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Objective: We hypothesized that morphine has a depressing effect on early brain activity, assessed using quantitative aEEG/EEG parameter and depressed activity will be associated with brain volumes at term in extremely preterm infants. Study design: 174 preterm infants were enrolled in 3 European tertiary NICUs (mean GA:26 +/- 1wks) and monitored during the first 72 h after birth with continuous 2 channel aEEG. Six epochs of aEEG recordings were selected and minimum amplitude of aEEG (min aEEG), percentage of time amplitude< 5 mu V (% of time < 5 mu V), spontaneous activity transients (SATrate) and interSAT interval (ISI) were calculated. For infants receiving morphine, the cumulative morphine dosage was calculated. In a subgroup of 58 infants, good quality MRI at term equivalent age (TEA) and the cumulative morphine dose until TEA were available. The effects of morphine administration and cumulative dose on aEEG/EEG measures and on brain volumes were investigated. Results: Morphine administration had a significant effect on all quantitative aEEG/EEG measures, causing depression of early brain activity [longer ISI (beta 2.900), reduced SAT rate (beta -1.386), decreased min aEEG (beta -0.782), and increased % of time < 5 mu V (beta 14.802)] in all epochs. A significant effect of GA and postnatal age on aEEG/EEG measures was observed. Cumulative morphine dose until TEA had a significant negative effect on total brain volume (TBV) (beta -8.066) and cerebellar volume (beta -1.080). Conclusions: Administration of sedative drugs should be considered when interpreting aEEG/EEG together with the negative dose dependent morphine impact on brain development.

OBJECTIVES: To investigate if Paco(2) and plasma glucose levels affect electrocortical activity. METHODS: Ours was an observational study of 32 infants with a gestational age of 22 to 27 weeks. We performed simultaneous single-channel electroencephalogram (EEG) and repeated blood gas/plasma glucose analyses during the first 3 days (n = 247 blood samples with corresponding EEG). Interburst intervals (IBIs) and EEG power were averaged at the time of each blood sample. RESULTS: There was a linear relationship between Paco(2) and IBI; increasing Paco(2) was associated with longer IBIs. One day after birth, a 1-kPa increase in Paco(2) was associated with a 16% increase in IBI in infants who survived the first week without severe brain injury. EEG power was highest at a Paco(2) value of 5.1 kPa and was attenuated both at higher and lower Paco(2) values. Corrected for carbon dioxide effects, plasma glucose was also associated with IBI. Lowest IBI appeared at a plasma glucose level of 4.0 mmol/L, and there was a U-shaped relationship between plasma glucose level and EEG with increasing discontinuity at glucose concentrations above and below 4.0 mmol/L. CONCLUSIONS: Both carbon dioxide and plasma glucose level influenced EEG activity in extremely preterm infants, and values considered to be within normal physiologic ranges were associated with the best EEG background. Increasing EEG discontinuity occurred at carbon dioxide levels frequently applied in lung-protection strategies; in addition, moderate hyperglycemia was associated with measurable EEG changes. The long-term effects of changes in carbon dioxide and glucose on brain function are not known.

Background: Extremely preterm infants generally experience postnatal growth failure. It is still unclear if this is related to micronutrient intakes. Aim: To investigate the effect of micronutrient intakes (calcium, zinc, iron, phosphorus, sodium, potassium, chloride, magnesium, vitamin A, vitamin D, vitamin E, folate and vitamin B12) on growth during the first 28 days of life in extremely preterm infants. Method: From the EXPRESS cohort (all infants born < 27 gestational weeks between 2004-2007 in Sweden), those who survived the first 28 days were included (n=524). Daily parenteral and enteral intakes and anthropometric measurements were retrieved from hospital records. Results: Preliminary analyses of data from 333 infants (mean±SD gestational age 25.2±1.0 weeks, birth weight 753±168g) showed that macronutrient intakes were lower than recommended (energy 98±13kcal/kg/day, protein 2.9±0.4g/kg/day). Infants showed postnatal growth failure: mean standard deviation scores decreased by 2.2 for weight, 2.3 for length and 1.4 for head circumference. Intakes of micronutrients were generally low, e.g. adjusted enteral intakes of calcium were 66.6±21.4 mg/kg/day. The exception was iron, with a high parenteral intake of 2.7±1.6 mg/kg/day, mainly from blood transfusions. Adjusting for protein intake and other confounders, calcium intakes were positively correlated with head growth (r=+0.19, p=0.006) and iron intakes were negatively correlated with length gain (r=-0.18, p=0.009). Conclusions: Low calcium intakes and high iron intakes were associated with poor growth with regard to head circumference and length, respectively. If these results are confirmed, optimized micronutrient intakes may improve early growth in extremely preterm infants.

OBJECTIVE: Mismatch responses are elicited to changes in sound streams in healthy newborns. In the ideal case, these responses can predict cognitive problems later in life. We employed a multiple deviant paradigm for a fast assessment of the ability of the newborn brain to respond to various types of acoustic changes. METHODS: In 12 healthy newborns, we recorded an electroencephalogram (EEG) and magnetoencephalogram while presenting auditory stimuli. Between repeated stimuli, four types of acoustic changes (frequency, intensity, duration, and a gap) were presented, varying in deviance magnitude. RESULTS: One major response was present in the neonatal evoked potentials and fields at 250-260 ms. Magnetic mismatch responses were elicited to all change types except for the duration deviant and they were positive in polarity. The frequency deviant elicited more positive EEG amplitudes than the standard, whereas the response to the duration deviant was more negative. CONCLUSIONS: These results show that newborns can detect changes to at least four types of deviances within a sound stream. Furthermore, the use of magneto- and electroencephalography is complementary in newborns, since the methods may reveal different outcomes. SIGNIFICANCE: Further studies are warranted to determine whether the present study design can play a role in testing auditory function in clinical infant populations.

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Objective: Behavioral experiments show that infants use both prosodic and statistical cues in acquiring language. However, it is not yet clear whether these prosodic and statistical tools are already present at birth. Methods: We recorded brain responses of sleeping newborns to natural sounds rich in prosody, namely singing and continuous speech, and to two impoverished manipulations of speech. A total of 11 newborns were presented with continuous speech, singing, and degraded speech, while MEG was recorded. Results: We found that a brain response elicited to the prosodically rich singing and continuous natural speech conditions decreased dramatically when the prosody in the speech was impoverished. Conclusions: We claim that this response is the indicator of the infants' sensitivity to prosodic cues in language, which is already present at birth during natural sleep. Significance: The indicators of detection of prosody may be crucial in assessing the normal and abnormal cortical function in newborns, especially of those infants at-risk for language problems.

We investigated whether newborns respond differently to novel and deviant sounds during quiet sleep.Twelve healthy neonates were presented with a three-stimulus oddball paradigm, consisting of frequent standard (76%), infrequent deviant (12%), and infrequent novel stimuli (12%). The standards and deviants were counterbalanced between the newborns and consisted of 500 and 750 Hz tones with two upper harmonics. The novel stimuli contained animal, human, and mechanical sounds. All stimuli had a duration of 300 ms and the stimulus onset asynchrony was 1s. Evoked magnetic responses during quiet sleep were recorded and averaged offline.Two deflections peaking at 345 and 615 ms after stimulus onset were observed in the evoked responses of most of the newborns. The first deflection was larger to novel and deviant stimuli than to the standard and, furthermore, larger to novel than to deviant stimuli. The second deflection was larger to novel and deviant stimuli than to standards, but did not differ between the novels and deviants.The two deflections found in the present study reflect different mechanisms of auditory change detection and discriminative processes.The early brain indicators of novelty detection may be crucial in assessing the normal and abnormal cortical function in newborns. Further, studying evoked magnetic fields to complex auditory stimulation in healthy newborns is needed for studying the newborns at-risk for cognitive or language problems.