Isuru Dasanayake

Multinational Home Use of Closed-Loop Control Is Safe and Effective

OBJECTIVE To evaluate the efficacy of a portable, wearable, wireless artificial pancreas system (the Diabetes Assistant [DiAs] running the Unified Safety System) on glucose control at home in overnight-only and 24/7 closed-loop control (CLC) modes in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS At six clinical centers in four countries, 30 participants 18–66 years old with type 1 diabetes (43% female, 96% non-Hispanic white, median type 1 diabetes duration 19 years, median A1C 7.3%) completed the study. The protocol included a 2-week baseline sensor-augmented pump (SAP) period followed by 2 weeks of overnight-only CLC and 2 weeks of 24/7 CLC at home. Glucose control during CLC was compared with the baseline SAP. RESULTS Glycemic control parameters for overnight-only CLC were improved during the nighttime period compared with baseline for hypoglycemia (time <70 mg/dL, primary end point median 1.1% vs. 3.0%; P < 0.001), time in target (70–180 mg/dL: 75% vs. 61%; P < 0.001), and glucose variability (coefficient of variation: 30% vs. 36%; P < 0.001). Similar improvements for day/night combined were observed with 24/7 CLC compared with baseline: 1.7% vs. 4.1%, P < 0.001; 73% vs. 65%, P < 0.001; and 34% vs. 38%, P < 0.001, respectively. CONCLUSIONS CLC running on a smartphone (DiAs) in the home environment was safe and effective. Overnight-only CLC reduced hypoglycemia and increased time in range overnight and increased time in range during the day; 24/7 CLC reduced hypoglycemia and increased time in range both overnight and during the day. Compared with overnight-only CLC, 24/7 CLC provided additional hypoglycemia protection during the day.

Control and Synchronization of Neuron Ensembles

Synchronization of oscillations is a phenomenon prevalent in natural, social, and engineering systems. Controlling synchronization of oscillating systems is motivated by a wide range of applications from surgical treatment of neurological diseases to the design of neurocomputers. In this paper, we study the control of an ensemble of uncoupled neuron oscillators described by phase models. We examine controllability of such a neuron ensemble for various phase models and, furthermore, study the related optimal control problems. In particular, by employing Pontryagins maximum principle, we analytically derive optimal controls for spiking single- and two-neuron systems, and analyze the applicability of the latter to an ensemble system. Finally, we present a robust computational method for optimal control of spiking neurons based on pseudospectral approximations. The methodology developed here is universal to the control of general nonlinear phase oscillators.

Early Detection of Physical Activity for People With Type 1 Diabetes Mellitus.

Background: Early detection of exercise in individuals with type 1 diabetes mellitus (T1DM) may allow changes in therapy to prevent hypoglycemia. Currently there is limited experience with automated methods that detect the onset and end of exercise in this population. We sought to develop a novel method to quickly and reliably detect the onset and end of exercise in these individuals before significant changes in blood glucose (BG) occur. Methods: Sixteen adults with T1DM were studied as outpatients using a diary, accelerometer, heart rate monitor, and continuous glucose monitor for 2 days. These data were used to develop a principal component analysis based exercise detection method. Subjects also performed 60 and 30 minute exercise sessions at 30% and 50% predicted heart rate reserve (HRR), respectively. The detection method was applied to the exercise sessions to determine how quickly the detection of start and end of exercise occurred relative to change in BG. Results: Mild 30% HRR and moderate 50% HRR exercise onset was identified in 6 ± 3 and 5 ± 2 (mean ± SD) minutes, while completion was detected in 3 ± 8 and 6 ± 5 minutes, respectively. BG change from start of exercise to detection time was 1 ± 6 and −1 ± 3 mg/dL, and, from the end of exercise to detection time was 6 ± 4 and −17 ± 13 mg/dL, respectively, for the 2 exercise sessions. False positive and negative ratios were 4 ± 2% and 21 ± 22%. Conclusions: The novel method for exercise detection identified the onset and end of exercise in approximately 5 minutes, with an average BG change of only −6 mg/dL.

Constrained minimum-power control of spiking neuron oscillators

In this article, we study optimal control problems of spiking neurons whose dynamics are described by a phase model. We design minimum-power current stimuli (controls) that lead to desired spiking times. In particular, we consider bounded control amplitude and characterize the range of possible spiking times according to the bound. The design of such bounded optimal controls is of fundamental importance as phase models are accurate under weak forcing. We show that for a given bound, the corresponding feasible spiking times are optimally achieved by switching controls. We present analytical expressions with numerical simulations of these minimum-power stimuli for various phase models of neurons.

Twelve-Week 24/7 Ambulatory Artificial Pancreas With Weekly Adaptation of Insulin Delivery Settings: Effect on Hemoglobin A1c and Hypoglycemia

OBJECTIVE Artificial pancreas (AP) systems are best positioned for optimal treatment of type 1 diabetes (T1D) and are currently being tested in outpatient clinical trials. Our consortium developed and tested a novel adaptive AP in an outpatient, single-arm, uncontrolled multicenter clinical trial lasting 12 weeks. RESEARCH DESIGN AND METHODS Thirty adults with T1D completed a continuous glucose monitor (CGM)-augmented 1-week sensor-augmented pump (SAP) period. After the AP was started, basal insulin delivery settings used by the AP for initialization were adapted weekly, and carbohydrate ratios were adapted every 4 weeks by an algorithm running on a cloud-based server, with automatic data upload from devices. Adaptations were reviewed by expert study clinicians and patients. The primary end point was change in hemoglobin A1c (HbA1c). Outcomes are reported adhering to consensus recommendations on reporting of AP trials. RESULTS Twenty-nine patients completed the trial. HbA1c, 7.0 ± 0.8% at the start of AP use, improved to 6.7 ± 0.6% after 12 weeks (−0.3, 95% CI −0.5 to −0.2, P < 0.001). Compared with the SAP run-in, CGM time spent in the hypoglycemic range improved during the day from 5.0 to 1.9% (−3.1, 95% CI −4.1 to −2.1, P < 0.001) and overnight from 4.1 to 1.1% (−3.1, 95% CI −4.2 to −1.9, P < 0.001). Whereas carbohydrate ratios were adapted to a larger extent initially with minimal changes thereafter, basal insulin was adapted throughout. Approximately 10% of adaptation recommendations were manually overridden. There were no protocol-related serious adverse events. CONCLUSIONS Use of our novel adaptive AP yielded significant reductions in HbA1c and hypoglycemia.

Design of charge-balanced time-optimal stimuli for spiking neuron oscillators

In this letter, we investigate the fundamental limits on how the interspike time of a neuron oscillator can be perturbed by the application of a bounded external control input (a current stimulus) with zero net electric charge accumulation. We use phase models to study the dynamics of neurons and derive charge-balanced controls that achieve the minimum and maximum interspike times for a given bound on the control amplitude. Our derivation is valid for any arbitrary shape of the phase response curve and for any value of the given control amplitude bound. In addition, we characterize the change in the structures of the charge-balanced time-optimal controls with the allowable control amplitude. We demonstrate the applicability of the derived optimal control laws by applying them to mathematically ideal and experimentally observed neuron phase models, including the widely studied Hodgkin-Huxley phase model, and by verifying them with the corresponding original full state-space models. This work addresses a fundamental problem in the field of neural control and provides a theoretical investigation to the optimal control of oscillatory systems.

Constrained charge-balanced minimum-power controls for spiking neuron oscillators

In this paper, we study the optimal control of phase models for spiking neuron oscillators. We focus on the design of minimum-power current stimuli that elicit spikes in neurons at desired times. We furthermore take the charge-balanced constraint into account because in practice undesirable side effects may occur due to the accumulation of electric charge resulting from external stimuli. Charge-balanced minimum-power controls are derived for a general phase model using the maximum principle, where the cases with unbounded and bounded control amplitude are examined. The latter is of practical importance since phase models are more accurate for weak forcing. The developed optimal control strategies are then applied to both mathematically ideal and experimentally observed phase models to demonstrate their applicability, including the phase model for the widely studied Hodgkin-Huxley equations.

Optimal control of neurons using the homotopy perturbation method

The behavior of many natural and engineered systems is determined by oscillatory phenomena for which the input-output relationship can be described using phase models. The use of such models significantly reduces the complexity of control design, and enables the application of powerful semi-analytical methods for optimal control synthesis. In this paper, we examine the optimal control of a collection of neuron oscillators described by phase models. In particular, we employ Pontryagins maximum principle to formulate the optimal control problem as a boundary value problem, which we then solve using the homotopy perturbation method. This iterative optimization-free technique is promising for neural engineering applications that involve nonlinear oscillatory systems for which phase model representations are feasible.

Charge-balanced time-optimal control for spiking neuron oscillators

In this paper, we investigate the fundamental limits on how the inter-spike time of a neuron oscillator can be perturbed by the application of an external control input (a current stimulus) with zero net electric charge accumulation. We derive the minimum and maximum inter-spike time assignment controls for phase models using the maximum principle, and fully characterize the possible range of neuronal spiking times with respect to a given bound on the control amplitude. We apply the derived optimal controls to both mathematically ideal and experimentally observed phase models of spiking neurons to demonstrate their applicability to neuroscience.

Empirical dynamic model identification for blood-glucose dynamics in response to physical activity

In this paper, the dynamic response of blood glucose concentration in response to physical activity of people with Type 1 Diabetes Mellitus (T1DM) is captured by subspace identification methods. Activity (input) and subcutaneous blood glucose measurements (output) are employed to construct a personalized prediction model through semi-definite programming. The model is calibrated and subsequently validated with non-overlapping data sets from 15 T1DM subjects. This preliminary clinical evaluation reveals the underlying linear dynamics between blood glucose concentration and physical activity. These types of models can enhance our capabilities of achieving tighter blood glucose control and early detection of hypoglycemia for people with T1DM.