Timothy R. Angeli

Abnormal initiation and conduction of slow-wave activity in gastroparesis, defined by high-resolution electrical mapping.

BACKGROUND & AIMS Interstitial cells of Cajal (ICC) generate slow waves. Disrupted ICC networks and gastric dysrhythmias are each associated with gastroparesis. However, there are no data on the initiation and propagation of slow waves in gastroparesis because research tools have lacked spatial resolution. We applied high-resolution electrical mapping to quantify and classify gastroparesis slow-wave abnormalities in spatiotemporal detail. METHODS Serosal high-resolution mapping was performed using flexible arrays (256 electrodes; 36 cm(2)) at stimulator implantation in 12 patients with diabetic or idiopathic gastroparesis. Data were analyzed by isochronal mapping, velocity and amplitude field mapping, and propagation animation. ICC numbers were determined from gastric biopsy specimens. RESULTS Mean ICC counts were reduced in patients with gastroparesis (2.3 vs 5.4 bodies/field; P < .001). Slow-wave abnormalities were detected by high-resolution mapping in 11 of 12 patients. Several new patterns were observed and classified as abnormal initiation (10/12; stable ectopic pacemakers or diffuse focal events; median, 3.3 cycles/min; range, 2.1-5.7 cycles/min) or abnormal conduction (7/10; reduced velocities or conduction blocks; median, 2.9 cycles/min; range, 2.1-3.6 cycles/min). Circumferential conduction emerged during aberrant initiation or incomplete block and was associated with velocity elevation (7.3 vs 2.9 mm s(-1); P = .002) and increased amplitudes beyond a low base value (415 vs 170 μV; P = .002). CONCLUSIONS High-resolution mapping revealed new categories of abnormal human slow-wave activity. Abnormalities of slow-wave initiation and conduction occur in gastroparesis, often at normal frequency, which could be missed by tests that lack spatial resolution. Irregular initiation, aberrant conduction, and low amplitude activity could contribute to the pathogenesis of gastroparesis.

Rapid high-amplitude circumferential slow wave propagation during normal gastric pacemaking and dysrhythmias.

Background  Gastric slow waves propagate aborally as rings of excitation. Circumferential propagation does not normally occur, except at the pacemaker region. We hypothesized that (i) the unexplained high‐velocity, high‐amplitude activity associated with the pacemaker region is a consequence of circumferential propagation; (ii) rapid, high‐amplitude circumferential propagation emerges during gastric dysrhythmias; (iii) the driving network conductance might switch between interstitial cells of Cajal myenteric plexus (ICC‐MP) and circular interstitial cells of Cajal intramuscular (ICC‐IM) during circumferential propagation; and (iv) extracellular amplitudes and velocities are correlated.

The gastrointestinal electrical mapping suite (GEMS): software for analyzing and visualizing high-resolution (multi-electrode) recordings in spatiotemporal detail

BackgroundGastrointestinal contractions are controlled by an underlying bioelectrical activity. High-resolution spatiotemporal electrical mapping has become an important advance for investigating gastrointestinal electrical behaviors in health and motility disorders. However, research progress has been constrained by the low efficiency of the data analysis tasks. This work introduces a new efficient software package: GEMS (Gastrointestinal Electrical Mapping Suite), for analyzing and visualizing high-resolution multi-electrode gastrointestinal mapping data in spatiotemporal detail.ResultsGEMS incorporates a number of new and previously validated automated analytical and visualization methods into a coherent framework coupled to an intuitive and user-friendly graphical user interface. GEMS is implemented using MATLAB®, which combines sophisticated mathematical operations and GUI compatibility. Recorded slow wave data can be filtered via a range of inbuilt techniques, efficiently analyzed via automated event-detection and cycle clustering algorithms, and high quality isochronal activation maps, velocity field maps, amplitude maps, frequency (time interval) maps and data animations can be rapidly generated. Normal and dysrhythmic activities can be analyzed, including initiation and conduction abnormalities. The software is distributed free to academics via a community user website and forum (http://sites.google.com/site/gimappingsuite).ConclusionsThis software allows for the rapid analysis and generation of critical results from gastrointestinal high-resolution electrical mapping data, including quantitative analysis and graphical outputs for qualitative analysis. The software is designed to be used by non-experts in data and signal processing, and is intended to be used by clinical researchers as well as physiologists and bioengineers. The use and distribution of this software package will greatly accelerate efforts to improve the understanding of the causes and clinical consequences of gastrointestinal electrical disorders, through high-resolution electrical mapping.

The bioelectrical basis and validity of gastrointestinal extracellular slow wave recordings

•  Extracellular recording techniques are commonly used to measure bioelectrical activity. However, the validity of gastrointestinal extracellular recordings has recently been challenged. •  In this joint experimental and modelling study, slow waves were recorded during contractile inhibition, biphasic and monophasic slow wave potentials were recorded simultaneously, and the biophysical basis of extracellular potentials was modelled with comparison to experimental data. •  The results showed that in vivo extracellular techniques reliably recorded slow waves in the absence of contractions, and potentials recorded using conventional serosal electrodes (biphasic) were concordant in phase and morphology with those recorded using suction electrodes (monophasic). •  Modelling further demonstrated that the morphology of experimental recordings is consistent with the biophysics underlying slow wave depolarisation. •  In total, these results demonstrate that gastrointestinal extracellular recordings are valid when performed and analysed correctly, reliably representing bioelectrical slow wave events. Motion suppression is not routinely required for in vivo extracellular studies.

Experimental and Automated Analysis Techniques for High-resolution Electrical Mapping of Small Intestine Slow Wave Activity.

Background/Aims Small intestine motility is governed by an electrical slow wave activity, and abnormal slow wave events have been associated with intestinal dysmotility. High-resolution (HR) techniques are necessary to analyze slow wave propagation, but progress has been limited by few available electrode options and laborious manual analysis. This study presents novel methods for in vivo HR mapping of small intestine slow wave activity. Methods Recordings were obtained from along the porcine small intestine using flexible printed circuit board arrays (256 electrodes; 4 mm spacing). Filtering options were compared, and analysis was automated through adaptations of the falling-edge variable-threshold (FEVT) algorithm and graphical visualization tools. Results A Savitzky-Golay filter was chosen with polynomial-order 9 and window size 1.7 seconds, which maintained 94% of slow wave amplitude, 57% of gradient and achieved a noise correction ratio of 0.083. Optimized FEVT parameters achieved 87% sensitivity and 90% positive-predictive value. Automated activation mapping and animation successfully revealed slow wave propagation patterns, and frequency, velocity, and amplitude were calculated and compared at 5 locations along the intestine (16.4 ± 0.3 cpm, 13.4 ± 1.7 mm/sec, and 43 ± 6 µV, respectively, in the proximal jejunum). Conclusions The methods developed and validated here will greatly assist small intestine HR mapping, and will enable experimental and translational work to evaluate small intestine motility in health and disease.

The Principles and Practice of Gastrointestinal High-Resolution Electrical Mapping

High resolution (multi-electrode) electrical mapping has become a prominent technique for investigating the propagation of electrical activity in the gastrointestinal (GI) tract. This technique involves the placement of dense arrays of many electrodes over the surface of the tissue, in order to reconstruct the spread of electrical activation in accurate spatiotemporal detail. Multi-electrode mapping can be performed in-vivo and in-vitro in a variety of animal models, and clinical methods for human mapping are also advancing. This chapter reviews the current status of GI multi-electrode mapping, with a particular focus on the principles of extracellular recordings, the design of mapping devices, the discrimination of artifacts, and the practical considerations for successful experimental work. Potential future directions for the field are considered.

Quantification of velocity anisotropy during gastric electrical arrhythmia

In this study, an automated algorithm was developed to identify the arrhythmic gastric slow wave activity that was recorded using high-resolution mapping technique. The raw signals were processed with a Savitzky-Golay filter, and the slow wave activation times were identified using a threshold-varying method and grouped using a region-growing method. Slow wave amplitudes and velocities were calculated for all cycles. Arrhythmic events were identified when the orientation of a slow wave at an electrode exceeded the 95% confidence interval of the averaged orientation of several normal cycles. A second selection criterion was further developed to identify the arrhythmic events by an anisotropy ratio. In both pig and human studies, arrhythmias were associated with the emergence of circumferential velocity components and higher amplitudes.

The virtual intestine: in silico modeling of small intestinal electrophysiology and motility and the applications.

The intestine comprises a long hollow muscular tube organized in anatomically and functionally discrete compartments, which digest and absorb nutrients and water from ingested food. The intestine also plays key roles in the elimination of waste and protection from infection. Critical to all of these functions is the intricate, highly coordinated motion of the intestinal tract, known as motility, which is coregulated by hormonal, neural, electrophysiological and other factors. The Virtual Intestine encapsulates a series of mathematical models of intestinal function in health and disease, with a current focus on motility, and particularly electrophysiology. The Virtual Intestine is being cohesively established across multiple physiological scales, from sub/cellular functions to whole organ levels, facilitating quantitative evaluations that present an integrative in silico framework. The models are also now finding broad physiological applications, including in evaluating hypotheses of slow wave pacemaker mechanisms, smooth muscle electrophysiology, structure–function relationships, and electromechanical coupling. Clinical applications are also beginning to follow, including in the pathophysiology of motility disorders, diagnosing intestinal ischemia, and visualizing colonic dysfunction. These advances illustrate the emerging potential of the Virtual Intestine to effectively address multiscale research challenges in interdisciplinary gastrointestinal sciences. WIREs Syst Biol Med 2016, 8:69–85. doi: 10.1002/wsbm.1324

Functional physiology of the human terminal antrum defined by high-resolution electrical mapping and computational modeling

High-resolution (HR) mapping has been used to study gastric slow-wave activation; however, the specific characteristics of antral electrophysiology remain poorly defined. This study applied HR mapping and computational modeling to define functional human antral physiology. HR mapping was performed in 10 subjects using flexible electrode arrays (128-192 electrodes; 16-24 cm2) arranged from the pylorus to mid-corpus. Anatomical registration was by photographs and anatomical landmarks. Slow-wave parameters were computed, and resultant data were incorporated into a computational fluid dynamics (CFD) model of gastric flow to calculate impact on gastric mixing. In all subjects, extracellular mapping demonstrated normal aboral slow-wave propagation and a region of increased amplitude and velocity in the prepyloric antrum. On average, the high-velocity region commenced 28 mm proximal to the pylorus, and activation ceased 6 mm from the pylorus. Within this region, velocity increased 0.2 mm/s per mm of tissue, from the mean 3.3 ± 0.1 mm/s to 7.5 ± 0.6 mm/s (P < 0.001), and extracellular amplitude increased from 1.5 ± 0.1 mV to 2.5 ± 0.1 mV (P < 0.001). CFD modeling using representative parameters quantified a marked increase in antral recirculation, resulting in an enhanced gastric mixing, due to the accelerating terminal antral contraction. The extent of gastric mixing increased almost linearly with the maximal velocity of the contraction. In conclusion, the human terminal antral contraction is controlled by a short region of rapid high-amplitude slow-wave activity. Distal antral wave acceleration plays a major role in antral flow and mixing, increasing particle strain and trituration.

Mapping small intestine bioelectrical activity using high-resolution printed-circuit-board electrodes

In this study, novel methods were developed for the in-vivo high-resolution recording and analysis of small intestine bioelectrical activity, using flexible printed-circuit-board (PCB) electrode arrays. Up to 256 simultaneous recordings were made at multiple locations along the porcine small intestine. Data analysis was automated through the application and tuning of the Falling-Edge Variable-Threshold algorithm, achieving 92% sensitivity and a 94% positive-predictive value. Slow wave propagation patterns were visualized through the automated generation of animations and isochronal maps. The methods developed and validated in this study are applicable for use in humans, where future studies will serve to improve the clinical understanding of small intestine motility in health and disease.