Lumbar multiunit activity power spectrum during air stepping in the spinal cat: evidence for a flexor-dominated rostrocaudally distributed locomotor center.

Clues about the organization of spinal networks responsible for rhythmic motor behaviors have come from the examination of reflex circuitry, lesioning studies, and single-cell recordings. Recently, more attention has been paid to extracellularly recorded multiunit signals thought to represent the general activity of local cellular potentials. Focusing on the gross localization of spinal locomotor networks, we used multiunit signals of the lumbar cord to classify the activation and organization of those networks. We employed power spectral analysis to compare multiunit power across rhythmic conditions and locations and to infer patterns of activation based on coherence and phase measures. We found greater multiunit power in midlumbar segments during stepping, supportive of previous lesioning studies isolating rhythm-generating capabilities to these segments. We also found much greater multiunit power during the flexion phase of stepping than during the extension phase for all lumbar segments. Greater multiunit power at flexion indicates increased neural activity during this phase and is suggestive of previously reported asymmetries between flexor- and extensor-related interneuronal populations of the spinal rhythm-generating network. Finally, the multiunit power showed no phase lag at coherent frequencies throughout the lumbar enlargement indicative of a longitudinal standing wave of neural activation. Our results suggest that the multiunit activity may be representative of the spinal rhythm-generating activity that is distributed in a rostrocaudal gradient. Additionally, our results indicate that this multiunit activity may operate as a flexor-dominant standing wave of activation that is synchronized throughout the rostrocaudal extent of the lumbar enlargement.NEW & NOTEWORTHY We report on the power spectral analysis of multiunit activity (MUA) of lumbar spinal interneurons during a locomotor task. In line with prior studies, we found evidence of greater power at the frequency of locomotion in high lumbar segments and during the flexion phase. Our results also confirm prior observations from our laboratory that the rhythmically active MUA behaves as a longitudinal standing wave of neural activation that is flexor dominant.

Single-cell and ensemble activity of lumbar intermediate and ventral horn interneurons in the spinal air-stepping cat.

We explored the relationship between population interneuronal network activation and motor output in the adult, in vivo, air-stepping, spinal cat. By simultaneously measuring the activity of large numbers of spinal interneurons, we explored ensembles of coherently firing interneurons and their relation to motor output. In addition, the networks were analyzed in relation to their spatial distribution along the lumbar enlargement for evidence of localized groups driving particular phases of the locomotor step cycle. We simultaneously recorded hindlimb EMG activity during stepping and extracellular signals from 128 channels across two polytrodes inserted within lamina V-VII of two separate lumbar segments. Results indicated that spinal interneurons participate in one of two ensembles that are highly correlated with the flexor or the extensor muscle bursts during stepping. Interestingly, less than half of the isolated single units were significantly unimodally tuned during the step cycle whereas >97% of the single units of the ensembles were significantly correlated with muscle activity. These results show the importance of population scale analysis in neural studies of behavior as there is a much greater correlation between muscle activity and ensemble firing than between muscle activity and individual neurons. Finally, we show that there is no correlation between interneurons' rostrocaudal locations within the lumbar enlargement and their preferred phase of firing or ensemble participation. These findings indicate that spinal interneurons of lamina V-VII encoding for different phases of the locomotor cycle are spread throughout the lumbar enlargement in the adult spinal cord.NEW & NOTEWORTHY We report on the ensemble organization of interneuronal activity in the spinal cord during locomotor movements and show that lumbar intermediate zone interneurons organize in two groups related to the two major phases of walking: stance and swing. Ensemble organization is also shown to better correlate with muscular output than single-cell activity, although ensemble membership does not appear to be somatotopically organized within the spinal cord.

Improved Real-World Glycemic Control With Continuous Glucose Monitoring System Predictive Alerts.

BACKGROUND: Most standalone real-time continuous glucose monitoring (RT-CGM) systems provide predictive low and high sensor glucose (SG) threshold alerts. The durations and risk of low and high SG excursions following Guardian™ Connect CGM system predictive threshold alerts were evaluated. METHODS: Continuous glucose monitoring system data uploaded between January 2, 2017 and May 22, 2018 by 3133 individuals using multiple daily injections (MDIs) or continuous subcutaneous insulin infusion (CSII) therapy were deidentified and retrospectively analyzed. Glucose excursions were defined as SG values that went beyond a preset low or high SG threshold for ≥15 minutes. For a control group, thresholds were based on the median of the low SG threshold limit (70 mg/dL) and the high SG threshold limit (210 mg/dL) preset by all system users. During periods when alerts were not enabled, timestamps were identified when a predictive alert would have been triggered. The time before low horizon was 17.5 minutes and the time before high horizon was 15 minutes, of all users who enabled alerts. Excursions occurring after a low SG or high SG predictive alert were segmented into prevented, ≤20, 20-60, and >60 minutes. RESULTS: Excursions were prevented after 59% and 39% of low and high SG predictive alerts, respectively. The risk of a low or high excursion occurring was 1.9 (P < 0.001, 95% CI, 1.88-1.93) and 3.3 (P < 0.001, 95% CI, 3.20-3.30) times greater, respectively, when alerts were not enabled. CONCLUSIONS: The predictive alerts of the RT-CGM system under study can help individuals living with diabetes prevent some real-world low and high SG excursions. This can be especially important for those unable to reach or maintain glycemic control with basic RT-CGM or CSII therapy.

The Relationship of Hemoglobin A1C to Time-in-Range in Patients with Diabetes.

BACKGROUND: There has been recent recognition of the limitations of hemoglobin A1C (HbA1C) in describing both short- and long-term glycemic control. Continuous glucose monitoring (CGM) provides robust data about short-term glycemic control and provides metrics such as percent time-in-range (%TIR) that are now routinely reported to describe the change in glycemic control after an intervention in a clinical study or a change in therapy in a patient's care. Recent studies have shown that %TIR may have similar associations with diabetes microvascular complications as does HbA1C. The relationship of %TIR to the long-standing metric of overall glycemic control has not been clearly defined to date. METHODS: Articles that report paired HbA1C and %TIR metrics (n = 1137) or HbA1C and frequent self-monitoring of blood glucose (SMBG) (n = 1440) across a wide range of HbA1Cs, technologies, and subject demographics were reviewed to determine the correlation of these metrics. RESULTS: Selected paired HbA1C and %TIR data from 18 articles were evaluated by linear regression analysis and Pearson's correlation coefficient. There was an excellent correlation between the two (R = -0.84; R2 = 0.71). This relationship did not change after excluding one study that used SMBG or six studies with ≤7 days of CGM. For every absolute 10% change in %TIR, there was a 0.8% (9 mmol/mol) change in HbA1C. CONCLUSIONS: There is a good correlation between HbA1C and %TIR that may permit the transition to %TIR as the preferred metric for determining the outcome of clinical studies, predicting of the risk of diabetes complications, and assessing of an individual patient's glycemic control.

The Comprehensive Glucose Pentagon: A Glucose-Centric Composite Metric for Assessing Glycemic Control in Persons With Diabetes.

BACKGROUND: Composite metrics have the potential to provide more complete and clinically useful information about glycemic control than traditional individual metrics such as hemoglobin A1C, %/time/area under curve of hypoglycemia and hyperglycemia. METHODS: Using five key metrics that are derived from continuous glucose monitoring, we developed a new, multicomponent composite metric, the Comprehensive Glucose Pentagon (CGP) that demonstrates glycemic control both numerically and visually. Two of its axes are composite metrics-the intensity of hypoglycemia and intensity of hyperglycemia. This approach eliminates the use of the surrogate marker, hemoglobin A1C (A1C), and replaces it with glucose-centric metrics. RESULTS: We reanalyzed the data from two randomized control trials, the STAR 3 and ASPIRE In-Home studies using the CGP. It provided new insights into the effect of sensor-augmented pumping (SAP) in the STAR 3 trial and sensor-integrated pumping with low-glucose threshold suspend (SIP+TS) in the ASPIRE In-Home trial. CONCLUSIONS: The CGP has the potential to enable health care providers, investigators and patients to better understand the components of glycemic control and the effect of various interventions on the individual elements of that control. This can be done on a daily, weekly, or monthly basis. It also allows direct comparison of the effects on different interventions among clinical trials which is not possible using A1C alone. This new composite metric approach requires validation to determine if it provides a better predictor of long-term outcomes than A1C and/or better predictor of severe hypoglycemia than the low blood glucose index (LBGI).

The Development of New Composite Metrics for the Comprehensive Analytic and Visual Assessment of Hypoglycemia Using the Hypo-Triad.

BACKGROUND: Quantifying hypoglycemia has traditionally been limited to using the frequency of hypoglycemic events during a given time interval using data from blood glucose (BG) testing. However, continuous glucose monitoring (CGM) captures three parameters-a Hypo-Triad-unavailable with BG monitoring that can be used to better characterize hypoglycemia: area under the curve (AUC), time (duration of hypoglycemia), and frequency of daily episodes below a specified threshold. METHODS: We developed two new analytic metrics to enhance the traditional Hypo-Triad of CGM-derived data to more effectively capture the intensity of hypoglycemia (IntHypo) and overall hypoglycemic environment called the "hypoglycemia risk volume" (HypoRV). We reanalyzed the CGM data from the ASPIRE In-Home study, a randomized, controlled trial of a sensor-integrated pump system with a low glucose threshold suspend feature (SIP+TS), using these new metrics and compared them to standard metrics of hypoglycemia. RESULTS: IntHypo and HypoRV provide additional insights into the benefit of a SIP+TS system on glycemic exposure when compared to the standard reporting methods. In addition, the visual display of these parameters provides a unique and intuitive way to understand the impact of a diabetes intervention on a cohort of subjects as well as on individual patients. CONCLUSION: The IntHypo and HypoRV are new and enhanced ways of analyzing CGM-derived data in diabetes intervention studies which could lead to new insights in diabetes management. They require validation using existing, ongoing, or planned studies to determine whether they are superior to existing metrics.

Effectiveness of Automated Insulin Management Features of the MiniMed® 640G Sensor-Augmented Insulin Pump.

BACKGROUND: Automated insulin management features of the MiniMed® 640G sensor-augmented pump system include suspension in response to predicted low sensor glucose (SG) values ("suspend before low"), suspension in response to existing low SG values ("suspend on low"), and automatic restarting of basal insulin delivery upon SG recovery. The effectiveness of these features was evaluated using CareLink® software data. METHODS: Anonymized data from MiniMed 640G system users (n = 4818), MiniMed 530G system users (n = 39,219), and MiniMed Paradigm® Veo™ system users (n = 43,193) who voluntarily uploaded pump and sensor data were retrospectively analyzed. Comparisons were made between days in which system features were enabled at any time and those in which they were not. Comparisons were also made between pump suspension events for which insulin delivery was automatically or manually resumed and between glycemic parameters of users who switched from the MiniMed Paradigm Veo system to the MiniMed 640G system. RESULTS: Days in which the MiniMed 640G "suspend before low" feature was enabled had lower percentages of SG readings ≤70 mg/dL (3.9 mmol/L) or ≥240 mg/dL (13.3 mmol/L) than days when it was not enabled (P < 0.001 for each). Users who switched from the MiniMed Paradigm Veo system to the MiniMed 640G system had fewer excursions below ≤70 mg/dL (P < 0.001) and ≥240 mg/dL (P < 0.001). SG values following automatically resumed pump suspension events recovered more rapidly and had a more stabilized endpoint than following manually resumed events. CONCLUSIONS: Automated insulin management features of the MiniMed 640G system can reduce the frequency of both high and low SG values and help stabilize SG after resumption of insulin delivery.