. This produces a motor size-weight illusion that consistently biases weight estimates toward prior expectations. In contrast, when subjects compared the weights of two objects, their perceptions defied Bayes' law, exaggerating the value of unexpected sensory information. This produces a perceptual size-weight illusion that biases weight perceptions away from prior expectations. We term this effect "anti-Bayesian" because the bias is opposite that seen in Bayesian integration. Our findings suggest that two fundamentally different strategies for the integration of prior expectations with sensory information coexist in the nervous system for weight estimation.

Primitives for motor adaptation reflect correlated neural tuning to position and velocity.

The motor commands required to control voluntary movements under various environmental conditions may be formed by adaptively combining a fixed set of motor primitives. Since this motor output must contend with state-dependent physical dynamics during movement, these primitives are thought to depend on the position and velocity of motion. Using a recently developed "error-clamp" technique, we measured the fine temporal structure of changes in motor output during adaptation. Interestingly, these measurements reveal that motor primitives echo a key feature of the neural coding of limb motion-correlated tuning to position and velocity. We show that this correlated tuning explains why initial stages of motor learning are often rapid and stereotyped, whereas later stages are slower and stimulus specific. With our new understanding of these primitives, we design dynamic environments that are intrinsically the easiest or most difficult to learn, suggesting a theoretical basis for the rational design of improved procedures for motor training and rehabilitation.