Motilis
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History

The idea of using magnetic markers is not new. In the Fifties, gastric activity was already observed using a permanent magnet and a compass. The idea was abandoned due to the poor efficiency of the magnet and detectors. In the Nineties the subject returned "a la mode" with very sophisticated detection systems (mainly SQUIDs) requiring a magnetic shielded area. The price of this technology (mainly used to study the electrical activity of the brain by magnetoencephalogram) was quite high and therefore of limited applications.



[Wenger 1970]


[biomagnetometer, Philips]


We have choosen to offer for the first time a simple and economic tool, permitting to work in a normal environment, and accessible to most researchers.

More detailed history below...


Spatial precision

The position of the marker is calculated with a precision which strongly depends on several parameters

  • the distance between the marker and the detector
  • the marker size
  • the position of the marker compared to the center of the detector
  • external perturbations (see below "artefacts" )
  • the duration of the recording
  • the orientation of the marker

The marker size must be chosen according to its application: it gives the maximal distance of use. Typically a marker of 5mm in diameter (length 15 mm, density 1.75) allows a maximum working distance of 25 cm, with a precision of 1 mm at 15 cm.


MTS - Magnet Tracking System

An array of magnetic sensors allows dynamic recording of the position and orientation of a solid magnetic marker. The tajectory of the marker is defined by 5 coordinates (10 HZ sampling rate) : x, y, z for translations and Theta and Phi for rotations.




Magnetic Environment

Artefacts

It is not necessary to work in a shielded area and the majority of conventional labs are suitable. But, on the contrary, moving metallic (ferromagnetic) objects near the experiment can create artefacts by locally altering the earth’s terrestrial magnetic field. MTS is not sensitive to electromagnetic perturbations (computer screens or other electric devices).
In the following examples, precision issues will be noticed in some applications

  • a pair of scissors less than 50 cm away
  • a chair with metallic parts less than 2 meters away
  • a lift less than 10 meters away
  • a car less than 10 meters away

If the ferromagnetic object is located further than 10 meters, the perturbation is homogeneous and does not alter the tracking system.

Calibration

Due to the earth's magnetic field it is not possible to move the detector once the recording has started. The earth's magnetic field is not homogeneous, especially inside buildings. An offset calibration is therefore needed. (the value of the local magnetic field is measured and substracted from subsequent measures)


Introduction to Gastrointestinal Motility

The purposes of the motility are the following:

  • Mechanical fragmentation of the ingested aliments by mastication and grinding of the ingesta in the stomach.
  • Mixing of the ingesta with gastric juices forming a suspension in a liquid called chyme.
  • Homogenisation by mixing of the chyme and ensuring an optimal contact between chyme and the absorptive cells.
  • Deglutition and peristalsis, i.e., progressive propulsion of the chyme in the oro-aboral direction.
  • Functional separation of the GI segments by zones of increased pressure, in certain areas called sphincters: oesophageal, pyloric, ileocecal and anal sphincters.
  • Storage and evacuation of faeces.

The GI motility is based on contractions of the smooth muscular layers. At any given location, either circular (constriction and elongation of the tube) or longitudinal (enlargement and shortening of the tube) contractions can appear. However, when these 2 patterns are distributed along the tube in a spatially and temporally ordered manner, contractions result in a complex motility pattern, which is specific to each GI segment. As far as the origin of GI motility is concerned, non-neural and neural mechanisms may be distinguished.



Intrinsic and extrinsic control of digestive function.


Firstly, a non-neural mechanism based on a self-generated rhythmic fluctuation of the electrical potential of smooth muscular cells. These electrical oscillations called slow waves are generated within special pacemaker cells, called interstitial cells of Cajal. They are then transmitted to the muscles by gap junctions. Video-analysis shows that the active pacemaker areas appear along the intestine in a quasi-segmental manner and generate periodic contraction waves being propagated at relatively short distances [Bercik 2000].



Motility patterns in isolated arterially perfused rat intestine


Secondly, smooth muscular cells and Cajal cells are innervated by neurons located within the organs' wall. These neurons, which emigrated in the early embryogenesis from the central nervous system, constitute the so called enteric nervous system (ENS). ENS consists of sensory neurons, interneurons and motor neurons and is thus able to respond to many GI stimuli may they be mechanical, chemical, electrical or thermal. In summary, these reflexes may inhibit the motility (e.g., to allow absorption) or force it into powerful propulsive movements, translocating the luminal contents to important distances.

Finally, the ENS communicates with the spinal cord and brain by means of afferent and efferent nerves (sympathetic and parasympathetic). In this way, the central nervous system (CNS) is informed (unconscious perception) about the digestive state and may influence it in turn. For example, a stressful situation may result in a sudden increase of peristaltis (diarrhoea) or, on the contrary, a strong inhibition (constipation). Even though the basic digestive functions may work independently, the role of the CNS is important in the remote modulations and according to extra-personal (circadian cycle, seasons) and intra-personal (psychical, somatic) contexts.

References
P. Bercik, L. Bouley, P. Dutoit, A. L. Blum, P. Kucera, "Quantitative analysis of intestinal motor patterns: Spatiotemporal organization of Nonneural pacemaker sites in the rat ileum", Gastroenterology, Vol. 119, pp. 386-394, 2000.


Clinical Considerations

Digestive diseases represent probably the second major medical problem after cardiovascular diseases. It is clear that motility is one of the principal functions of the digestive system (Intro to GI Motility) and that without good motility all our digestive but also psychical condition will be altered. The motility disorders are of organic or functional origin and display numerous forms such as dyspepsia, gastroparesis, ileus, irritable bowel syndrome, diarrhoea, chronic constipation, etc.

The diagnosis of these pathologies is based on several recognized exploratory approaches. As there is no in vivo method to measure the neuronal or motor function directly, the clinical approaches are based namely on extracellular electromyography (e.g. electrogastrography), intraluminal manometry (perfusion catheters, pressure gauges, barostat) and imaging (x-rays, scintigraphy, CT scan, Nuclear Magnetic Resonance).

Each of these techniques have their own indications, advantages and disadvantages and is beyond the scope of this introduction to discuss them in detail. An excellent recent review on GI motility [Schuster 2002] confirms a very surprising fact: there is no simple technique allowing a description of the ultimate result of the motor activity, namely, the patterns and dynamics of the progression of luminal contents. Indeed, the continuity of luminal content displacement along the GI tract (GIT) is difficult to study. Manometry and electromyography contribute in characterizing the rhythmical phenomena and pressure gradients [Szurszewski 1969, Sarna 1985], they do not allow a description of luminal flow patterns. They are also mainly limited to proximal and distal segments. By principle, the imagery represents the most powerful approach to analyze luminal transport owing to the fact that certain characteristics of flow can result from the movements of the walls of the digestive tract [Christensen 1998]. However, on a larger time scale, this approach becomes very expensive and also heavy for the patient. Transit tests, scintigraphy or use of radio-labelled pellets are well-established and widely used techniques [Camilleri 1998], which provide general information concerning the luminal transport.

By using the available methods, phenomena such as gastric emptying, continuous [Nguyen 1995] or intermittent [Kerlin 1982] transport of chyme in the small intestinal and movements of colic content [Holzknecht 1909] have been documented. However, detailed information about the characteristics of movement of intraluminal contents during fasting and postprandial states is still much awaited.

References

M. Camilleri, W. L. Hasler, H. P. Parkmann, E. Quigley, E. Soffer, "Measurement of gastrointestinal motility in the GI laboratory", Gastroenterology, Vol. 115, pp. 747-762, 1998.

J. Christensen, "Intestinal motor physiology", in M. Feldman, B. F. Scharschmidt, M. H. Sleisinger, "Sleisinger & Fordtran gastrointestinal and liver diseases", 6th edition, Vol. 2, pp. 1437-1450, WB Sauders Company, 1998.

G. Holzknecht, "Peristaltik des Colon", Muench Med Wochensch, Vol. LVI, pp. 2401-2403, 1909. (in German).

P. Kerlin, A. Zinsmeister, S. Philips, "Relationship of motility to flow contents in the human small intestine", Gastroenterology, Vol. 82, pp. 701-706, 1982.

H. N. Nguyen, J. Silny, S. Wueller, H. U. Marschall, G. Rau, S. Matern, "Chyme transport patterns in human duodenum, determined by multiple intraluminal impedancometry", Am J Physiol, Vol. 268, pp. G700-708, 1995.

S. K. Sarna, "Cyclic motor activity; migrating motor complex", Gastroenterology, Vol. 89, pp. 894-913, 1985.

M. M. Schuster, M. D. Crowell, K. L. Koch, "Schuster atlas of gastrointestinal motility in health and disease", 2nd edition, BC Decker Inc., Hamilton, London, 2002.


Magnetic Tracer (MT)

More recently, measurements with magnetic tracers have resumed mainly to study intragastric movements and gastric emptying. Since 1992, Miranda, Baffa et al., have used an AC (10kHz) bio-susceptometer for this purpose [Miranda 1992]. In addition to the gastric emptying rate, the rhythmic gastric contractions are also visible thanks to the strong dependence of the signals on the distance (proportionally to the distance to the power -6). One paper has also compared the orocecal transit time (OCTT) measured by the magnetic method and by the breath H2 output, noting a close similarity between the two methods [Baffa 1995a]. Recently, they have also studied the feasibility of obtaining an image of the distribution of the tracer by scanning the area over the sample with the susceptometer [Moreira 2000].

Another option is to magnetize a ferromagnetic powder, once it has been ingested (e.g. within a meal), with an external homogeneous field, and then to measure the remanent magnetic field. This was already mentioned as a possible solution by Frei et al. [1970]. Baffa [1995b], Caneiro [1999] and Forsman [1998b, 2000] use fluxgate magnetometers to estimate the strength of the remanent field. The exposed particles are aligned and exhibit a permanent magnetization. After switching off the external field, the mixing movements in the GIT will result in a misalignment of the magnetic moments, and, hence, in a decay of the measured magnetic field. Once again, most of the publications deal with gastric emptying, but lately the gastrocolic reflex was also examined [Ferreira 2002].


Magnetic Marker (MM)

We will now discuss the cases where a permanent magnet is used as a solid marker.
Spelman, Prakash, et al. [Spelman 1994, Prakash 1996, 1999b, Heitkemper 2002], at the University of Washington, resumed the first study from Wenger with an ingested magnet and a single magnetometer. They measured contractions in stomach, small intestine and large intestine, and correlated the magnetic signal with pressure sensors in the stomach. The marker is a cylindrical Teflon coated stir-bar magnet, with a diameter of 7.8 mm, a length of 25.0 mm, and a magnetic moment of 0.18 Am2. The sensor is an electronic compass, a fluxgate sensor with two orthogonal sensing coils. The sampling rate is set to 1 Hz. With this method, only the intrinsic frequencies of the GI motility are measured, but neither the intensity of the contraction nor the position of the marker can be calculated.

Of course, much more information would be obtained by retrieving the position of the marker. For this purpose the magnetic field generated by the marker has to be measured at different locations.

The first approach is to scan different places with one sensor, with the main disadvantage of time consumption and errors due to movements of the marker during the scan. Basile et al. [1992] used a single-channel SQUID 2nd order gradiometer, and a magnetized steel sphere (Ø2 mm, in a 3x6 mm tube, relative density of 1.9 g/cm3), to measure the oro-anal segmental TT with one scan taken every hour. Forsman et al. [1995b] implemented the same setup with a fluxgate gradiometer. The time needed for a scan is 25 s and the volunteer is lying on a pneumatically driven bed, the small ingested magnet has a magnetization of 1 mAm2 (Ø1.5 mm, 4 mm with the coating, 1.4 g/cm3). Finally, Andrä et al. [1997, 2000, 2001], propose a more complicated system not (yet) tested in vivo. Their system includes external coils to repeatedly align a spherical permanent magnet, which is free to rotate in a "bearing liquid" inside the capsule. The magnet has a magnetization of 20 mAm2 (3.5 mm in diameter, in a capsule with a diameter of 7 mm, a length of 20 mm, and a final density of 1.2 g/cm3). In order to eliminate slowly changing background fields, the measuring procedure comprises in reversing the orientation of the marker and subsequently taking the difference of the measured values. The 3 components of the field at one point are measured with a commercial integrated magnetoresistive sensor (Honeywell). Since the orientation of the magnet is known, the 3 measured values are enough to recalculate the position. Note that the external coils need to be motorized to follow the position of the capsule to insure a constant orientation of the marker. The temporal resolution is at best 1 Hz, and the spatial resolution is less than 10 mm within a test volume of 40x40x15 cm3.

To solve the problem of temporal resolution and inaccuracy due to the rotation of the marker during the scanning procedure, the next step is to use an array of sensors.
This has been done for the first time, by Weitschies et al., with multi-channels SQUIDs (up to 63-channels), similar to the established tool used for magnetoencephalography and magnetocardiography, leading to a very accurate but expensive tool operating in an environment shielded against external magnetic fields [Weitschies 1990, 1994, 1997, 1999, Osmanoglou 2002]. A typical temporal resolution of 250 Hz and a spatial resolution within a range of a few millimeters is achieved with a magnetic moment of 100 nAm2. The main interest is, for the pharmaceutical sciences, to investigate the behavior (e.g. transit time) of a solid oral dosage. This is the reason why the latest studies deal with disintegrating capsules [Weitschies 2001, Hartmann 2002]. The complexity and the cost of the infrastructure prevent the use of this system for a lot of applications, especially if long term measurements are necessary. Having said this, some interesting recordings have been published concerning the whole GIT: esophagal, gastric and duodenal transit of a non-disintegrating capsule [Weitschies 1999], and even a mass movement of the marker through the transverse colon [Weitschies 2000].

One of their latest papers (Weitschies et al., in collaboration with Universität Jena, Germany) [Romanus 2002], brings together the works described above. Although the application does not concern the GIT, the experiment is interesting: a SQUID sensor, operating in an unshielded environment, detects the magnetic relaxation of magnetic nanoparticles in mice after intravenous injection.

Prakash et al. [1997] (see in vivo measurements with a single sensor, at the beginning of this section), have tested, but only in vitro, an array of 8 fluxgate magnetometers, in a shielded booth (see above for magnet specification). In parallel, they published a nice solution for solving the equations to localize a single dipole, with some constraints on the positioning of the sensors [Prakash 1999a].

For this review of minimally-invasive solid markers for the GIT to be exhaustive, we must mention the work of Ewe et al. [1989, 1991, 1995] who used a portable metal detector to track a hollow metallic sphere (Ø6 mm, 1.4 g/cm3). The localization accuracy is 0.5 to 1 cm for a detection distance between 2 to 12 cm. An interesting result is the good correlation between the transit time of the metallic marker and the Hinton radio-opaque markers method.


Catheter Tracking

Magnetic markers are also used to track the position of catheters, especially in cardiology. The advantage is that clinicians may locate and navigate their device without fluoroscopy (or at least with less x-rays), and without cumbersome systems, in order to move from an expensive operating room to less costly procedure rooms. Moreover, fluoroscopy is only a two-dimensional imaging system, whereas the three dimensions can be retrieved with a magnetic marker.

In the previous section, an ingested maker and external sensors were used, whereas here, different solutions for the tracking of catheters have been developed. Indeed, an electrical connection to the outside, through the catheter, is possible. In this case, the magnetic marker, a magnetic dipole in fact, may be produced by a coil driven by an alternative current. Furthermore, the sensor(s) may be located in the catheter, while the magnetic source remains outside. Almost all the imaginable strategies have been realized, and different products exist on the market. The systems with emitting coils have two obvious advantages: Firstly, the information is modulated at high frequencies, thus the large quasi-DC noise due to the inhomogeneous magnetic field of the earth is no longer a problem. Secondly, many markers may be tracked simultaneously by multiplexing the signals, in time or in frequency. On the other hand, the ease with which one can adapt a permanent magnet to a standard device and the absence of power supply for the magnetic marker, leading to less expensive devices, are good assets for solutions based on permanent magnets.

The next paragraphs list the existing devices based either on a permanent or on a modulated magnetic dipole, to find the position of an indwelling device. Note that other non-invasive techniques, on which this review will not focus, are also used, such as ultrasound (measuring distances by measuring the time between two crystals) [Meyer 1997, Vilkomerson 1992, 1997, Vesely 1998], electrical impedance (measuring distances by measuring the impedance between two electrodes) [Wittkampf 1997, 1999, Wrublewski 1999], or radiofrequency (measuring distances by measuring the power of the signal) [Iddan 1997]; when at least three distances have been measured, the three-dimensional position can be recalculated by triangulation. These later solutions are not very accurate, due largely to the inhomogeneities of the medium, the most accurate systems being based on coils. This emphasizes another advantage of the magnetic dipole solution: the human body can be considered as a homogeneous medium for the magnetic field (same permeability as the air), at least up to a certain frequency (100 kHz, according to our own measurement).

Permanent magnetic dipole

Lucent Medical System Inc. (ZortranTM), are the only ones who opted for a permanent magnet [Golden 1995, Somogyi 1999, Tobin 2000, Beck 2001]. Their work has been developed together with the University of Washington (see above). Three cylindrical magnets are needed (total length 16.8 mm, Ø1.8 mm). The hand-held detector utilizes four integrated magnetoresistive magnetic field sensors (Honeywell). The position of the tube tip is displayed on a transparent screen 6x4 cm. Very little detailed information about the accuracy of the positioning system are given. A new prototype with 16 sensors has also been tested in nasogastric tube placements.

Another firm, Teslev Scientific Inc. (project Cathfinder, funded by SIMS Deltec), tried to achieve the same goal with a permanent magnet. They stopped their project in 1994. SIMS Deltec has now developed another system based on coils (see below). The idea was to use a cylindrical magnet, 0.64 mm in diameter and 7.6 mm in length, together with eight induction type sensors (inductance changes of a ferrite core coil in a resonant circuit) not all in the same plane. Standard fluxgate sensors were not suitable due to their high cost.

High frequency signal emitted by a coil

When a modulated signal is used, the background magnetic field of the earth does not interfere with the measurement, therefore a small handheld detector can be moved over the patient's skin to track the marker. Cath-finderTM from Deltec [Strohl 1990, Starkhammar 1990, 1996] and CathTrackTM [Strohl 1995] are two inexpensive handheld tracking systems for catheters. They use a small coil in the catheter as a sensor, and external emitting coils. To keep the system simple, the position of the marker can be calculated only if the locator is centered above the marker and perpendicular to it, leaving only two-degrees-of-freedom (depth and orientation in the horizontal plane). With a detection coil of 1 mm in diameter, or even less, the detection depth is 18 cm and the accuracy approximately 1 cm.

Working on the same principle, more expensive systems are more accurate and determine all six-degrees-of-freedom of the tip of the catheter (the three translations and the three rotations). Actually, many markers are used, and thus not only the tip but all the catheter can be visualized. CARTOTM and NOGATM are the reference systems [Ben-Haim 1996, Acker 1998]. Developed by Biosense Webster, they are used in cardiology, and have a resolution better than 1 mm, at a distance of 30 cm. Another device, developed at St Mark's Hospital in London [Bladen 1993, Saunders 1995, Kitchen 1999], is used mainly for colonoscopy. The catheter contains 12 to 15 sensor coils 2 mm wide and spaced at 12 cm intervals.

With external emitting coils, yet other sensors have been used. ARTMA, for endonasal surgery, uses integrated Hall sensors attached to the head, as external landmarks, and to surgical instruments [Gunkel 1995]. A navigation system for endovascular interventions, still in prototype form, at the Delft University of Technology [Tanase 2003], is based on integrated Hall or magnetoresistive sensors. This imaging system, attached to a fluoroscope, aims to reduce the x ray dose needed for an intervention. The advantage of the use of these sensors over coils, can certainly be proven at low frequency and small size.

Finally, systems with emitting coils in the catheter can also be found. A handheld "Cathlocator" at the Royal Adelaide Hospital [Williams 1996] has been tested (conflicting data about the accuracy was given). The idea was also patented in 1991, for a more complex system to be used together with x-rays, by a leader in medical imaging [Darrow 1993]. Note that when the emitting coil is external, the field may be stronger and the field gradient in space can be kept more constant. Otherwise, with a small emitting coil, the field decreases very rapidly with distance, which requires a larger dynamic range.


Other Applications

A few other systems, developed for other applications, work on the same principles as the ones described in the previous section. The main difference is that the size of the marker can be larger. Ascension Technology propose a versatile product Flock of BirdsTM [www.ascension-tech.com], with an accuracy of 0.5 mm and 0.1° at 30 cm, based on a pulsed dc magnetic field.

Magnets together with Hall sensors are widely used in one-degree-of-freedom applications, mostly angular but also linear positioning systems [Demierre 2003]. However, the detection range is, in these examples, very limited. Maenaka et al. [1996] describe an application with three-degrees-of-freedom.


Summary

We have seen that small magnets and ferromagnetic powders have already been used to assess the gastrointestinal motility. Yet, these method are, for the moment, limited. Most of the measurements concern stomach contractions and emptying. If we consider the rest of the GIT, almost no study exists. The explanation is that the existing techniques are cumbersome, very expensive, and most of the time need a shielded environment, limiting the number and duration of the recordings. The remaining less expensive systems, are based on a single sensor (eventually two). Consequently, they allow only the recording of the intrinsic rhythmic activity, which is not very useful if the position of the marker is not known. The devices using a single mobile sensor to make a mapping of the magnetic field, strongly limit the time accuracy, and also the spatial accuracy due to movements of the marker during the scan; moreover, we end up with a cumbersome apparatus. For all these methods, the major intrinsic constraint is the magnetic field of the earth.

An interesting alternative is to use a modulated electromagnetic signal (AC, pulsed, etc.) instead of a DC field. We have seen many advantages, such as better spatial accuracy, simultaneous tracking of several markers, no limitations due to the earth magnetic field. Unfortunately, a connection to the outside is always needed.


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References

D. E. Acker, patent US5833608, "Magnetic determination of position and orientation", Applicant: Biosense Inc., 1998-11-10.

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Book

"Magnetism in Medicine", eds. W. Andrä, H. Novak (University of Jena), Wiley-VCH, 1998.