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Auditory evoked responses: A tool to assess the fetal neurological activity
Applied Acoustics 68 (2007) 270–280 www.elsevier.com/locate/apacoust
Auditory evoked responses: A tool to assess the fetal neurological activity Hari Eswaran a
a,*
, Rossitza Draganova a, Hubert Preissl
a,b
SARA Research Center, Department of Obstertrics and Gynecology, University of Arkansas for Medical Sciences, 4301 W Markham St. Slot 518, Little Rock, AR 72205, United States b MEG Center, University of Tuebingen, Tuebingen, Germany Received 30 September 2005; received in revised form 7 March 2006; accepted 8 March 2006 Available online 19 May 2006
Abstract An intact auditory system at birth is requisite for the successful accomplishment of many developmental skills. Evoked responses to auditory stimuli have been used as a sensitive test to determine the functional status of the adult and neonatal brain. It has been established that fetuses can hear in utero and respond to external acoustic stimuli. We present an overview of the transmission of sound through the maternal abdomen to the fetal ear and the recordings of an auditory evoked response obtained from the fetus using a non-invasive magnetoencephalography technique. The investigation of cortical activity of the fetus in response to auditory stimulation can help understand and track the neurological development of the fetus. Ó 2006 Elsevier Ltd. All rights reserved. Keywords: Fetus; Auditory; In utero sound transmission; Evoked response; Magnetoencephlography
1. Introduction The fact that soon after birth the newborn is capable of perceiving and discriminating different sounds points to the fact that development occurs in the fetal life itself. Morphological structures of the peripheral auditory system essential to hearing are developed in the fetus by the 20th week of gestation [1]. It is widely accepted that sound transmits *
Corresponding author. Tel.: +1 501 686 5847; fax: +1 501 603 1544. E-mail address: [email protected] (H. Eswaran).
0003-682X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.apacoust.2006.03.004
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through the maternal abdomen and can reach the fetus [2,3]. Behavioral studies have shown that auditory and vibroacoustic sound stimulation leads to changes in fetal behavior determined by fetal movement, fetal eye movements and fetal heart rate, or heart rate variability changes [4,5]. But with advances in non-invasive technologies, it is now possible to make direct fetal brain response measurements to auditory stimuli. In this article, we provide an overview of the sound transmission through maternal abdomen and how sound can be applied to assess the neurological status of the fetus. 2. Intrauterine sound environment and external sound transmission Inside the uterus, the fetal auditory environment consists of internal noises (maternalintestinal, cardiovascular, respiratory and placental vascular sounds) and external noises. Many researchers [6–8] have tried to measure the intrauterine sound levels from both internal and external sound sources. The sound level due to internal sources has been measured to reach as high as 90 dB SPL (Ref. [20] lPa) for low frequencies [3]. These high sound levels are predominantly at low frequencies (<32 Hz) to which the human auditory system does not show much response, hence the basal noises do not mask the exterior sounds. Early measurements of sound intensity reaching the uterus from external sources were made using a microphone encased in rubber placed near the cervix. Bench [9] reported the fetus was insulated from external sounds and measured a sound attenuation of 19 dB at 200 Hz and up to 48 dB at 4000 Hz in a 37 week pregnant woman. Grimwade [10], using a similar procedure, reported attenuation loss ranging from 39 dB at 500 Hz to 85 dB at 5000 Hz. Also, Walker [11] reported attenuation values ranging from 30 to 90 dB using microphones. Later, advanced technology and the use of hydrophones showed that the attenuation values, especially at higher frequencies, were overestimated using microphones. The impedance mismatch between the microphone, rubber and fluid interface cast doubts on the reported microphone based attenuation values. The hydrophone provides a better impedance match in a fluid environment as compared to a microphone. Using hydrophones, Querleu [3] reported the average attenuation due to external sounds was around 30 dB. This value is closer to the number reported by Armitage [12] and Gerhardt [8] on sheep. External stimulation of the fetus is only possible if an effective transmission of sound through the maternal abdomen is guaranteed. Animal and modeling studies have shown that frequencies above 1000 Hz are strongly attenuated by the abdomen, and frequencies below this cut-off frequency are transmitted with an attenuation of around 30 dB in loudness [2]. 3. Perception of and response to auditory stimuli by the fetus Hepper and Shahidullah [5] reported as early as the 19th week of gestation fetuses showed motor responses to pure tone stimuli in the low frequency range of human hearing (500 Hz). They demonstrated that by the 27th week of gestational age, 96% of the fetuses in their study responded to 250 and 500 Hz tones. Furthermore, 100% of the fetuses responded to tones with frequencies of 1000 and 3000 Hz at 33 and 35 weeks of gestational age, respectively.
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Other studies indicate that fetuses are able to discern musical notes, syllables and voices [13]. It has also been established that the fetus has a basic capacity for learning and memory. Van Heteren et al. [14] used fetal habituation to repeated vibroacoustic stimulation to assess fetal memory and reported that fetuses exhibited short-term memory of at least 10 min, and a long-term memory of at least 24 h. The human capacity to learn and understand language is dependent on the cognitive function of sound discrimination, which seems to be functional in the fetus. It is known that newborns can demonstrate this cognitive ability in the first hours after birth [15]. However, the question of when the process of sound discrimination actually begins in the human fetus remains unclear. This kind of learning and auditory perception is further substantiated by the investigation of newborns, which show a preference for their mother’s voice shortly after birth [16]. The fact that the fetus can hear in utero and respond to acoustic stimuli by characteristic behavioral and heart signal changes led to the supposition that this cause and effect could be used as an indicator to monitor the progress of the functional development of the brain. 4. Auditory evoked response and neurological assessment The auditory evoked response is the neuroelectric response of the auditory system in the brainstem, midbrain, and the cortex to sound stimulation. A large number of components have been described in the human averaged auditory evoked potential. These components can be divided into brainstem (first 10 ms), middle latency (40 ms) and long latency (50– 250 ms). Several authors have reviewed the utility of evoked responses in predicting neurological outcome in neonates [17–19]. It is generally agreed that auditory evoked responses (AER) are useful in diagnosing hearing loss [20] and are associated with neuromotor impairment, though they produce a high rate of false negative results. Some of these negative results may be a consequence of the sensitivity of evoked responses to time elapsed following injury [21] arguing for the earliest possible measurements (e.g., fetus in utero). Tharp associated fetal brain injury with the development of abnormal evoked response in the newborn [22]. He also suggested that hydrocephalus can produce severe changes in the brainstem auditory evoked response [23,24]. Several studies show that the auditory evoked response is a useful predictor of brain death [25,26]. 5. Non-invasive method for fetal neurological assessment With the advent of fetal magnetoencephalography (fMEG) it is now possible to perform auditory evoked response measurements from the fetus in a non-invasive fashion. This technology allows the non-invasive recording of the magnetic field corresponding to any electric current produced in the body. Electrophysiological phenomena are characterized by the flow of ion currents within the body. These currents are detectable by measuring potentials inside or on the surface of the body. The physics of electromagnetism predicts the flow of current will also result in a magnetic field. Consequently, common clinical electrophysiological measures such as the electrocardiogram (ECG) and electroencephalogram (EEG) have magnetic homologues: the magnetocardiogram (MCG) and the magnetoencephalogram (MEG), respectively. Magnetic signals have been detected from nearly all electrophysiologically active organs of the body. However, unlike bioelectric signals, biomagnetic signals are detectable outside the boundary of the skin without making electrical contact with the body [27].
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6. Direct measurement of fetal brain activity in response to auditory stimulus The approach of recording magnetic signals (MEG) from the human adult brain is at present a well established technique. With the advantage of this being a non-invasive procedure, this technique over the past few years has been applied to study the fetal brain. Fetal evoked magnetic brain responses to auditory stimuli between 27 and 34 weeks have been reported in several MEG studies [28–34]. In order to obtain auditory evoked magnetic responses, various stimulation protocols were examined. These protocols were adapted from standard procedures used in infant and adult studies. In the following section, we describe the general recording procedure, the stimulus delivery mechanism and the various stimulation protocols that were applied specifically to our study. Although there are variations in protocols and signal processing approaches between various research groups performing fetal auditory evoked studies, the overall goals and recording procedures are similar. 6.1. General recording procedure All the studies performed on squid array for reproductive assessment (SARA) were approved by the University of Arkansas for Medical Sciences – Human Research Advisory Committee, and informed written consent was obtained from all the subjects. The routine recording sessions range from 6 to 12 min in a continuous mode at a sampling rate of 312.5 Hz and a bandpass of dc to 100 Hz. The position and orientation of the mother’s abdomen, relative to the sensor array, are determined using three localization coils placed at fiduciary points on the mother’s right and left side and spine at the level of the umbilicus. These coils do not interfere with the MEG recordings. We also define the fetal head position as the patient sits down in front of the array using a portable ultrasound scanner. The ultrasound probe is placed on the surface of the maternal abdomen exactly over the fetal head. A fourth localization coil is then attached to the maternal abdomen at that Table 1 Fetal standard AER studies performed using SARA Studies
Auditory stimulus (tones)
Interstimulus interval (s)
Duration (ms)
1. Eswaran et al. [31] 2. Preissl et al. [35]
1 kHz 80% 500 Hz 20% 1 kHz 80% 500 Hz 20% 1 kHz 80% 500 Hz 20% 1 kHz 80% 500 Hz 20% 700 or 1 kHz
1–2 2
100 100
1
3. Eswaran et al. [34] 4. Eswaran et al. [36] 5. Holst et al. [37]
No. subjects (% AER detection)
Average latency (ms)
Average amplitude (fT)
4 (75%) 22 (63%)
175 220
38 24
100
10a (80%)
249
18
2
1
11b (62%)
264
30
2
500
18c (83%)
245
69
Summary of standard fetal AER studies performed using SARA system. a 51 independent sessions with short-term serial recordings at least 3 different days during 1 week of gestation. 80% of subjects detected at least once in short-term repeated trials. 50% when considering the ratio of successful detection to total number of recordings (24/51). b 34 independent sessions with recordings every 2 weeks starting at 28 weeks till delivery. c 62 independent sessions with recordings every 2 weeks starting at 28 weeks till delivery.
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point to provide additional positional information related to sensor coordinates. The ultrasound exam to evaluate fetal head position is repeated at the end of the study. 6.2. Standard auditory evoked studies The standard auditory stimulus used by fMEG researchers is a tone burst. A summary of studies performed by our group is shown in Table 1 [31,34–37]. The experimental protocols we have tested include the following parameters: frequency – 500 Hz to 1 kHz, duration – 100 ms to 1 s, interstimulus interval – 1–2 s and intensity (measured outside in the air) 100–120 dB. Our auditory stimulation device consists of a speaker placed outside a shielded room, attached to a 12 ft long piece of Tygon tubing (2 cm inner diameter) with the distal end of the tubing attached to an air-filled bag. This bag is secured with an elastic belt high up over the maternal abdomen being careful not to increase distance between the sensors and fetal head. The sound intensity was measured in the air, both
Fig. 1. (Top) Mother positioned on the SARA system with the auditory stimulus delivery system attached. (Bottom) A lay-out of the 151 sensor array spread across the maternal abdomen.
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at the air-filled bag (120 dB) and in the shielded room (100 dB). This means our sound system generates a focused and a diffused sound source (see Fig. 1). The general approach of most fetal AER studies is to search for an evoked component around 200 ms, which is interpreted as a delayed component corresponding to the adult N100. Various fMEG investigators (including our group) have recorded a peak AER amplitude ranging from approximately 30 to 175 fT and the latency of the primary response component from 125 to over 200 ms [28–37]. Table 1 shows the number of AER recordings performed along with stimulus parameters and the detection rate using the SARA system. Fig. 2 shows a representative response with 500 ms tone duration obtained from serial recordings of a fetus starting at 27 weeks until 37 weeks of gestation. 6.3. Sound discrimination studies Apart from the standard auditory evoked studies, more recently, we have initiated protocols to assess the discriminative capability of the fetus. In the so-called oddball paradigm, sounds are presented in a sequence of a standard (frequent) sound intermixed with a deviant (infrequent) sound of different frequency, duration or intensity. Na¨a¨ta¨nen [38,39] showed that the difference waveform obtained by subtracting the evoked response to the standard from those of the deviant tones exhibits a specific component. This com50
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Fig. 2. Representative standard auditory evoked response from a single fetus recorded at 32 (right) and 34 (left) weeks of gestation.
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ponent is called mismatch negativity (MMN) because it appears as a negative deflection in electroencephalographic (EEG) recordings of adult subjects. The latency of the MMN varies from 100 to 200 ms in adults. A sequence of two complex sounds was presented to the subjects in an oddball protocol. Fig. 3 shows a sample layout of the auditory tone sequence. The ‘‘standard’’ frequent stimulus (probability of 88%) consisted of a 500 Hz tone with additional harmonics at 1000 and 1500 Hz, attenuated in amplitude by 3 and 6 dB, respectively. The ‘‘deviant’’ infrequent stimulus (probability of 12%) consisted of a 750 Hz tone with harmonics at 1500 and 2250 Hz with the same amplitude attenuation as in the standard tone. The stimuli were generated as tone bursts with a duration of 100 ms (including 10 ms rise and fall times). The interstimulus interval (ISI) varied between 500 and 1100 ms. Two different stimulus conditions were designed. In the first, the ISI was 800 with ±300 ms randomization (RND condition). In the second, the ISI was fixed at 800 ms (NORND condition). The recordings were performed in two consecutive measurements of 8 min each. We used a fixed order sequence starting with the randomized stimulation and continuing after a short break with the non-randomized condition. Fig. 4 shows a representative response from a fetus starting at a gestation of age 28 weeks and recorded every 2 weeks up to 36 weeks of gestation. A total of 25 fetal and 10 newborn measurements were performed with the SARA system. The newborn data were measured as a follow-up to the fetal recordings within 2 weeks after they were born. The neonates were positioned in a cradle that was attached to the SARA system. A response corresponding to detection of sound changes was found in 60% of the fetal data and in 80% of the neonatal data [40]. The percent of MMN detection was calculated from the records when both responses (to the standard and deviant tones) were observed. The average MMN latencies in fetuses and newborns were 321±31 and 307±39 ms, respectively. The latency of fetal response to the standard tone calculated across all measurements was 260 ± 61 and 206±52 ms in newborns [40]. This response represents the evidence of frequency discrimination capability of the fetal brain.
Tones Standard (frequently) tone Deviant (rare) tone (12 %)
ISI
500 + 1500 + 2000 Hz 750 + 1500 + 2250 Hz
Tone-burst
Randomized ISI (800 ms ± 300 ms) Nonrandomized ISI (800 ms) 10ms
100 ms
10ms
Fig. 3. Sample layout of the auditory tone sequence to evoke sound discrimination response. A sequence of two complex sounds was presented to the subjects in an oddball protocol.
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MMN 30 20
28wk
0 -20 -30
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Amplitude [fT]
-20 -30 20 32wk 0 -20 -30 30 20
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0 -20 -30 30 20
36wk
0 -20 - 0.1 0
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0.3 0.4
0.6
Time [s] Fig. 4. Representative auditory mismatch negativity (MMN) response a from single fetus recorded starting at 28 weeks to 36 weeks of gestational age. This response represents the frequency discrimination capability of the fetus.
7. Discussion The feasibility of recording fetal brain responses to auditory stimulus is evident from the studies that have been described above. In addition, the recording of mismatch negativity (MMN) responses to auditory stimuli, which is an indicator of sound discrimination, points to the existence of the development of the elementary cognitive processes in the fetus. Sound discrimination is a prerequisite for normal speech development, and we found that fetuses show this basic capability as early as the 28th gestational week. The investigation of sound discrimination and related cortical activity of the fetus may help to identify and determine the nature of deficits caused by central processes in the auditory system at very early stages. The success of using auditory stimuli depends on the successful transmission of sound through the maternal abdomen and reaching the fetal ear to evoke a response from the fetus. Various studies have been performed to assess the transmission loss across the
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maternal abdomen and to understand the pathway by which the sound reaches and activates the fetal ear [2,6–12,41]. The externally produced auditory stimuli must pass through the maternal tissues and fluids surrounding the fetal head before reaching the ear. It has been shown that lower frequencies (<500 Hz, 5 dB attenuation) are less attenuated as compared to higher frequencies (up to 20–30 dB attenuation) [6]. Also there is evidence that the dominant pathway for the sound energy in the amniotic fluid that stimulates the fetal ear is through bone conduction rather than the external and middle ear systems [42]. Additional attenuation occurs during the transmission through the bones of the skull with 10– 20 dB attenuation for frequencies less that 250 Hz and about 40–50 dB for frequencies from 500 to 2000 Hz [6]. Based on these studies and technical considerations of our sound system, we had chosen an optimal frequent tone of 500 Hz in most our protocols to insure minimal loss of sound transmission to the fetal ear. Apart from the sound transmission, there are other factors that can affect the successful recording of evoked responses which include fetal state, movement, position and orientation of the head with respect to the sensor array. These factors leading to unsuccessful recording of auditory evoked responses could provide false-positive results, if we accept the premise that the absence of an observable evoked response in the fetus could be an indicator for fetal neurological impairment. In order to reduce false-positives in our recent studies (Table 1, studies 3, 4, and 5), we have applied a standard procedure of performing repetitive measurements. The hypothesis is that even if the evoked response is dependent on certain conditions such as fetal state or position, it will be possible to obtain it in the normal fetus through repeated trials, since it should be observable once it is developed. However, in the fetus with impaired brain function, observation of a response would be unlikely despite repeated trials. More importantly, the amplitude of the MMN can be ‘‘calibrated’’ as a proportion of auditory evoked response amplitude, providing a ‘‘dimensionless’’ estimate of the brain development. In summary, the testing of the neurological status of the fetus by recording a response to auditory stimuli is being developed as an additional tool to monitor the fetal well-being. Currently we are performing recordings on subjects who are categorized as high-risk based on maternal risk factors including genetic and environmental factors such as maternal smoking. In the case of fetuses with abnormalities, early detection of neurological problems could help in better management and timing of labor and delivery. References [1] Tucci D. Deafness and disorders of central auditory processing. In: Berg BO, editor. Principles of child neurology. New York: McGraw-Hill Companies Inc.; 1996. p. 155–88. [2] Lecanuet JP, Gautheron B, Locatelli A, Schaal B, Jacquet AY, Busnel MC. What sounds reach fetuses: biological and non-biological modeling of the transmission of pure tones. Dev Psychobiol 1998;33:203–19. [3] Querleu D, Renard X, Boutteville C, et al. Hearing by the human fetus? Semin Perinatol 1989;13(5):409–20. [4] Kiuchi M, Nagata N, Ikeno S, Terakawa N. The relationship between the response to external light stimulation and behavioral states in the human fetus: how it differs from vibroacoustic stimulation. Early Hum Dev 2000;58:153–65. [5] Hepper PG, Shahidullah BS. Development of fetal hearing. Arch Dis Child 1994;71(2):F81–7. [6] Gerhardt KJ, Abrams RM. Fetal hearing: characterization of stimulus and response. Semin Perinatol 1996;20(1):11–20. [7] Gerhardt KJ. Characteristics of the fetal sheep sound environment. Semin Perinatol 1989;13(5):362–70. [8] Gerhardt KJ, Ambrams RM, Oliver CC. Sound environment of the fetal sheep. Am J Obstet Gynecol 1990;162:282–7.
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Auditory evoked responses: A tool to assess the fetal neurological activity Hari Eswaran a
a,*
, Rossitza Draganova a, Hubert Preissl
a,b
SARA Research Center, Department of Obstertrics and Gynecology, University of Arkansas for Medical Sciences, 4301 W Markham St. Slot 518, Little Rock, AR 72205, United States b MEG Center, University of Tuebingen, Tuebingen, Germany Received 30 September 2005; received in revised form 7 March 2006; accepted 8 March 2006 Available online 19 May 2006
Abstract An intact auditory system at birth is requisite for the successful accomplishment of many developmental skills. Evoked responses to auditory stimuli have been used as a sensitive test to determine the functional status of the adult and neonatal brain. It has been established that fetuses can hear in utero and respond to external acoustic stimuli. We present an overview of the transmission of sound through the maternal abdomen to the fetal ear and the recordings of an auditory evoked response obtained from the fetus using a non-invasive magnetoencephalography technique. The investigation of cortical activity of the fetus in response to auditory stimulation can help understand and track the neurological development of the fetus. Ó 2006 Elsevier Ltd. All rights reserved. Keywords: Fetus; Auditory; In utero sound transmission; Evoked response; Magnetoencephlography
1. Introduction The fact that soon after birth the newborn is capable of perceiving and discriminating different sounds points to the fact that development occurs in the fetal life itself. Morphological structures of the peripheral auditory system essential to hearing are developed in the fetus by the 20th week of gestation [1]. It is widely accepted that sound transmits *
Corresponding author. Tel.: +1 501 686 5847; fax: +1 501 603 1544. E-mail address: [email protected] (H. Eswaran).
0003-682X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.apacoust.2006.03.004
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through the maternal abdomen and can reach the fetus [2,3]. Behavioral studies have shown that auditory and vibroacoustic sound stimulation leads to changes in fetal behavior determined by fetal movement, fetal eye movements and fetal heart rate, or heart rate variability changes [4,5]. But with advances in non-invasive technologies, it is now possible to make direct fetal brain response measurements to auditory stimuli. In this article, we provide an overview of the sound transmission through maternal abdomen and how sound can be applied to assess the neurological status of the fetus. 2. Intrauterine sound environment and external sound transmission Inside the uterus, the fetal auditory environment consists of internal noises (maternalintestinal, cardiovascular, respiratory and placental vascular sounds) and external noises. Many researchers [6–8] have tried to measure the intrauterine sound levels from both internal and external sound sources. The sound level due to internal sources has been measured to reach as high as 90 dB SPL (Ref. [20] lPa) for low frequencies [3]. These high sound levels are predominantly at low frequencies (<32 Hz) to which the human auditory system does not show much response, hence the basal noises do not mask the exterior sounds. Early measurements of sound intensity reaching the uterus from external sources were made using a microphone encased in rubber placed near the cervix. Bench [9] reported the fetus was insulated from external sounds and measured a sound attenuation of 19 dB at 200 Hz and up to 48 dB at 4000 Hz in a 37 week pregnant woman. Grimwade [10], using a similar procedure, reported attenuation loss ranging from 39 dB at 500 Hz to 85 dB at 5000 Hz. Also, Walker [11] reported attenuation values ranging from 30 to 90 dB using microphones. Later, advanced technology and the use of hydrophones showed that the attenuation values, especially at higher frequencies, were overestimated using microphones. The impedance mismatch between the microphone, rubber and fluid interface cast doubts on the reported microphone based attenuation values. The hydrophone provides a better impedance match in a fluid environment as compared to a microphone. Using hydrophones, Querleu [3] reported the average attenuation due to external sounds was around 30 dB. This value is closer to the number reported by Armitage [12] and Gerhardt [8] on sheep. External stimulation of the fetus is only possible if an effective transmission of sound through the maternal abdomen is guaranteed. Animal and modeling studies have shown that frequencies above 1000 Hz are strongly attenuated by the abdomen, and frequencies below this cut-off frequency are transmitted with an attenuation of around 30 dB in loudness [2]. 3. Perception of and response to auditory stimuli by the fetus Hepper and Shahidullah [5] reported as early as the 19th week of gestation fetuses showed motor responses to pure tone stimuli in the low frequency range of human hearing (500 Hz). They demonstrated that by the 27th week of gestational age, 96% of the fetuses in their study responded to 250 and 500 Hz tones. Furthermore, 100% of the fetuses responded to tones with frequencies of 1000 and 3000 Hz at 33 and 35 weeks of gestational age, respectively.
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Other studies indicate that fetuses are able to discern musical notes, syllables and voices [13]. It has also been established that the fetus has a basic capacity for learning and memory. Van Heteren et al. [14] used fetal habituation to repeated vibroacoustic stimulation to assess fetal memory and reported that fetuses exhibited short-term memory of at least 10 min, and a long-term memory of at least 24 h. The human capacity to learn and understand language is dependent on the cognitive function of sound discrimination, which seems to be functional in the fetus. It is known that newborns can demonstrate this cognitive ability in the first hours after birth [15]. However, the question of when the process of sound discrimination actually begins in the human fetus remains unclear. This kind of learning and auditory perception is further substantiated by the investigation of newborns, which show a preference for their mother’s voice shortly after birth [16]. The fact that the fetus can hear in utero and respond to acoustic stimuli by characteristic behavioral and heart signal changes led to the supposition that this cause and effect could be used as an indicator to monitor the progress of the functional development of the brain. 4. Auditory evoked response and neurological assessment The auditory evoked response is the neuroelectric response of the auditory system in the brainstem, midbrain, and the cortex to sound stimulation. A large number of components have been described in the human averaged auditory evoked potential. These components can be divided into brainstem (first 10 ms), middle latency (40 ms) and long latency (50– 250 ms). Several authors have reviewed the utility of evoked responses in predicting neurological outcome in neonates [17–19]. It is generally agreed that auditory evoked responses (AER) are useful in diagnosing hearing loss [20] and are associated with neuromotor impairment, though they produce a high rate of false negative results. Some of these negative results may be a consequence of the sensitivity of evoked responses to time elapsed following injury [21] arguing for the earliest possible measurements (e.g., fetus in utero). Tharp associated fetal brain injury with the development of abnormal evoked response in the newborn [22]. He also suggested that hydrocephalus can produce severe changes in the brainstem auditory evoked response [23,24]. Several studies show that the auditory evoked response is a useful predictor of brain death [25,26]. 5. Non-invasive method for fetal neurological assessment With the advent of fetal magnetoencephalography (fMEG) it is now possible to perform auditory evoked response measurements from the fetus in a non-invasive fashion. This technology allows the non-invasive recording of the magnetic field corresponding to any electric current produced in the body. Electrophysiological phenomena are characterized by the flow of ion currents within the body. These currents are detectable by measuring potentials inside or on the surface of the body. The physics of electromagnetism predicts the flow of current will also result in a magnetic field. Consequently, common clinical electrophysiological measures such as the electrocardiogram (ECG) and electroencephalogram (EEG) have magnetic homologues: the magnetocardiogram (MCG) and the magnetoencephalogram (MEG), respectively. Magnetic signals have been detected from nearly all electrophysiologically active organs of the body. However, unlike bioelectric signals, biomagnetic signals are detectable outside the boundary of the skin without making electrical contact with the body [27].
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6. Direct measurement of fetal brain activity in response to auditory stimulus The approach of recording magnetic signals (MEG) from the human adult brain is at present a well established technique. With the advantage of this being a non-invasive procedure, this technique over the past few years has been applied to study the fetal brain. Fetal evoked magnetic brain responses to auditory stimuli between 27 and 34 weeks have been reported in several MEG studies [28–34]. In order to obtain auditory evoked magnetic responses, various stimulation protocols were examined. These protocols were adapted from standard procedures used in infant and adult studies. In the following section, we describe the general recording procedure, the stimulus delivery mechanism and the various stimulation protocols that were applied specifically to our study. Although there are variations in protocols and signal processing approaches between various research groups performing fetal auditory evoked studies, the overall goals and recording procedures are similar. 6.1. General recording procedure All the studies performed on squid array for reproductive assessment (SARA) were approved by the University of Arkansas for Medical Sciences – Human Research Advisory Committee, and informed written consent was obtained from all the subjects. The routine recording sessions range from 6 to 12 min in a continuous mode at a sampling rate of 312.5 Hz and a bandpass of dc to 100 Hz. The position and orientation of the mother’s abdomen, relative to the sensor array, are determined using three localization coils placed at fiduciary points on the mother’s right and left side and spine at the level of the umbilicus. These coils do not interfere with the MEG recordings. We also define the fetal head position as the patient sits down in front of the array using a portable ultrasound scanner. The ultrasound probe is placed on the surface of the maternal abdomen exactly over the fetal head. A fourth localization coil is then attached to the maternal abdomen at that Table 1 Fetal standard AER studies performed using SARA Studies
Auditory stimulus (tones)
Interstimulus interval (s)
Duration (ms)
1. Eswaran et al. [31] 2. Preissl et al. [35]
1 kHz 80% 500 Hz 20% 1 kHz 80% 500 Hz 20% 1 kHz 80% 500 Hz 20% 1 kHz 80% 500 Hz 20% 700 or 1 kHz
1–2 2
100 100
1
3. Eswaran et al. [34] 4. Eswaran et al. [36] 5. Holst et al. [37]
No. subjects (% AER detection)
Average latency (ms)
Average amplitude (fT)
4 (75%) 22 (63%)
175 220
38 24
100
10a (80%)
249
18
2
1
11b (62%)
264
30
2
500
18c (83%)
245
69
Summary of standard fetal AER studies performed using SARA system. a 51 independent sessions with short-term serial recordings at least 3 different days during 1 week of gestation. 80% of subjects detected at least once in short-term repeated trials. 50% when considering the ratio of successful detection to total number of recordings (24/51). b 34 independent sessions with recordings every 2 weeks starting at 28 weeks till delivery. c 62 independent sessions with recordings every 2 weeks starting at 28 weeks till delivery.
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point to provide additional positional information related to sensor coordinates. The ultrasound exam to evaluate fetal head position is repeated at the end of the study. 6.2. Standard auditory evoked studies The standard auditory stimulus used by fMEG researchers is a tone burst. A summary of studies performed by our group is shown in Table 1 [31,34–37]. The experimental protocols we have tested include the following parameters: frequency – 500 Hz to 1 kHz, duration – 100 ms to 1 s, interstimulus interval – 1–2 s and intensity (measured outside in the air) 100–120 dB. Our auditory stimulation device consists of a speaker placed outside a shielded room, attached to a 12 ft long piece of Tygon tubing (2 cm inner diameter) with the distal end of the tubing attached to an air-filled bag. This bag is secured with an elastic belt high up over the maternal abdomen being careful not to increase distance between the sensors and fetal head. The sound intensity was measured in the air, both
Fig. 1. (Top) Mother positioned on the SARA system with the auditory stimulus delivery system attached. (Bottom) A lay-out of the 151 sensor array spread across the maternal abdomen.
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at the air-filled bag (120 dB) and in the shielded room (100 dB). This means our sound system generates a focused and a diffused sound source (see Fig. 1). The general approach of most fetal AER studies is to search for an evoked component around 200 ms, which is interpreted as a delayed component corresponding to the adult N100. Various fMEG investigators (including our group) have recorded a peak AER amplitude ranging from approximately 30 to 175 fT and the latency of the primary response component from 125 to over 200 ms [28–37]. Table 1 shows the number of AER recordings performed along with stimulus parameters and the detection rate using the SARA system. Fig. 2 shows a representative response with 500 ms tone duration obtained from serial recordings of a fetus starting at 27 weeks until 37 weeks of gestation. 6.3. Sound discrimination studies Apart from the standard auditory evoked studies, more recently, we have initiated protocols to assess the discriminative capability of the fetus. In the so-called oddball paradigm, sounds are presented in a sequence of a standard (frequent) sound intermixed with a deviant (infrequent) sound of different frequency, duration or intensity. Na¨a¨ta¨nen [38,39] showed that the difference waveform obtained by subtracting the evoked response to the standard from those of the deviant tones exhibits a specific component. This com50
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Fig. 2. Representative standard auditory evoked response from a single fetus recorded at 32 (right) and 34 (left) weeks of gestation.
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ponent is called mismatch negativity (MMN) because it appears as a negative deflection in electroencephalographic (EEG) recordings of adult subjects. The latency of the MMN varies from 100 to 200 ms in adults. A sequence of two complex sounds was presented to the subjects in an oddball protocol. Fig. 3 shows a sample layout of the auditory tone sequence. The ‘‘standard’’ frequent stimulus (probability of 88%) consisted of a 500 Hz tone with additional harmonics at 1000 and 1500 Hz, attenuated in amplitude by 3 and 6 dB, respectively. The ‘‘deviant’’ infrequent stimulus (probability of 12%) consisted of a 750 Hz tone with harmonics at 1500 and 2250 Hz with the same amplitude attenuation as in the standard tone. The stimuli were generated as tone bursts with a duration of 100 ms (including 10 ms rise and fall times). The interstimulus interval (ISI) varied between 500 and 1100 ms. Two different stimulus conditions were designed. In the first, the ISI was 800 with ±300 ms randomization (RND condition). In the second, the ISI was fixed at 800 ms (NORND condition). The recordings were performed in two consecutive measurements of 8 min each. We used a fixed order sequence starting with the randomized stimulation and continuing after a short break with the non-randomized condition. Fig. 4 shows a representative response from a fetus starting at a gestation of age 28 weeks and recorded every 2 weeks up to 36 weeks of gestation. A total of 25 fetal and 10 newborn measurements were performed with the SARA system. The newborn data were measured as a follow-up to the fetal recordings within 2 weeks after they were born. The neonates were positioned in a cradle that was attached to the SARA system. A response corresponding to detection of sound changes was found in 60% of the fetal data and in 80% of the neonatal data [40]. The percent of MMN detection was calculated from the records when both responses (to the standard and deviant tones) were observed. The average MMN latencies in fetuses and newborns were 321±31 and 307±39 ms, respectively. The latency of fetal response to the standard tone calculated across all measurements was 260 ± 61 and 206±52 ms in newborns [40]. This response represents the evidence of frequency discrimination capability of the fetal brain.
Tones Standard (frequently) tone Deviant (rare) tone (12 %)
ISI
500 + 1500 + 2000 Hz 750 + 1500 + 2250 Hz
Tone-burst
Randomized ISI (800 ms ± 300 ms) Nonrandomized ISI (800 ms) 10ms
100 ms
10ms
Fig. 3. Sample layout of the auditory tone sequence to evoke sound discrimination response. A sequence of two complex sounds was presented to the subjects in an oddball protocol.
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MMN 30 20
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36wk
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Time [s] Fig. 4. Representative auditory mismatch negativity (MMN) response a from single fetus recorded starting at 28 weeks to 36 weeks of gestational age. This response represents the frequency discrimination capability of the fetus.
7. Discussion The feasibility of recording fetal brain responses to auditory stimulus is evident from the studies that have been described above. In addition, the recording of mismatch negativity (MMN) responses to auditory stimuli, which is an indicator of sound discrimination, points to the existence of the development of the elementary cognitive processes in the fetus. Sound discrimination is a prerequisite for normal speech development, and we found that fetuses show this basic capability as early as the 28th gestational week. The investigation of sound discrimination and related cortical activity of the fetus may help to identify and determine the nature of deficits caused by central processes in the auditory system at very early stages. The success of using auditory stimuli depends on the successful transmission of sound through the maternal abdomen and reaching the fetal ear to evoke a response from the fetus. Various studies have been performed to assess the transmission loss across the
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maternal abdomen and to understand the pathway by which the sound reaches and activates the fetal ear [2,6–12,41]. The externally produced auditory stimuli must pass through the maternal tissues and fluids surrounding the fetal head before reaching the ear. It has been shown that lower frequencies (<500 Hz, 5 dB attenuation) are less attenuated as compared to higher frequencies (up to 20–30 dB attenuation) [6]. Also there is evidence that the dominant pathway for the sound energy in the amniotic fluid that stimulates the fetal ear is through bone conduction rather than the external and middle ear systems [42]. Additional attenuation occurs during the transmission through the bones of the skull with 10– 20 dB attenuation for frequencies less that 250 Hz and about 40–50 dB for frequencies from 500 to 2000 Hz [6]. Based on these studies and technical considerations of our sound system, we had chosen an optimal frequent tone of 500 Hz in most our protocols to insure minimal loss of sound transmission to the fetal ear. Apart from the sound transmission, there are other factors that can affect the successful recording of evoked responses which include fetal state, movement, position and orientation of the head with respect to the sensor array. These factors leading to unsuccessful recording of auditory evoked responses could provide false-positive results, if we accept the premise that the absence of an observable evoked response in the fetus could be an indicator for fetal neurological impairment. In order to reduce false-positives in our recent studies (Table 1, studies 3, 4, and 5), we have applied a standard procedure of performing repetitive measurements. The hypothesis is that even if the evoked response is dependent on certain conditions such as fetal state or position, it will be possible to obtain it in the normal fetus through repeated trials, since it should be observable once it is developed. However, in the fetus with impaired brain function, observation of a response would be unlikely despite repeated trials. More importantly, the amplitude of the MMN can be ‘‘calibrated’’ as a proportion of auditory evoked response amplitude, providing a ‘‘dimensionless’’ estimate of the brain development. In summary, the testing of the neurological status of the fetus by recording a response to auditory stimuli is being developed as an additional tool to monitor the fetal well-being. Currently we are performing recordings on subjects who are categorized as high-risk based on maternal risk factors including genetic and environmental factors such as maternal smoking. In the case of fetuses with abnormalities, early detection of neurological problems could help in better management and timing of labor and delivery. References [1] Tucci D. Deafness and disorders of central auditory processing. In: Berg BO, editor. Principles of child neurology. New York: McGraw-Hill Companies Inc.; 1996. p. 155–88. [2] Lecanuet JP, Gautheron B, Locatelli A, Schaal B, Jacquet AY, Busnel MC. What sounds reach fetuses: biological and non-biological modeling of the transmission of pure tones. Dev Psychobiol 1998;33:203–19. [3] Querleu D, Renard X, Boutteville C, et al. Hearing by the human fetus? Semin Perinatol 1989;13(5):409–20. [4] Kiuchi M, Nagata N, Ikeno S, Terakawa N. The relationship between the response to external light stimulation and behavioral states in the human fetus: how it differs from vibroacoustic stimulation. Early Hum Dev 2000;58:153–65. [5] Hepper PG, Shahidullah BS. Development of fetal hearing. Arch Dis Child 1994;71(2):F81–7. [6] Gerhardt KJ, Abrams RM. Fetal hearing: characterization of stimulus and response. Semin Perinatol 1996;20(1):11–20. [7] Gerhardt KJ. Characteristics of the fetal sheep sound environment. Semin Perinatol 1989;13(5):362–70. [8] Gerhardt KJ, Ambrams RM, Oliver CC. Sound environment of the fetal sheep. Am J Obstet Gynecol 1990;162:282–7.
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