Hierarchical data visualization of experimental erythrocyte aggregation employing cross correlation and optical flow applications.

Appraisal of microvascular erythrocyte velocity as well as aggregation are critical features of hemorheological assessment. Examination of erythrocyte velocity-aggregate characteristics is critical in assessing disorders associated with coagulopathy. Microvascular erythrocyte velocity can be assessed using various methodologic approaches; however, the shared assessment of erythrocyte velocity and aggregation has not been well described. The purpose of this study therefore is to examine three independent erythrocyte assessment strategies with and without experimentally induced aggregation in order to elucidate appropriate analytic strategy for combined velocity/aggregation assessment applicable to in-vivo capillaroscopy. We employed a hierarchical microfluidic model combined with Bland-Altman analysis to examine agreement between three methodologies to assess erythrocyte velocity appropriate for interpretation of cinematography of in-vivo microvascular hemorheology. We utilized optical and manual techniques as well as a technique which we term transversal temporal cross-correlation (TTC) to observe and measure both erythrocyte velocity and aggregation. In general, optical, manual and TTC agree in estimation of velocity at relatively low flow rate, however with an increase in infusion rate the optical flow method yielded the velocity estimates that were lower than the TTC and manual velocity estimates. We suggest that this difference was due to the fact that slower moving particles close to the channel wall were better illuminated than faster particles deeper in the channel which affected the optical flow analysis. Combined velocity/aggregation appraisal using TTC provides an efficient approach for estimating erythrocyte aggregation appropriate for in-vivo applications. We demonstrated that the optical flow and TTC analyses can be used to estimate erythrocyte velocity and aggregation both in ex-vivo microfluidics laboratory experiments as well as in-vivo recordings. The simplicity of TTC method may be advantageous for developing velocity estimate methods to be used in the clinic. The trade-off is that TTC estimation cannot capture features of the flow based on optical flow analysis of individually tracked particles.

Adaptive Susceptible-Infectious-Removed Model for Continuous Estimation of the COVID-19 Infection Rate and Reproduction Number in the United States: Modeling Study.

BACKGROUND: The dynamics of the COVID-19 pandemic vary owing to local population density and policy measures. During decision-making, policymakers consider an estimate of the effective reproduction number Rt, which is the expected number of secondary infections spread by a single infected individual. OBJECTIVE: We propose a simple method for estimating the time-varying infection rate and the Rt. METHODS: We used a sliding window approach with a Susceptible-Infectious-Removed (SIR) model. We estimated the infection rate from the reported cases over a 7-day window to obtain a continuous estimation of Rt. A proposed adaptive SIR (aSIR) model was applied to analyze the data at the state and county levels. RESULTS: The aSIR model showed an excellent fit for the number of reported COVID-19 cases, and the 1-day forecast mean absolute prediction error was <2.6% across all states. However, the 7-day forecast mean absolute prediction error approached 16.2% and strongly overestimated the number of cases when the Rt was rapidly decreasing. The maximal Rt displayed a wide range of 2.0 to 4.5 across all states, with the highest values for New York (4.4) and Michigan (4.5). We found that the aSIR model can rapidly adapt to an increase in the number of tests and an associated increase in the reported cases of infection. Our results also suggest that intensive testing may be an effective method of reducing Rt. CONCLUSIONS: The aSIR model provides a simple and accurate computational tool for continuous Rt estimation and evaluation of the efficacy of mitigation measures.

Suppression of proprioceptive feedback control in movement sequences through intermediate targets.

Simple movements can be seen as building blocks for complex action sequences, and neural control of an action sequence can be expected to preserve some control features of its constituent blocks. It was previously found that during single-joint elbow movements to a single target, the proprioceptive feedback control is initially suppressed, and we tested this feedback suppression in a two-segment sequence during which subjects momentarily slowed down at an intermediate target at a 30° distance (first segment) and then immediately moved another 30° to the final target (second segment). Either the first or second segment was unexpectedly perturbed; the latency of the earliest response to the perturbation in the muscle surface electromyogram was analyzed. The perturbations were delivered either at the onset of each segment or about 0.1 s later. We found that in both segments, the response latency to the late perturbation was shorter than the latency to the early perturbation, which suggests that the proprioceptive feedback control is suppressed in the beginning of each segment. Next, we determined the latency of the response to unexpected perturbations in 30° movements to a single target. We found that the response latency was not significantly different in the movement to a single target and in each segment in the sequence. This result suggests that the initial suppression of the proprioceptive feedback control in movements to single targets is preserved in movements through intermediate targets and supports the idea of modular organization of neural control of movement sequences.

Temporal shift from velocity to position proprioceptive feedback control during reaching movements.

Reaching movements to a target usually have stereotypical kinematics. Although this suggests that the desired kinematics of a movement might be planned, does it also mean that deviations from the planned kinematics are corrected by proprioceptive feedback control? To answer this question, we designed a task in which the subjects made center-forward movements to a target while holding the handle of a robot. Subjects were instructed to make movements at a peak velocity of 1 m/s. No further instructions were given with respect to the movement trajectory or the velocity time profile. In randomly chosen trials the robot imposed servo-controlled deviations from the previously computed unperturbed velocity and position time profiles. The duration of the velocity deviations and the magnitude of accumulated position deviations were manipulated. The subjects were instructed to either "Attempt to correct" or "Do not correct" the movement. The responses to the imposed deviations in the surface electromyograms in the elbow and shoulder agonist muscles consisted of an initial burst followed by a sharp decrease in the "Do not correct" condition or by sustained activity in the "Attempt to correct" condition. The timing and magnitude of the initial response burst reflected those of the velocity deviations and were not affected by the instruction. The timing and magnitude of the late response activity reflected position feedback control and were strongly affected by the instruction. We suggest that proprioceptive feedback control is suppressed in the beginning of the movement, then velocity feedback control is activated in the middle of the movement to control a desired velocity, whereas position feedback control is facilitated late in the movement to acquire the final position.

Proprioceptive feedback during point-to-point arm movements is tuned to the expected dynamics of the task.

It has previously been found that in point-to-point movements against inertial loads, proprioceptive feedback is centrally suppressed in the beginning of movement and is facilitated at a time that is correlated with the expected time of peak velocity. This suggests that the modulation of proprioceptive feedback is governed by the desired movement kinematics. Here we show that in movements against inertial and viscous loads, the correlation of the time when the feedback is facilitated is strongest with the time when the joint torque is expected to be maximal. This suggests that the modulation of proprioceptive feedback is governed by the desired movement dynamics. We applied unexpected perturbations in point-to-point elbow flexion movements against known light and heavy inertial and viscous loads and determined the time and magnitude of responses in the electromyogram (EMG) of the biceps and triceps muscles. In movements against the inertial and viscous loads, the time of the EMG responses was better predicted by the time of the peak joint torque in the unperturbed movement than by the time of peak velocity or the time of peak acceleration or by measures related to the agonist EMG. Moreover, the EMG response changed from a reciprocal pattern in the inertial load conditions to a co-contraction pattern in the viscous load conditions. Our results suggest that during movements against known stable dynamic loads, proprioceptive feedback is tuned to the expected task dynamics and is facilitated so as to maintain muscle stiffness at a time when the muscles are expected to generate maximal force.

EMG responses to unexpected perturbations are delayed in slower movements.

It has previously been found that in fast point-to-point arm movements, proprioceptive feedback is centrally suppressed at the beginning of movement and is facilitated at a time that is correlated with temporal parameters of the planned movement. Here, we show that this correlation holds when subjects are explicitly instructed to move at less than maximal speed. We studied elbow flexion movements made at maximal speed and at 70% of maximal speed over a short distance against a light inertial load and over a long distance against a heavy inertial load. A small number of trials were unexpectedly perturbed by using a servo-controlled motor to decrease the movement velocity. The servo control was turned on early in the movement. The main novel finding is that responses in the surface EMG in the elbow muscles to the perturbation occurred later in the slow-speed conditions than fast-speed conditions. When viewed across all conditions, the onset of the EMG responses to the perturbation increased with the time to peak acceleration in unperturbed movements. In the inertial loaded movements, the time of peak acceleration coincides with the time of peak inertial torque, and so the observed correlation can be interpreted as reflecting the relation between either the planned movement kinematics or the planned movement dynamics. These results are compatible with a hypothesis that a descending command suppresses the proprioceptive feedback control at the movement onset and facilitates it at a time that depends on the time parameters of the planned movement.

Effect of short and long term STN stimulation periods on parkinsonian signs.

Currently, no study of subthalamic nucleus (STN) stimulation has compared continuous stimulation with a period of short-term stimulation, which is frequently employed in the clinic and in research studies. Therefore, this study examined the effects of STN stimulation over 90 min (short) and greater than 3 months (long) on the cardinal signs of Parkinson's disease. The 90 min time period immediately followed a 12 hour withdrawal from both STN stimulation and medication. Ten PD patients who received STN stimulation were studied. Bradykinesia, rigidity, and tremor were evaluated using the UPDRS and motor control measures which included peak velocity (bradykinesia), work (rigidity), and amplitude (tremor). Results showed no difference between 90 min and greater than 3 months of STN stimulation for the UPDRS or motor control measures. This finding confirms that the treatment efficacy that is derived from a relatively short time course of stimulation generalizes to longer time periods of high frequency STN stimulation that patients experience in their daily lives. As such, it is reasonable to evaluate the effect of DBS after 90 min of stimulation in clinical trials and research studies.

Effects of STN DBS on rigidity in Parkinson's disease.

We quantified the effects of deep brain stimulation (DBS) of the subthalamic nucleus (STN) and medication on Parkinsonian rigidity using an objective measure of work about the elbow joint during a complete cycle of imposed 1-Hz sinusoidal oscillations. Resting and activated rigidity were analyzed in four experimental conditions: 1) off treatment; 2) on DBS; 3) on medication; and 4) on DBS plus medication. Rigidity at the elbow joint was also assessed using the Unified Parkinson's Disease Rating Scale (UPDRS). We tested ten patients who received STN DBS and ten age-matched neurologically healthy control subjects. The activated rigidity condition increased work in both Parkinson's disease (PD) patients and control subjects. In PD patients, STN DBS reduced both resting and activated rigidity as indicated by work and the UPDRS rigidity score. This is the first demonstration that STN stimulation reduces rigidity using an objective measure such as work. In contrast, the presurgery dose of antiparkinsonian medication did not significantly improve the UPDRS rigidity score and reduced work only in the activated rigidity condition. Our results suggest that STN DBS may be more effective in alleviating rigidity in the upper limb of PD patients than medications administered at presurgery dosage level.

Muscle activation is different when the same muscle acts as an agonist or an antagonist during voluntary movement.

During movement, the intrinsic muscle force-velocity property decreases the net force for the shortening muscle (agonist) and increases it for the lengthening muscle (antagonist). The authors present a quantitative analysis of the effect of that muscle property on activation and force output of the same muscle acting as agonist and antagonist in fast and medium speed goal-oriented movements. They compared biceps activation and force output when that muscle was the agonist in a series of elbow flexions and when it was the antagonist in a series of elbow extensions. They performed the same analysis for the lateral, long, and medial heads of the triceps muscle. Muscle EMG was about 2 times larger and the angular impulse developed by the modeled contractile torque was up to 3 times larger when the muscle or muscles acted as the agonist than when the same muscle or muscles acted as the antagonist in movements with similar kinematics. The large effect of the muscle force-velocity property strongly suggests that the neural controller must account for intrinsic muscle properties to generate movements with a commonly observed bell-shaped velocity profile.

EMG responses to an unexpected load in fast movements are delayed with an increase in the expected movement time.

When moving an object, the motor system estimates the dynamic properties of the object and then controls the movement using a combination of predictive feedforward control and proprioceptive feedback. In this study, we examined how the feedforward and proprioceptive feedback processes depend on the expected movement task. Subjects made fast elbow flexion movements from an initial position to a target. The experimental protocol included movements made over a short and a long distance against an expected light or heavy inertial load. In each task in a few randomly chosen trials, a motor applied an unexpected viscous load that produced a velocity error, defined as the difference between the expected and unexpected velocities, and electromyographic (EMG) responses. The EMG responses appeared not earlier than 170-250 ms from the agonist EMG onset. Our main finding is that the onset of the EMG responses was correlated with the expected time of peak velocity, which increased for longer distances and larger loads. An analysis of the latency of the EMG responses with respect to the velocity error suggested that the EMG responses were due to segmental reflexes. We conclude that segmental reflex gains are centrally modulated with the time course dependent on the expected movement task. According to this view, the control of fast point-to-point movement is feedforward from the agonist EMG onset until the expected time of peak velocity after which the segmental reflex feedback is briefly facilitated.

Electromyographic responses to an unexpected load in fast voluntary movements: descending regulation of segmental reflexes.

This study examined the effects of unexpected loading on muscle activation during fast goal-oriented movements. We tested the hypothesis that the electromyographic (EMG) response to an unexpected load occurs at a short latency after the difference between the expected and the unexpected movement velocity exceeds a fixed threshold. Subjects performed two movement tasks as follows: 1) 30 degrees fast elbow flexion movement with an inertial load added by a torque motor; and 2) 50 degrees fast elbow flexion movement with no added load. These movement tasks were chosen to have similar timing parameters, such as movement time, time-to-peak velocity, and duration of the first agonist burst, while the magnitudes of the angular displacement, velocity, and acceleration were different. In task 1, in random trials a viscous load was substituted for the inertial load at movement onset. In task 2, the same viscous load was added in random trials. The earliest consistent response to the unexpected load was detected in the agonist (biceps) EMG at the same time, about 200 ms from the EMG onset, in both tasks. However, the velocity errors were different in the two tasks and no velocity error threshold dependency could be found. Therefore we reject the hypothesis that the timing of the EMG response to an unexpected load is related to a velocity error threshold. Instead, we suggest that the timing of the EMG response is primarily determined by descending regulation of segmental reflex gain.

Reaction time is not impaired by stimulation of the ventral-intermediate nucleus of the thalamus (Vim) in patients with tremor.

We studied the effect of high-frequency electrical stimulation of the ventral-intermediate nucleus of the thalamus (Vim) in four patients implanted with chronic stimulators to determine whether this procedure adversely affects reaction time to a proprioceptive stimulus. Two patients had undergone this surgery for treatment of tremor resulting from Parkinson's disease insufficiently responsive to levodopa therapy and two patients for treatment of essential tremor. Reaction times to auditory, visual, cutaneous, and proprioceptive stimuli were tested in a simple motor task requiring flexion of the elbow joint to a visual target in response to each stimulus. Reaction times were tested postoperatively with and without the stimulator turned on. We found that reaction time for all stimulus modalities was not increased when the stimulator was turned on; in fact, reaction times were, on average, slightly shorter during stimulation, but this difference was not statistically significant. We conclude that transmission of somatosensory inputs, necessary for initiating voluntary movement, from the periphery to the cortex is not significantly impaired by stimulation of the ventral-intermediate nucleus of the thalamus in patients with pathological tremor.