Franziska Schleger

Auditory habituation in the fetus and neonate: an fMEG study.

Habituation--the most basic form of learning--is used to evaluate central nervous system (CNS) maturation and to detect abnormalities in fetal brain development. In the current study, habituation, stimulus specificity and dishabituation of auditory evoked responses were measured in fetuses and newborns using fetal magnetoencephalography (fMEG). An auditory habituation paradigm consisting of 100 trains of five 500 Hz tones, one 750 Hz tone (dishabituator) and two more 500 Hz tones, respectively, were presented to 41 fetuses (gestational age 30-39 weeks) and 22 newborns or babies (age 6-89 days). A response decrement between the first and fifth tones (habituation), an increment between the fifth tone and the dishabituator (stimulus specificity) and an increment between the fifth (last tone before the dishabituator) and seventh tones (first tone after the dishabituator) (dishabituation) were expected. Fetuses showed weak responses to the first tone. However, a significant response decrement between the second and fifth tones (habituation) and a significant increment between the fifth tone and the dishabituator (stimulus specificity) were found. No significant difference was found for dishabituation nor was a developmental trend found at the group level. From the neonatal data, significant values for stimulus specificity were found. Sensory fatigue or adaptation was ruled out as a reason for the response decrement due to the strong reactions to the dishabituator. Taken together, the current study used fMEG to directly show fetal habituation and provides evidence of fetal learning in the last trimester of pregnancy.

Gestational Diabetes Impairs Human Fetal Postprandial Brain Activity

CONTEXT Gestational diabetes (GDM) influences the fetal phenotype. OBJECTIVE In the present study, our aim was to determine the effect of GDM specifically on fetal brain activity. DESIGN Pregnant participants underwent an oral glucose tolerance test (OGTT, 75 g). At 0, 60, and 120 minutes, maternal metabolism was determined, and fetal auditory evoked fields were recorded with a fetal magnetoencephalographic device. SETTING All measurements were performed at the fMEG Center in Tübingen. PARTICIPANTS Twelve women with GDM and 28 normal glucose-tolerant (NGT) pregnant women participated on a voluntary basis. INTERVENTIONS OGTT (75 g, 120 minutes) was used in this study. MAIN OUTCOMES AND MEASURES Fetal auditory evoked response latencies were determined for this study. RESULTS In the fetuses of NGT women, latencies decreased between 0 and 60 minutes from 260 ± 90 to 206 ± 74 ms (P = .008) and remained stable until 120 minutes (206 ± 74 vs 230 ± 79, P =.129). In fetuses of women with GDM, there was no change in response latencies during OGTT (P = .11). Sixty minutes after glucose ingestion, fetal latencies in the GDM group were longer than in the NGT group (296 ± 82 vs 206 ± 74 ms, P = .001). Linear regression revealed a significant effect of maternal glucose, insulin levels, and insulin sensitivity on response latencies after 60 minutes. CONCLUSIONS Fetal postprandial brain responses were slower in the offspring of women with GDM. This might indicate that gestational diabetes directly affects fetal brain development and may lead to central nervous insulin resistance in the fetus.

Magnetoencephalographic Signatures of Numerosity Discrimination in Fetuses and Neonates

Numerosity discrimination has been demonstrated in newborns, but not in fetuses. Fetal magnetoencephalography allows non-invasive investigation of neural responses in neonates and fetuses. During an oddball paradigm with auditory sequences differing in numerosity, evoked responses were recorded and mismatch responses were quantified as an indicator for auditory discrimination. Thirty pregnant women with healthy fetuses (last trimester) and 30 healthy term neonates participated. Fourteen adults were included as a control group. Based on measurements eligible for analysis, all adults, all neonates, and 74% of fetuses showed numerical mismatch responses. Numerosity discrimination appears to exist in the last trimester of pregnancy.

Sensitivity to Auditory Spectral Width in the Fetus and Infant – An fMEG Study

Auditory change detection is crucial for the development of the auditory system and a prerequisite for language development. In neonates, stimuli with broad spectral width like white noise (WN) elicit the highest response compared to pure tone and combined tone stimuli. In the current study we addressed for the first time the question how fetuses react to “WN” stimulation. Twenty-five fetuses (Mage = 34.59 weeks GA, SD ± 2.35) and 28 healthy neonates and infants (Mage = 37.18 days, SD ± 15.52) were tested with the first paradigm, wherein 500 Hz tones, 750 Hz tones, and WN segments were randomly presented and auditory evoked responses (AERs) were measured using fetal magnetoencephalography (fMEG). In the second paradigm, 12 fetuses (Mage = 25.7 weeks GA, SD ± 2.4) and 6 healthy neonates (Mage = 23 days and SD ± 6.2) were presented with two auditory oddball conditions: condition 1 consisted of attenuated WN as standard and 500 Hz tones and WN as deviants. In condition 2, standard 500 Hz tones were intermixed with WN and attenuated WN. AERs to volume change and change in spectral width were evaluated. In both paradigms, significantly higher AER amplitudes to WN than to pure tones replicated prior findings in neonates and infants. In fetuses, no significant differences were found between the auditory evoked response amplitudes of WN segments and pure tones (both paradigms). A trend toward significance was reached when comparing the auditory evoked response amplitudes elicited by attenuated WN with those elicited by WN (loudness change, second paradigm). As expected, we observed high sensibility to spectral width in newborns and infants. However, in the group of fetuses, no sensibility to spectral width was observed. This negative finding may be caused by different attenuation levels of the maternal tissue for different frequency components.

Functional brain development in growth-restricted and constitutionally small fetuses: a fetal magnetoencephalography case–control study

Fetal magnetoencephalography records fetal brain activity non‐invasively. Delayed brain responses were reported for fetuses weighing below the tenth percentile. To investigate whether this delay indicates delayed brain maturation resulting from placental insufficiency, this study distinguished two groups of fetuses below the tenth percentile: growth‐restricted fetuses with abnormal umbilical artery Doppler velocity (IUGR) and constitutionally small‐for‐gestational‐age fetuses with normal umbilical artery Doppler findings (SGA) were compared with fetuses of adequate weight for gestational age (AGA), matched for age and behavioural state.

Gestational diabetes alters the fetal heart rate variability during an oral glucose tolerance test: a fetal magnetocardiography study

Gestational diabetes mellitus (GDM) potentially harms the child before birth. We previously found GDM to be associated with developmental changes in the central nervous system. We now hypothesise that GDM may also impact on the fetal autonomic nervous system under metabolic stress like an oral glucose tolerance test (OGTT).

Neuromagnetic signatures of syllable processing in fetuses and infants provide no evidence for habituation

BACKGROUND Habituation, as a basic form of learning, is characterized by decreasing amplitudes of neuronal reaction following repeated stimuli. Recent studies indicate that habituation to pure tones of different frequencies occurs in fetuses and infants. AIMS Neural processing of different syllables in fetuses and infants was investigated. STUDY DESIGN An auditory habituation paradigm including two different sequences of syllables was presented to each subject. Each sequence consisted of eight syllables (sequence /ba/: 5× /ba/, 1× /bi/ (dishabituator), 2× /ba/; sequence /bi/: 5× /bi/, 1× /ba/ (dishabituator), 2× /bi/). Each subject was stimulated with 140 sequences. Neuromagnetic signatures of auditory-evoked responses (AER) were recorded by fetal magnetoencephalography (fMEG). SUBJECTS Magnetic brain signals of N=30 fetuses (age: 28-39weeks of gestation) and N=28 infants (age: 0-3months) were recorded. Forty-two of the 60 fetal recordings and 29 of the 58 infant recordings were included in the final analysis. OUTCOME MEASURES AERs were recorded and amplitudes were normalized to the amplitude of the first stimulus. RESULTS In both fetuses and infants, the amplitudes of AERs were found not to decrease with repeated stimulation. In infants, however, amplitude of syllable 6 (dishabituator) was significantly increased compared to syllable 5 (p=0.026). CONCLUSIONS Fetuses and infants showed AERs to syllables. Unlike fetuses, infants showed a discriminative neural response to syllables. Habituation was not observed in either fetuses or infants. These findings could be important for the investigation of early cognitive competencies and may help to gain a better understanding of language acquisition during child development.

Impact of Intrauterine Growth Restriction on Cognitive and Motor Development at 2 Years of Age

Intrauterine growth restriction (IUGR), which is already known to be a risk factor for pathological intrauterine development, perinatal mortality, and morbidity, is now also assumed to cause both physical and cognitive alterations in later child development. In the current study, effects of IUGR on infantile brain function were investigated during the fetal period and in a follow-up developmental assessment during early childhood. During the fetal period, visual and auditory event-related responses (VER and AER) were recorded using fetal magnetoencephalography (fMEG). VER latencies were analyzed in 73 fetuses (14 IUGR fetuses) while AER latencies were analyzed in 66 fetuses (11 IUGR fetuses). Bayley Scales of Infant Development, Second Edition (BSID-II) were used to assess the developmental status of the infants at the age of 24 months. The Mental Development Index (MDI) was available from 66 children (8 IUGR fetuses) and the Psychomotor Development Index (PDI) from 63 children (7 IUGR fetuses). Latencies to visual stimulation were more delayed in IUGR than in small for gestational age (SGA) or appropriate for gestational age (AGA) fetuses, albeit not to any significant extent (p = 0.282). The MDI in former IUGR infants was significantly lower (p = 0.044) than in former SGA and AGA infants. However, IUGR had no impact on PDI (p = 0.213). These findings support the hypothesis that IUGR may constitute a risk factor for neurodevelopmental delay. Further investigation of the possible underlying mechanisms, as well as continued long-term developmental research, is therefore necessary.

Maternal Insulin Sensitivity and Fetal Brain Activity

There is increasing evidence that an adverse intrauterine environment may have lifelong consequences for the offspring related to disease development. One determining factor can be the metabolic status of the mother. We present data addressing the relationship between maternal insulin sensitivity and fetal brain activity in humans. We briefly review the current knowledge on insulin sensitivity in the adult brain and on studies investigating fetal programming in animal models. Fetal brain activity can be recorded completely non-invasively in humans with fetal magnetoencephalography. First studies on the influence of maternal metabolism on fetal brain activity are described. These findings indicate that maternal insulin sensitivity directly affects fetal brain development.

Electro/magnetoencephalographic signatures of human brain insulin resistance

Human insulin action influences eating behavior, peripheral metabolism and cognition. Detailed insights into the neuronal processes related to human brain insulin action can be obtained by direct measures of neuronal activity with electroencephalography and magnetoencephalography. Results of recent studies show that spontaneous, task and stimulus related neuronal activity is modulated by insulin and that several factors like increased body weight and body composition can result in brain insulin resistance. Recent technological advances even allow the investigation of human brain functions in utero in relation to the metabolic status of the mother and indicate an effect of the mothers insulin sensitivity on the brain function of the fetus. In conclusion, studies based on direct neuronal measurements may help to determine the developmental trajectory related to insulin action and resistance.