Objective. Behavior is encoded across multiple scales of brain activity, from binary neuronal spikes to continuous fields including local field potentials (LFP). Multiscale models need to describe both the encoding of behavior and the conditional dependencies in simultaneously recorded spike and field signals, which form a high-dimensional multiscale network. However, learning spike-field dependencies in high-dimensional recordings is challenging due to the prohibitively large number of spike-field signal pairs, which makes standard learning techniques subject to overfitting. Approach. We present a sparse model-based estimation algorithm to learn these multiscale network dependencies. We develop a multiscale encoding model consisting of a point process model of binary spikes for each neuron whose firing rate is a function of the LFP network features and behavioral states. Doing so, spike-field dependencies constitute the model parameters to be learned. We resolve the parameter learning challenge by forming a constrained optimization problem to maximize the likelihood with an L1 penalty term that eases the detection of significant spike-LFP dependencies. We then apply the Akaike information criterion (AIC) to force a sparse number of nonzero dependency parameters in the model. Main results. We validate the algorithm using simulations and spike-field data from two non-human primates (NHP) in a 3D motor task with motor cortical recordings and a pro-saccade visual task with prefrontal recordings. We find that by identifying a model with a sparse set of dependency parameters, the algorithm improves spike prediction compared with models without dependencies. Further, the algorithm identifies significantly fewer dependency parameters compared with standard methods while improving their spike prediction likely due to detecting fewer spurious dependencies. Also, spike prediction on any electrode improves by including LFP features from all electrodes compared with using only those on the same electrode. Finally, unlike standard methods, the algorithm uncovers patterns of spike-field network dependencies as a function of distance, brain region, and frequency band. Significance. This algorithm can help study functional dependencies in high-dimensional spike-field networks and leads to more accurate multiscale encoding models.

Vasopressor infusion (VPI) is used to treat hypotension in an ICU. We studied compliance with blood pressure (BP) goals during VPI and whether a statistical model might be efficacious for advance warning of impending hypotension, compared with a basic hypotension threshold alert. Retrospective data were obtained from a public database. Studying adult ICU patients receiving VPI at submaximal dosages, we analyzed characteristics of sustained hypotension episodes (>15 min) and then developed a logistic regression model to predict hypotension episodes using input features related to BP trends. The model was then validated with prospective data. In the retrospective dataset, 102-of-215 ICU stays experienced >1 hypotension episode (median of 2.5 episodes per day in this subgroup). When trained with 75% of retrospective dataset, testing with the remaining 25% of the dataset showed that the model and the threshold alert detected 99.6% and 100% of the episodes, respectively, with median advance forecast times (AFT) of 12 and 0 min. In a second, prospective dataset, the model detected 100% of 26 episodes with a median AFT of 22 min. In conclusion, episodes of hypotension were common during VPI in the ICU. A logistic regression model using BP temporal trend features predicted the episodes before their onset.

This paper presents a physiological model to reproduce hemodynamic responses to blood volume perturbation. The model consists of three sub-models: a control-theoretic model relating blood volume response to blood volume perturbation; a simple physics-based model relating blood volume to stroke volume and cardiac output; and a phenomenological model relating cardiac output to blood pressure. A unique characteristic of this model is its balance for simplicity and physiological transparency. Initial validity of the model was examined using experimental data collected from 11 animals. The model may serve as a viable basis for the design and evaluation of closed-loop fluid resuscitation controllers.

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This paper presents a lumped-parameter model that can reproduce blood volume response to fluid infusion. The model represents the fluid shift between the intravascular and interstitial compartments as the output of a hypothetical feedback controller that regulates the ratio between the volume changes in the intravascular and interstitial fluid at a target value (called “target volume ratio”). The model is characterized by only three parameters: the target volume ratio, feedback gain (specifying the speed of fluid shift), and initial blood volume. This model can obviate the need to incorporate complex mechanisms involved in the fluid shift in reproducing blood volume response to fluid infusion. The ability of the model to reproduce real-world blood volume response to fluid infusion was evaluated by fitting it to a series of data reported in the literature. The model reproduced the data accurately with average error and root-mean-squared error (RMSE) of 0.6 and 9.5% across crystalloid and colloid fluids when normalized by the underlying responses. Further, the parameters derived for the model showed physiologically plausible behaviors. It was concluded that this simple model may accurately reproduce a variety of blood volume responses to fluid infusion throughout different physiological states by fitting three parameters to a given dataset. This offers a tool that can quantify the fluid shift in a dataset given the measured fractional blood volumes.

Physiological closed-loop controlled (PCLC) medical devices are complex systems integrating one or more medical devices with a patient’s physiology through closed-loop control algorithms; introducing many failure modes and parameters that impact performance. These control algorithms should be tested through safety and efficacy trials to compare their performance to the standard of care and determine whether there is sufficient evidence of safety for their use in real care setting. With this aim, credible mathematical models have been constructed and used throughout the development and evaluation phases of a PCLC medical device to support the engineering design and improve safety aspects. Uncertainties about the fidelity of these models and ambiguities about the choice of measures for modeling performance need to be addressed before a reliable PCLC evaluation can be achieved. This research develops tools for evaluating the accuracy of physiological models and establishes fundamental measures for predictive capability assessment across different physiological models. As a case study, we built a refined physiological model of blood volume (BV) response by expanding an original model we developed in our prior work. Using experimental data collected from 16 sheep undergoing hemorrhage and fluid resuscitation, first, we compared the calibration performance of the two candidate physiological models, i.e., original and refined, using root-mean-squared error (RMSE), Akiake information criterion (AIC), and a new multi-dimensional approach utilizing normalized features extracted from the fitting error. Compared to the original model, the refined model demonstrated a significant improvement in calibration performance in terms of RMSE (9%, P = 0.03) and multi-dimensional measure (48%, P = 0.02), while a comparable AIC between the two models verified that the enhanced calibration performance in the refined model is not due to data over-fitting. Second, we compared the physiological predictive capability of the two models under three different scenarios: prediction of subject-specific steady-state BV response, subject-specific transient BV response to hemorrhage perturbation, and leave-one-out inter-subject BV response. Results indicated enhanced accuracy and predictive capability for the refined physiological model with significantly larger proportion of measurements that were within the prediction envelope in the transient and leave-one-out prediction scenarios (P < 0.02). All together, this study helps to identify and merge new methods for credibility assessment and physiological model selection, leading to a more efficient process for PCLC medical device evaluation.

Arterial pulse pressure has been widely used as surrogate of stroke volume, for example, in the guidance of fluid therapy. However, recent experimental investigations suggest that arterial pulse pressure is not linearly proportional to stroke volume. However, mechanisms underlying the relation between the two have not been clearly understood. The goal of this study was to elucidate how arterial pulse pressure and stroke volume respond to a perturbation in the left ventricular blood volume based on a systematic mathematical analysis. Both our mathematical analysis and experimental data showed that the relative change in arterial pulse pressure due to a left ventricular blood volume perturbation was consistently smaller than the corresponding relative change in stroke volume, due to the nonlinear left ventricular pressure-volume relation during diastole that reduces the sensitivity of arterial pulse pressure to perturbations in the left ventricular blood volume. Therefore, arterial pulse pressure must be used with care when used as surrogate of stroke volume in guiding fluid therapy.

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