Toward the "Perfect" Shunt: Historical Vignette, Current Efforts, and Future Directions.

As a concept, drainage of excess fluid volume in the cranium has been around for more than 1000 years. Starting with the original decompression-trepanation of Abulcasis to modern programmable shunt systems, to other nonshunt-based treatments such as endoscopic third ventriculostomy and choroid plexus cauterization, we have come far as a field. However, there are still fundamental limitations that shunts have yet to overcome: namely posture-induced over- and underdrainage, the continual need for valve opening pressure especially in pediatric cases, and the failure to reinstall physiologic intracranial pressure dynamics. However, there are groups worldwide, in the clinic, in industry, and in academia, that are trying to ameliorate the current state of the technology within hydrocephalus treatment. This chapter aims to provide a historical overview of hydrocephalus, current challenges in shunt design, what members of the community have done and continue to do to address these challenges, and finally, a definition of the "perfect" shunt is provided and how the authors are working toward it.

A Soft Robotic Actuator System for In Vivo Modeling of Normal Pressure Hydrocephalus.

OBJECTIVE: The intracranial pressure (ICP) affects the dynamics of cerebrospinal fluid (CSF) and its waveform contains information that is of clinical importance in medical conditions such as hydrocephalus. Active manipulation of the ICP waveform could enable the investigation of pathophysiological processes altering CSF dynamics and driving hydrocephalus. METHODS: A soft robotic actuator system for intracranial pulse pressure amplification was developed to model normal pressure hydrocephalus in vivo. Different end actuators were designed for intraventricular implantation and manufactured by applying cyclic tensile loading on soft rubber tubing. Their mechanical properties were investigated, and the type that achieved the greatest pulse pressure amplification in an in vitro simulator of CSF dynamics was selected for application in vivo. A hydraulic actuation device based on a linear voice coil motor was developed to enable automated and fast operation of the end actuators. The combined system was validated in an acute ovine pilot in vivo study. RESULTS: in vitro results show that variations in the used materials and manufacturing settings altered the end actuator's dynamic properties, such as the pressure-volume characteristics. In the in vivo model, a cardiac-gated actuation volume of 0.125 mL at a heart rate of 62 bpm caused an increase of 205% in mean peak-to-peak amplitude but only an increase of 1.3% in mean ICP. CONCLUSION: The introduced soft robotic actuator system is capable of ICP waveform manipulation. SIGNIFICANCE: Continuous amplification of the intracranial pulse pressure could enable in vivo modeling of normal pressure hydrocephalus and shunt system testing under pathophysiological conditions to improve therapy for hydrocephalus.

Data-Driven Investigation of Gait Patterns in Individuals Affected by Normal Pressure Hydrocephalus.

Normal pressure hydrocephalus (NPH) is a chronic and progressive disease that affects predominantly elderly subjects. The most prevalent symptoms are gait disorders, generally determined by visual observation or measurements taken in complex laboratory environments. However, controlled testing environments can have a significant influence on the way subjects walk and hinder the identification of natural walking characteristics. The study aimed to investigate the differences in walking patterns between a controlled environment (10 m walking test) and real-world environment (72 h recording) based on measurements taken via a wearable gait assessment device. We tested whether real-world environment measurements can be beneficial for the identification of gait disorders by performing a comparison of patients' gait parameters with an aged-matched control group in both environments. Subsequently, we implemented four machine learning classifiers to inspect the individual strides' profiles. Our results on twenty young subjects, twenty elderly subjects and twelve NPH patients indicate that patients exhibited a considerable difference between the two environments, in particular gait speed (p-value p=0.0073), stride length (p-value p=0.0073), foot clearance (p-value p=0.0117) and swing/stance ratio (p-value p=0.0098). Importantly, measurements taken in real-world environments yield a better discrimination of NPH patients compared to the controlled setting. Finally, the use of stride classifiers provides promise in the identification of strides affected by motion disorders.

Knee Compliance Reduces Peak Swing Phase Collision Forces in a Lower-Limb Exoskeleton Leg: A Test Bench Evaluation.

Powered lower limb exoskeletons are a viable solution for people with a spinal cord injury to regain mobility for their daily activities. However, the commonly employed rigid actuation and pre-programmed trajectories increase the risk of falling in case of collisions with external objects. Compliant actuation may reduce forces during collisions, thus protecting hardware and user. However, experimental data of collisions specific to lower limb exoskeletons are not available. In this work, we investigated how a variable stiffness actuator at the knee joint influences collision forces transmitted to the user via the exoskeleton. In a test bench experiment, we compared three configurations of an exoskeleton leg with a variable stiffness knee actuator in (i) compliant or (ii) stiff configurations, and with (iii) a rigid actuator. The peak torque observed at the pelvis was reduced from 260.2 Nm to 116.2 Nm as stiffness decreased. In addition, the mechanical impulse was reduced by a factor of three. These results indicate that compliance in the knee joint of an exoskeleton can be favorable in case of collision and should be considered when designing powered lower limb exoskeletons. Overall, this could decrease the effort necessary to maintain balance after a collision, and improved collision handling in exoskeletons could result in safer use and benefit their usefulness in daily life.

Performance comparison of prediction filters for respiratory motion tracking in radiotherapy.

PURPOSE: In precision radiotherapy, the intrafractional motion causes substantial uncertainty. Traditionally, the target volume is expanded to cover the tumor in all positions. Alternative approaches are gating and adaptive tracking, which require a time delay as small as possible between the actual tumor motion and the reaction to effectively compensate the motion. Current treatment machines often exhibit large time delays. Prediction filters offer a promising means to mitigate these time delays by predicting the future respiratory motion. METHODS: A total of 18 prediction filters were implemented and their hyperparameters optimized for various time delays and noise levels. A set of 93 traces were standardized to a sampling frequency of 25 Hz and smoothed using the Fourier transform with a 3 Hz cutoff frequency. The hyperparameter optimization was carried out with ten traces, and the optimal hyperparameters were evaluated on the remaining 83 traces. RESULTS: For smooth traces, the wavelet least mean squares prediction filter and the linear filter reached normalized root mean square errors of below 0.05 for time delays of 160 and 480 ms, respectively. For noisy signals, the performance of the prediction filters deteriorated and led to similar results. CONCLUSIONS: Linear methods for prediction filters are sufficient for respiratory motion signals. Reducing the measurement noise generally improves the performance of the prediction filters investigated in this study, even during breathing irregularities.

The ideal couch tracking system-Requirements and evaluation of current systems.

INTRODUCTION: Intrafractional motion can cause substantial uncertainty in precision radiotherapy. Traditionally, the target volume is defined to be sufficiently large to cover the tumor in every position. With the robotic treatment couch, a real-time motion compensation can improve tumor coverage and organ at risk sparing. However, this approach poses additional requirements, which are systematically developed and which allow the ideal robotic couch to be specified. METHODS AND MATERIALS: Data of intrafractional tumor motion were collected and analyzed regarding motion range, frequency, speed, and acceleration. Using this data, ideal couch requirements were formulated. The four robotic couches Protura, Perfect Pitch, RoboCouch, and RPSbase were tested with respect to these requirements. RESULTS: The data collected resulted in maximum speed requirements of 60 mm/s in all directions and maximum accelerations of 80 mm/s2 in the longitudinal, 60 mm/s2 in the lateral, and 30 mm/s2 in the vertical direction. While the two robotic couches RoboCouch and RPSbase completely met the requirements, even these two showed a substantial residual motion (40% of input amplitude), arguably due to their time delays. CONCLUSION: The requirements for the motion compensation by an ideal couch are formulated and found to be feasible for currently available robotic couches. However, the performance these couches can be improved further regarding the position control if the demanded speed and acceleration are taken into account as well.

Body motion during dynamic couch tracking with healthy volunteers.

In precision radiotherapy, the intrafractional motion can cause a considerable uncertainty of the location of the tumor to be treated. An established approach is the expansion of the target volume to account for the motion. An alternative approach is couch-tracking, in which the patient is continually moved to compensate the intrafractional motion. However, couch-tracking itself might induce uncertainty of the patient's body position, because the body is non-rigid. One hundred healthy volunteers were positioned supine on a robotic couch. Optical markers were placed on the torso of the volunteers as well as on the couch, and their positions were tracked with an optical surface measurement system. Using these markers, the uncertainty of the body position relative to the couch position was estimated while the couch was static or moving. Over the included 83 healthy volunteers, the median of the uncertainty increased by 0.8 mm (SI), 0.4 mm (LR) and 0.4 mm (AP) when the couch moved. Couch motion was found to increase the uncertainty of the body position relative to the couch. However, this uncertainty is one order of magnitude smaller than the intrafractional tumor motion amplitudes to be compensated. Therefore, even with body motion present, the couch-tracking approach is a viable option. The study was registered at ClinicalTrials.gov (NCT02820532) and the Swiss national clinical trials portal (SNCTP000001878).

Unconscious physiological response of healthy volunteers to dynamic respiration-synchronized couch motion.

BACKGROUND: Intrafractional motion can be a substantial uncertainty in precision radiotherapy. Conventionally, the target volume is expanded to account for the motion. Couch-tracking is an alternative, where the patient is moved to compensate for the tumor motion. However, the couch motion may influence the patient's stress and respiration behavior decreasing the couch-tracking effectiveness. METHODS: In total, 100 volunteers were positioned supine on a robotic couch, which moved dynamically and respiration synchronized. During the measurement, the skin conductivity, the heartrate, and the gaze location were measured indicating the volunteer's stress. Volunteers rated the subjective motion sickness using a questionnaire. The measurement alternated between static and tracking segments (three cycles), each 1 min long. RESULTS: The respiration amplitude showed no significant difference between tracking and static segments, but decreased significantly from the first to the last tracking segment (p < 0.0001). The respiration frequency differed significantly between tracking and static segments (p < 0.0001), but not between the first and the last tracking segment. The physiological parameters and the questionnaire showed mild signals of stress and motion sickness. CONCLUSION: Generally, people tolerated the couch motions. The interaction between couch motion and the patient's breathing pattern should be considered for a clinical implementation. TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov (NCT02820532) and the Swiss national clinical trials portal ( SNCTP000001878 ) on June 20, 2016.

A novel computational model of the circadian clock in Arabidopsis that incorporates PRR7 and PRR9.

In plants, as in animals, the core mechanism to retain rhythmic gene expression relies on the interaction of multiple feedback loops. In recent years, molecular genetic techniques have revealed a complex network of clock components in Arabidopsis. To gain insight into the dynamics of these interactions, new components need to be integrated into the mathematical model of the plant clock. Our approach accelerates the iterative process of model identification, to incorporate new components, and to systematically test different proposed structural hypotheses. Recent studies indicate that the pseudo-response regulators PRR7 and PRR9 play a key role in the core clock of Arabidopsis. We incorporate PRR7 and PRR9 into an existing model involving the transcription factors TIMING OF CAB (TOC1), LATE ELONGATED HYPOCOTYL (LHY) and CIRCADIAN CLOCK ASSOCIATED (CCA1). We propose candidate models based on experimental hypotheses and identify the computational models with the application of an optimization routine. Validation is accomplished through systematic analysis of various mutant phenotypes. We introduce and apply sensitivity analysis as a novel tool for analyzing and distinguishing the characteristics of proposed architectures, which also allows for further validation of the hypothesized structures.