The present invention relates to basic developmental neuroscience, portable medical obstetric procedures and devices, and more particularly to the non-invasive monitoring of the brain physiology states of a developing human embryo inside the mother's womb.
Many of the developmental disorders of childhood—cerebral palsy, epilepsy, cognitive impairment from prematurity and autism—appear to result from an interaction of complex genetic traits and environmental factors. Likewise, adult psychiatric diseases may have their origins in impaired early, even fetal development, as proposed for schizophrenia [1]. Despite major efforts, these prevalent, debilitating, life-long disorders remain biologically unexplained. Based on animal studies, the development of most types of epilepsy, cerebral palsy, autism and schizophrenia is suggested to link to neonatal seizures and various disturbances during embryogenesis. The intimate connection between mother, fetus and placenta, the vast array of neuroactive hormones expressed in the mother or in the placenta, or a variety of other environmental factors (injuries, drug treatments, immune responses, infections, hypoxic stress) make the targets when investigating fetal environmental disruptions that can affect the brain.
Perhaps one of the most important and challenging neuroscience research tasks would be to study the role of early brain activity in developmental plasticity and in the activity-dependent formation of neural circuits. It is evident that before birth, the immature brain expresses primitive, self-balancing rhythmic activity—with no complex excitatory and inhibitory synapses—in order to protect the developing brain from uncoordinated network activities or hyperexcitation. This early electrographic pattern was recorded in preterm human infants and newborn animals during sleep, immobility or feeding behavior and contains long silence periods. Although it is poor in information content, and it is not necessarily associated with any specific information—e.g. presence in the retina before eye opening—, but still, it is indispensable to turn on the machine and ignite the network [2].
In previous human studies (for review see [3]) it was noted that the cortical EEG (electroencephalogram) recorded in neonates during the second half of gestation is organized in intermittent bursts that are separated by periods of virtually complete suppression of activity that could last for minutes. With maturation, suppression of activity between the bursts becomes less pronounced. At full-term, some discontinuity is still evident. At mid-gestation, the activity is dominated by delta waves of 0.3-2.0 Hz. By the seventh month of gestation, slow oscillations are intermixed with rapid rhythms. Each event of rapid activity consists of 8-25 Hz spindle-like, rhythmic activity superimposed on 0.3-1.5 Hz delta waves. These rhythms (referred as “delta brushes”) are predominantly expressed in central areas before 28 weeks, and are then recorded in central, temporal and occipital areas from 28 weeks to near term. Presence of delta brushes in EEG from preterm infants serves as a criterion of normal development, whereas their absence is indicative of brain pathology and poor prognosis. In addition to delta brushes, several other patterns have been described in premature neonates.
In most cases, it is already too late after birth to permanently reverse the poor neurological outcomes, as they are being developed during embryogenesis due to microenvironmental alterations, which may change the process of neuronal migration and result in brain malformations or the establishment of incorrect or defective synaptic connections. Even though these specific, immature rhythmic activity patterns could be perfect indicators to identify each stage of the healthy functional brain development, it is very difficult to capture them due to lack of continuity or the movements of the fetus. Interestingly in the adult brain, focused ultrasound stimulation has been shown to both enhance and suppress spontaneous or electrically evoked field potentials; depending on its mode of operation (8-14). Therefore, non-invasive constant-wave (CW) and pulsed-wave Doppler (PW) ultrasound stimulation are powerful tools for generating fetal brain potentials, and use them for diagnostic purposes.
Recording of EEG signals is generally known in the medical arts. Use of ultrasound to display a fetus or to measure cerebral circulation by using the transcranial Doppler method is also generally known in the medical arts. Further, recording of fetal brain wave signals is known in the prior art, for example in U.S. Patent No. 20020193670, U.S. Patent No. 20100274145, U.S. Pat. No. 6,556,861 to Prichep, and in U.S. Pat. No. 7,016,722 to Prichep. The entire disclosures of these patents are expressly referred to and incorporated herein by reference thereto.
A flowchart of the device of U.S. Pat. No. 6,556,861 is shown herein as
It is a problem in the prior art to detect signs of epilepsy or other brain injuries or disorders in a developing fetus, as in most cases these are not correlated with responses to auditory stimuli. There is accordingly a need in the prior art for a non-invasive, safe brain stimulator that induces brain activity reproducibly, in different stages of the brain development.
It is a further problem and need in the prior art to provide a portable fetal-EEG recording device that is extremely sensitive, detecting potentials of even below 1-2 microvolts, capable of detecting and recording signals over an extended period of time, and perform the steps of analyzing the recorded signals for signs of developmental brain disorders in the developing fetus.
In the present invention, the brain activity of the fetus is non-invasively induced by exposure to a series of constant-wave and/or pulsed-wave ultrasound irradiation treatment; and detected and analyzed in a portable fetal-EEG recording device. This is a procedure performed for an extended period of time using sensitive but comfortable, lightweight equipment (preferably a hand-held device). Recording fetal-EEG signals is of great importance, as these can serve as indicators for certain unhealthy conditions or environmental factors (e.g. altered maternal hormone levels, stress, drug treatment, etc.) that may risk the normal brain development of the fetus. The identification and exclusion of such factors and conditions during embryogenesis may help to avoid the development and progression of several neural disorders that are already untreatable after birth.
One or a grid of detecting sensor electrodes is removably attached to the abdominal skin of the pregnant woman, in close proximity to the head of the fetus. The electrical connectivity between the sensor and the abdominal skin can be improved by using an adhesive gel enriched with electrolytes. The visualization of the fetus can be performed using the “augmented reality” smartphone and tablet tool, for the user's convenience.
The sensor electrode connected to the fetal-EEG recording device is capable of detecting microvolt level fetal brain activity patterns, which can be recorded using similar low-noise ( 1/28l microvolt) amplification and optional bandpass filtering methods as known to be used for neurophysiology research purposes.
In order to better understand the measured data, an ultrasound probe (operated at 3.5-5 MHz frequency) can be connected to the “portable fetal-EEG recording device”, and the position of the fetus can be real-time monitored on the display of the device, in order to avoid the misinterpretation of data caused by movement of the fetus subsequent to the application of the electrodes resulting in incorrect readings, and which could therefore cause certain movement artifacts. The same or another ultrasound probe (operated at 2-8 MHz) connected to the same device may serve as a Doppler heart monitor for the fetus. When placing one of the sensor electrodes in close proximity to the heart of the fetus, it may serve as an ECG electrode. The simultaneous use of the Doppler ultrasound probe and ECG electrode may help the user make sure that the operation mode of the device is correct and both of the methods work properly. Monitoring the fetal heart frequency may provide additional information about the current activity of the fetus (e.g. allow the determination of its awake and sleep states).
Further computational (software) filtration and analysis of all electrical recordings can be performed in accordance with those known from conventional routine clinical EEG-recording methods. This may help in identifying electrical artifacts, as well as noise derived from the heart or muscles of the fetus or mother (e.g. fetal eye-movements). The portable fetal-EEG recording device provides an output for an Internet connection, and therefore allows all of the recorded ultrasound images and videos, raw and analyzed EEG recordings to be broadcasted in real-time, or later shared with the obstetrician/gynecologist, pediatric neurologist or any friends or family members of the user.
The present invention, discussed in detail hereunder, relates to device and a method for using the device to induce fetal EEG signals by exposing the fetus to constant-wave or pulsed-wave brain stimulation, and to detect signs of normal and abnormal embryonic development. The device of the present invention provides an Internet connection, and it serves as an apparatus for performing and analyzing fetal-EEG and ECG recordings, ultrasound imaging and Doppler heartbeat detection.
Technologies which can be used in the present invention and which are commercially known and available for use, are known in the art and samples of these are as follows. The type of electrodes and method of use feasible for the present invention are known, for example in U.S. Pat. No. 6,162,101 issued on Sep. 3, 1998 to Fisher and Iversen; U.S. Pat. No. 6,024,702 issued on Feb. 3, 1997 to Iversen; U.S. Pat. No. 5,961,909 issued on Sep. 3, 1997 to Iverson; U.S. Pat. No. 5,902,236 issued on Sep. 3, 1997 to Iversen; as well as in other patent documents. The possibility of recording electrical brain and heart activity of a fetus in utero has also been published [4, 5].
An abdominal ultrasound unit capable of performing advanced ultrasound measurements for obstetrical use is known and commercially available. Portable scalp-EEG recording instruments and portable Doppler devices capable of determining fetal cerebral circulation and heart rate have been commonly used and commercially available for a long time.
The ultrasound module 140 is an abdominal probe operated at 3.5-5 MHz in order to determine the position of the fetus, and is operated by a special imaging software capable of recording high-resolution videos and images, and can be any commercially available ultrasound device compatible with the present invention. It is also capable of Doppler fetal heartbeat and cerebral blood flow detection (operated at a range of 2-8 MHz). The fetal EEG detecting device 160 can be that shown in the above-mentioned prior art excluding the stimulator unit (
In
The portable device 100 combined with the fetal EEG detecting device 160 and the ultrasound module 140, constitutes a small, compact and portable EEG monitoring system, which can make it possible for physicians to follow the maturation of fetal brain activity in a real-time manner during high-risk pregnancies, maternal infections, hypoxia, stress, or other conditions. Qualitative and quantitative data evaluation methods described in the prior art and studies [6, 7] can be applied to determine the functional developmental status of the fetus. The raw and analyzed ultrasound-induced and spontaneous fetal EEG data can be compared to reference spontaneous fetal EEG data from a control group to determine one of an abnormality and normality of the brain activity and heart rate of the fetus being monitored. However, in the lack of a proper instrument capable of inducing and detecting human fetal brain waves in utero, yet little is known about the brain activity of unborn human fetuses. Therefore this present invention will be a useful tool for scientific research purposes, in order to better address and understand the functional brain development process of human embryos.
The small, portable EEG-device 100 of the present invention is capable of recording data all day long, causing no inconvenience in continuing the usual activities of the user's everyday life. The registered waves can be analyzed either real-time, or later in the office of a gynecologist or pediatric neurologist. This technology can be applied in construction of the portable device 100 of the present invention, which is thereby made as a small, user-friendly and affordable fetal-EEG device specifically designed for clinical purposes, which will be ideal for everyday usage and reliable diagnostics.
The steps include (step 42) providing at least one biosensor electrode and a portable ultrasound device, or—where the biosensor electrode is replaced by an electrode grid or sheet—providing an electrode grid or sheet and a portable ultrasound device, then determining the position of the fetus (step 44) by ultrasound imaging. Step 44 includes attaching the sensor or electrode sheet having the EEG electrodes to the surface of the abdomen right above the head and/or heart of the fetus (e.g., in close proximity to the head and/or heart of the fetus).
Following the above steps 42 and 44, further providing (step 46) a portable fetal-EEG recording device (such as the portable device 100 described hereinabove with reference to
As noted above, the above steps 42, 44 and 46 are followed by the fetal ultrasound-stimulation (step 48). At step 48, fetal brain activity is evoked by directing the constant-wave or pulsed-wave ultrasound probe (2-8 MHz, 1 Hz-2 kHz pulse-repetition frequency in case if pulsed stimulation is applied) to the head of the fetus. The duration of the exposure may vary, but not exceed 30 minutes to avoid any disturbances in nerve cell migration. In some cases, even a combination of stimuli can be delivered to the fetal brain, and data of each response should be collected for analysis.
Following the above steps 42, 44, 46, 48, and 50, the method of the present invention includes further analyzing the result of step 50 (step 52). The purpose of step 52 is to integrate and perform further software corrections on the data, and to analyze the EEG signals to determine the health and developmental stage of the fetus. More specifically, in step 52 the recorded fetal-EEG signals are further analyzed for signs of neural network activity patterns indicative of brain disorders, and such analysis can include the steps of digitizing the signals, filtering the signals from all non-specific noise, amplifying the signals, integrating the signals, and storing the signals in a relatively small portable storage medium and/or an internet connection.
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The portable device 100A includes a memory device 102 which can, for example, be a high capacity SD card or other type of memory device. The portable device 100A also includes a controller 104 which can, for example, be a computer or computer chip, a smartphone, smart touchpad device having computer techology, etc. Controllers are well known in the electronics arts, and have many types of variations and features; the present invention is not limited to any specific type of controller.
The portable device 100A also includes an analyzing function means 106 such as local software used by the controller 104, or else supplies data to a remotely based computer for software analysis using the internet or cell phone technology.
The portable device 100A provides outputs, which can include fetal heart rate 200, noise and artifact filtered stimulated or spontaneous EEG, ECG and/or integrated EEG signals 202, and an indication of fetal developmental abnormalities such as intrauterine seizures or other abnormal brain activity 204. These signals can be obtained using the software, and the detection and determination of normal and abnormal human fetal brain activity is an evolving field. It is anticipated that future discoveries may be made in this evolving field, and it is contemplated that the results of such discoveries can be used in the indication of abnormal fetal development 204.
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Lastly, the optional step 270 is the step of using the ultrasound device 180 to take pictures and/or videos and/or sound files of the baby to send to relatives, friends, and/or medical professionals, and/or to provide a continuous stream of video for webcam or videoconferencing purposes.
The present invention in contemplated as further including additional features. One such additional feature is a function of the imaging software that transforms the ultrasound images in order to make the electrode positioning easier. Such image transforming software would be within the ambit of any one having skill in the art of medical ultrasound imaging software. Originally, fetal ultrasound generates images of 45-90 degrees, kind of like virtual “sections”—these need to be rotated and projected to the abdominal plane. The software is also contemplated to utilize automatic image processing (e.g. head-shape recognition) to calculate and determine the proper positions where the electrodes need to be placed. This too would be within the ambit of skill of any one having skill in the art of medical ultrasound imaging software.
Another feature relates to future disease diagnosis. Typically, maternal blood is collected during pregnancy, in addition to umbilical chord blood and placenta samples during delivery. Comparison of the concentrations certain chemical compounds (e.g. hormones, enzymes, immune proteins) in certain patient groups in correlation with the fetal-EEG patters may propose novel prenatal therapies. For example, if certain abnormal fetal brain wave patterns can be correlated to high maternal blood component levels, then they may receive injections during pregnancy to prevent their fetus from developing certain neurological diseases.
The invention being thus described, it will be evident that the same may be varied in many ways. Such variations are not to be regarded as a departure from the spirit and scope of the invention and all such modifications are intended to be included within the scope of the claims.
This application is a continuation-in-part of U.S. Ser. No. 13/396,233 in the name of the inventor Marianna Kiraly filed on Feb. 14, 2012, now pending, which in turn claims the priority of Provisional Patent Application Ser. No. 61/627,626, filed on Oct. 14, 2011, in the name of the inventor Marianna Kiraly.
Number | Date | Country | |
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Parent | 13396233 | Feb 2012 | US |
Child | 14068951 | US |