PEDIATRICS Vol. 123 No. 1 January 2009, pp. 294-300 (doi:10.1542/peds.2007-3475)
ARTICLE |
Functional Magnetic Resonance Imaging of the Sensorimotor System in Preterm Infants
Departments of a Neonatology
b Radiology, University of Bonn, Bonn, Germany
c Department of Pediatrics, University Medical Centre, Groningen, Netherlands
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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OBJECTIVE. Preterm birth at <32 weeks' gestational age has a specific predilection for periventricular white matter injury. Early prediction of concomitant motor sequelae is a fundamental clinical issue. Recently, functional MRI was introduced as a noninvasive method for investigating the functional integrity of the neonatal brain. We aimed at implementing a unilateral passive forearm extension/flexion functional MRI paradigm in a routine clinical MRI setup to allow noninvasive mapping of the sensorimotor system in preterm infants and to relate the functional data to structural and behavioral data.
PATIENTS AND METHODS. Eight patients (median gestational age: 26.5 weeks; median birth weight: 885 g) were included. The functional MRI was performed at term-equivalent age (median: 39 weeks' postconceptional age) under chloral hydrate (50 mg/kg) sedation. In 5 of 8 patients, functional MRI data acquisition was successful. This resulted in 10 functional data sets (5 for passive stimulation of each forearm).
RESULTS. Unilateral stimulation was associated with mainly bilateral activation of the primary sensorimotor cortex (n = 7 of 10 data sets), the prevailing hemodynamic response being a negative blood oxygenation level–dependent signal. Positive blood oxygenation level–dependent response or failure to activate the sensorimotor cortex (n = 3 of 10 data sets) were seen in those patients with aberrant structural/behavioral indices.
CONCLUSIONS. Our data show the feasibility of passive unilateral sensorimotor stimulation during neonatal clinical MRI protocols. The bilateral activation pattern observed at this age is compatible with a bilaterally distributed sensorimotor system. Our data validate initial accounts for a raised incidence of negative blood oxygenation level–dependent responses in the primary sensorimotor cortex at this developmental stage. The negative blood oxygenation level–dependent response is likely to reflect a reduction of the oxy/deoxy–hemoglobin ratio during a maturational stage characterized by rapid formation of synapses, yet ineffective processing. Positive blood oxygenation level–dependent responses or failure to activate the sensorimotor cortex may be an early indicator of abnormal development and will have to be followed up carefully.
Key Words: fMRI • preterm infant • BOLD response • sensorimotor cortex • perinatal brain damage
Abbreviations: GA—gestational age • PWMI—periventricular white matter injury • WM—white matter • fMRI—functional MRI • BOLD—blood oxygenation level dependent • PCA—postconceptional age • GM—general movement • DQ—developmental quotient • IVH—intraventricular hemorrhage • WMD—white matter damage • TR—repetition time • TE—echo time • TSE—turbo spin echo • DEHSI—diffuse excessive high signal intensity • ADC—apparent diffusion coefficient • FWE—family-wise error • FDR: false discovery rate • SMC—sensorimotor cortex • Hb—hemoglobin
The complex functional organization and development of the preterm brain is still poorly understood. Both preterm delivery and associated cerebral morbidity impact considerably on the cerebral organization and affect the functional integrity of the sensorimotor system in surviving infants. Preterm birth at <32 weeks' gestational age (GA) has a specific predilection for periventricular white matter injury (PWMI). Thus, early prediction of concomitant motor sequelae is a fundamental clinical issue, in particular with regard to custom-tailored early rehabilitative treatment options.
Until 3 months' postterm age, no method is completely reliable for early identification of concomitant motor deficits in preterm children. Neurologic examination focusing on muscle tone, reflexes, and other clinical features is poorly predictive in the first months of life.1–3 Detection of motor developmental delay is sensitive and specific for later cerebral palsy, however, only in children 
6 months of age.2
Currently, structural neuroimaging methods provide the most predictive measures of long-term neurodevelopmental deficits4,5 and cerebral palsy5–7 in preterm and term infants. PWMI can be identified during the early postnatal period by means of ultrasound imaging.8 MRI provides an optimal differentiation of brain tissue and pathology.9–12 In addition, MRI of extremely preterm infants has shown reduced cortical surface area and regional complexity,13 as well as volumetric reductions of the cortical gray matter and the unmyelinated white matter (WM) of the sensorimotor cortex.14 Also, subcortical components of the sensorimotor system, notably the thalamus and lentiform nucleus, show reduced volumes at term-equivalent age.15,16 Recent MRI data indicate that the presence of T1-hyperintensities or cysts located in the corona radiata above the posterior limb of the internal capsule have predictive value for motor prognosis of preterm infants with PWMI.17
However, despite this remarkable progress in neonatal MRI, structural imaging allows inference only indirectly on functional states. Functional MRI (fMRI) is the most widely used noninvasive functional imaging tool in adults. Despite some initial observations using fMRI to study the sensorimotor system in the neonatal brain,18,19 the establishment of reliable and safe neonatal procedures faces considerable difficulties. In particular, the physiologic basis of the neonatal hemodynamic response to neural activation is not well understood. Initial data indicate considerable differences of blood oxygenation level–dependent (BOLD) responses, depending on the maturational stage of the sensorimotor system. Furthermore, the impact of structural damage on evoked BOLD responses is unknown, and in particular, no longitudinal data regarding early reorganization processes are yet available.
In this study, we examined BOLD responses to unilateral passive forearm extension/flexion in a group of preterm infants with a median GA of 26.5 weeks (fMRI at term-equivalent age). We aimed to relate the fMRI findings to the results of cerebral ultrasound and structural MRI, general movement patterns, and neurodevelopmental testing. Thereby, we intended to validate previous initial accounts for a raised incidence of "negative BOLD" responses at this early developmental stage.
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METHODS |
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Ethics
The ethical committee of the Medical Faculty of the University of Bonn approved the study protocol. Written parental consent was obtained for all study patients. All study procedures followed the declaration of Helsinki of 1975 in the current revision.
Patients
Eight inborn preterm infants, median GA 26.5 weeks (range: 24–30 weeks) who were admitted consecutively to the tertiary NICU at the University of Bonn were included in the study. One patient was excluded from analysis because of incomplete MRI acquisition and 2 patients because of major movement artifacts. All fMRI acquisitions were performed at term-equivalent (median: 39 weeks' postconceptional age [PCA]; range: 38–39 weeks). Stable respiratory and circulatory function by continuous monitoring during at least 1 week before fMRI was a prerequisite for inclusion in the study.
Neurologic Evaluation
A standardized neurologic newborn examination of cranial nerves, muscle tone, and reflexes was performed in all infants before fMRI. The evaluation included assessment of general movement (GM) patterns. At a term age, 2 researchers (Drs Bos and Sival), blinded to the patient's history, assessed the quality of GMs independently by Gestalt Perception.20–22
The psychomotor development at the age of 4 to 6 months' PCA was evaluated by using the Griffiths Mental Development Scales.23 This test includes 5 subscales describing different developmental categories: locomotor (A), personal-social (B), hearing and speech (C), hand and eye coordination (D), and performance (E). A developmental quotient (DQ = chronological age/developmental age) was calculated. According to Griffiths, the diagnosis of developmental delay can be made when the score is 2 SD below the mean. In the German version, the lower limit of the "normal" range is 78.23
Diagnosis of Perinatal Brain Damage
Perinatal brain damage was characterized according to the degree of intraventricular hemorrhage (IVH), white matter damage (WMD), and ventricular dilatation diagnosed on serial cerebral ultrasound investigations and on conventional MRI at term-equivalent age.
Ultrasound
Cerebral ultrasound was performed with the use of an 8.5- to 10-MHz transducer (Vingmed Vivid FiVe, GE Vingmed Ultrasound, Horten, Norway) after birth, at days 7 and 28 postnatal age, and at term-equivalent age. The sonographic findings of IVH and WMD were classified by using the criteria of Papile24: (1) grade I (mild): germinal matrix hemorrhage with no or minimal intraventricular hemorrhage; (2) grade II (moderate): intraventricular hemorrhage (10%–50% of ventricular area in parasagital scan); (3) grade III (severe): >50% of ventricular area in parasagital scan; and (4) grade IV: apparent periventricular hemorrhagic infarction. WMD was defined as single or multiple cystic periventricular leukomalacia or gross cystic WM defect after hemorrhagic infarction of the periventricular WM.25
Patient Monitoring/Safety
One hour before the MRI session, the infants were fed orally to obtain natural sleep. In addition, chloralhydrate (50 mg/kg) was administered via a gastric tube for sedation 30 minutes before MRI. Vital signs (body temperature, heart rate, and oxygen saturation) of the study patients were continuously monitored during the fMRI (FTI-10, FISO Technologies Inc, Québec, Canada; Nonin 8600 F0, Nonin Medical Inc, Plymouth, MN). A triple acoustic protection (ear prongs, mini muff acoustic shells, head phones) was used in all infants. To rule out any relevant hearing impairment associated with the MRI, brainstem evoked response audiometry (Echo-screen system; Mack Medizintechnik, Pfaffenhofen, Germany) were performed pre- and post-MRI.
Structural MRI
All MRI scans were performed on a 3.0T Achieva system (Philips, Best, Netherlands) using an 8-channel adult SENSE head coil. The clinical protocol consisted of a standard T1-weighted SpinEcho sequence (repetition time [TR]/echo time [TE]/flip: 580 milliseconds/13 milliseconds/90°, 22 slices, resolution: 0.8 x 1.0 x 4.0 mm3), a T2-weighted TSE-sequence (TR/TE/flip: 4200 milliseconds/80 milliseconds/90°, 22 slices, reconstruction resolution: 0.6 x 0.8 x 4.0 mm3) and a diffusion weighted sequence (TR/TE/flip: 2858 milliseconds/40 milliseconds/90°, 22 slices, reconstruction resolution: 2.0 x 2.0 x 5.0 mm3; max b value: 1 second/mm2).
For superposition of the statistical maps, a high resolution T1-weighted data set was obtained (T1-TFE, TR/TE/flip: 9.38 milliseconds/4.32 milliseconds/8°, 120 slices, resolution: 0.78 x 0.78 x 0.83 mm3). The diagnosis of diffuse excessive high signal intensity (DEHSI) in the periventricular WM was made on the T2-TSE sequence as well as based on the measurement of the apparent diffusion coefficient (ADC ratio). The ADC ratio was determined in the periventricular WM in each patient on a diffusion-weighted sequence according to Counsell et al.26
fMRI
The fMRI was performed as part of the diagnostic MRI session using a Single Shot EPI sequence (TE/TR/flip: 35 milliseconds/2.60 milliseconds/90°, spatial resolution: 1.88 x 1.88 x 3.59 mm3). For passive sensorimotor stimulation, wristbands (Infant limb holder; J.T. Posey Company, Arcadia, CA) were attached to both wrists. Unilateral forearm extension/flexion movements were induced by manual traction at a frequency of 
1 Hz by a physician standing in proximity to the scanner gantry. The stimuli were delivered in a block-design, consisting of 10 alternating periods of 20 seconds each, 5 times rest (no movement) and 5 times activation (passive movement), independently for the left and right forearm.
Data Analysis
Preprocessing and data analysis was performed with SPM5 (Wellcome Department of Imaging Neuroscience, London, United Kingdom) based on Matlab 7.1 (The Mathworks Inc, Natick, MA). All functional images were spatially realigned to the first functional image to correct for head motion during the fMRI session. The resulting data sets were coregistered to the individual T1-weighted MRI and smoothed spatially using a 6-mm isotropic Gaussian kernel. The smoothed data were analyzed using the principles of the general linear model.27. The design matrix consisted of 2 event types (movement and rest). The movement parameters obtained during the motion correction were included as covariates of no interest in the model. The following functional contrasts were considered using t tests on a voxel-by-voxel basis: (1) movement – rest, (2) rest – movement. The first contrast assesses the positive BOLD response, whereas the second contrast assesses the negative BOLD response on stimulation.
Based on the well-established neuroanatomic knowledge of the sensorimotor cortex, significance was considered when the activation in this region surpassed an uncorrected height threshold of P < .001. To explore the data of this exploratory single-subject study qualitatively, we report the activation at 3 different statistical thresholds, 2 corrected (P < .05, family-wise error [FWE]27; P < .05, false discovery rate [FDR],28) and 1 uncorrected (P < .001) for multiple comparisons. The uncorrected threshold is equal to the chosen threshold used by Erberich et al18 and assures that weak activations are not overlooked. The corrected thresholds (FWE/FDR) correct for multiple comparisons and therefore are more conservative but, at the same time, ensure the robustness of the results.
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RESULTS |
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The fMRI was well tolerated by all enrolled infants. No adverse effects of the sedation were observed under continuous monitoring for vital signs. The brainstem evoked response audiometries showed no changes in auditory thresholds resulting from MRI. Ten fMRI data sets from 5 children were analyzed, 5 for each side. The patient characteristics, ultrasound, and clinical MRI findings of the study population are summarized in Table 1. In all 5 children IVH was diagnosed on routine ultrasound during the first week of life. On MRI at term-equivalent age, 2 patients demonstrated bilateral DEHSI in the periventricular WM and increased ADC values in the frontal and occipital WM. None of the patients demonstrated additional evidence of cystic WMD (Table 1).
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On passive unilateral sensorimotor stimulation, bilateral activation in the sensorimotor cortex was observed in 9 of 10 trials. The prevailing BOLD response was a negative BOLD signal (n = 7 of 10 data sets). Differing from these findings, 1 patient (NEO 05) showed a positive BOLD response in the sensorimotor cortex and 1 patient (NEO 01) a failure to activate the sensorimotor cortex on left-sided stimulation. Table 2 summarizes the fMRI findings (positive, negative BOLD response) and the statistical significance level of the activations in the primary sensorimotor cortices. Exemplary cases are illustrated in Figure 1A–C.
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Table 3 summarizes the results of the neurologic examination and video assessment of GMs at term-equivalent age, as well as the neurodevelopmental testing at the mean age of 4 to 6 months' corrected PCA. NEO 05 was the only patient with aberrant findings in all 3 clinical tests (mild muscular hypertonia, poor movement repertoire, and motor skills, 1.7 month below median age; subscale A, Griffiths test). NEO 01 was characterized by a predominantly left-sided IVH, a poor motor repertoire, and bilateral DEHSI.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Preterm birth impacts fundamentally on the normal development of the neonatal brain. PWMI is a major cause of neurologic impairment in the high-risk newborn and has a strong predilection for long-term motor sequelae. The proportion of PWMI from prenatal origin accounts for approximately one third of cases.29 In affected preterm infants, long-term motor competence is significantly impaired.30
Because of the high frequency and overall developmental implications of motor sequelae after preterm delivery, early identification of concomitant motor deficits is an extremely important clinical issue. Reliable and early "functional biomarkers" will be crucial for designing individually tailored early intervention and rehabilitation programs starting at the NICU31–33 or as early home intervention34 to maximize the recovery processes in affected preterm infants.35 Because structural imaging allows only indirect inference on functional states, Cioni et al9 proposed already in the 1990s a more "comprehensive approach, including longitudinal functional and electrophysiological testing." Observation of gross movement patterns provides sensitive measures of impaired motor function in the neonatal brain long before neurologic deficits like cerebral palsy become evident.20,36,37
In addition to these time-intensive and challenging tests of gross movement abnormalities, direct functional biomarkers that can be obtained in a standardized fashion with high sensitivity and specificity are warranted at this early time point of human brain development. Therefore, the rationale of our approach, namely using fMRI in preterm children as a tool to study the integrity of the principal ascending and descending sensorimotor pathways, is based on the assumption that functional deficits may be directly visualized within a clinical MRI setting.
fMRI is a noninvasive imaging tool that allows identifying task-related activation changes in the human brain. Presently, this technique has not been validated sufficiently in neonates, and functional responses to sensorimotor stimulation have not been systematically studied within the first months of life, therefore, limiting pathophysiological assignments. Up until now, only 2 fMRI studies have been published using a standardized passive movement protocol in infants during the first months of life.18,19 In contrast to our study, preterm infants of different GA as well as term infants were studied within the first month of life, without stratification according to cerebral morbidity.18 It was demonstrated that the cortical activation pattern on passive sensorimotor stimulation around term-equivalent age involves bilateral sensorimotor cortices (SMCs), indexed as both positive and negative BOLD responses.18 This observation contrasted with predominantly contralateral activations of the sensorimotor cortex (eg, positive BOLD responses only) between months 3 and 9 of life, thereby depicting with fMRI different maturation stages of the sensorimotor system within the first year of life.
In contrast to Erberich et al,18,19 we implemented a 20-minute duration fMRI protocol as part of a diagnostic MRI session at term-equivalent age to specifically focus on patients at highest risk of perinatal brain damage. The patient assignment followed a stratification by clinical risk factors (preterm birth 
30 weeks' GA), as well as morphologic brain lesions (IVH, WMD) diagnosed on serial routine ultrasound examinations. The fMRI/MRI session took place between 38 and 39 weeks' PCA to allow for functional studies at a precisely defined maturational stage of the neonatal brain. None of the infants showed cystic WMD or asymmetric myelinization of the internal capsula on MRI predicting gross motor deficit (Table 1). In 2 patients, DWI revealed elevated ADC ratios in the bilateral periventricular WM. DEHSI has been related to oligodendrocyte or axonal abnormality throughout the WM18 and to poor developmental outcome in preterm infants without additional signs of WMD on MRI at term-equivalent age.38
From our 10 data sets, we can conclude that a bilateral negative BOLD response in primary sensorimotor cortices is the predominant hemodynamic response in preterm infants studied at term-equivalent age. The bilateral activation pattern in primary SMC is compatible with a bilaterally distributed system at this age. Considering previous accounts of negative bilateral BOLD responses also in infants born at term,18,19 it is likely that this is the prototypical hemodynamic response at this stage of brain maturation. However, future comparative studies with neonates born at term will have to prove this assumption.
It cannot be ruled out at present, that extrauterine environmental influences affect the BOLD response in preterm infants at that early time point. Even in the absences of traceable structural brain damage, the infantile phase of cortical development is highly susceptible to extrauterine environmental influences.39 In animal studies, the effects of precocious sensory stimulation have been investigated experimentally. For instance, Bourgeois and coworkers40 delivered rhesus monkey fetuses by cesarean section 3 weeks before term and exposed them to normal light intensity and day/night cycles. They were killed within the first postnatal month to study time course, magnitude, and pattern of perinatal synaptic overproduction. Quantitative electron microscopy of the primary visual cortex revealed that the size, type, and laminar distribution of synapses differed significantly between preterm and control animals. Similar effects can also be expected in human neonates. Thus, understanding the functional consequences of extrauterine environmental stimulation will be an interesting topic of future research.
Basic studies of the type presented here, aimed at characterizing response patterns (positive BOLD/negative BOLD) in relation to maturation status, are important prerequisites for thorough detection of brain pathology with fMRI. Indeed, the significance of the inversion of the hemodynamic response in functional neuronal systems during early brain development is still under debate. According to postnatal studies in the visual system, the inversion of the hemodynamic response occurs during an accelerated phase of neuronal organization and synapse formation, as evidenced by histologic means.41 Thus, reductions of the oxy/deoxy-hemoglobin (Hb) ratio in activated brain tissue, as seen in our infants, may reflect a maturational stage characterized by rapid formation of synapses, yet ineffective processing, which will result in high metabolic demand that is not compensated by increased local perfusion. Interestingly, 2-deoxy-2[18F]fluoro-D-glucose positron emission tomography performed in infants 5 weeks of age and younger, showed that cortical glucose use at this early time point is highest in the SMC,42 which is compatible with an early reduction of the oxy/deoxy-Hb ratio in this region, compared with the visual system, where the inversion of the oxy/deoxy-Hb ratio has been observed starting at the age of 2 months.41 Similarly, Born et al43 have described either positive or negative BOLD responses in primary visual cortex induced by 8-Hz flicker light stimulation during natural sleep in children <60 weeks' PMA. Despite physiologic issues, technical aspects also have to be considered. Up until now, the exact shape of the hemodynamic response in the newborn brain was not known. Therefore, one might argue that the observed negativity of the BOLD response might only reflect an incorrectly estimated hemodynamic response function. However, using a block design in this study, we argue that the influence of the exact shape of the hemodynamic response function on the resulting BOLD signal is minimized and, therefore, a change of the sign of the BOLD response (positive versus negative) could only result from a large phase shift (>20 seconds). This, however, is extremely unlikely.
To further advance the understanding of the intrinsic hemodynamic response in relation to maturational stage of different brain systems, in the future, event-related approaches, possibly in combination with near infrared spectroscopy, will be required.
Presently, the small number of patients in this sample of extremely preterm children precludes from inferring on later motor status. Neurologic examination and neurodevelopmental tests at the age of 4 to 6 months did not show a constant pathologic pattern, except 1 patient (NEO 05), who demonstrated a positive BOLD response, thus differing from all other infants. Despite no major findings of cerebral morbidity on ultrasound, he presented bilateral periventricular DEHSI on MRI, abnormalities on neurologic examination at term-equivalent age (muscular hypertonia, poor movement repertoire), and impaired motor skills in Griffiths developmental scales at 4 months' corrected age (DQ: 82.5; motor skills: –1.7 months). In contrast to the other infants, NEO 05 was exposed to long-term total intravenous anesthesia in the course of 3 surgical interventions. This aberrant behavior in clinics and imaging may reflect a delayed developmental organization of the sensorimotor system. Clearly, additional long-term neurodevelopmental follow-up will be crucial to validate the significance of these findings.
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CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Our preliminary data show the feasibility of neonatal fMRI using passive unilateral hand extension/flexion in a clinical diagnostic MRI session. Acoustic noise is one of the major safety issues and warrants adequate protection and monitoring. The bilateral activation pattern is compatible with a bilaterally distributed arrangement of the principal sensorimotor pathways. Long-term clinical follow-up will determine whether fMRI is capable of identifying functional deficits at this early preclinical stage and whether fMRI may serve as a predictor for clinical outcome. Correlations with other structural and functional information, for instance indices of spontaneous gross motor activity, will be crucial. The reductions of the oxy/deoxy-Hb ratio in activated brain tissue, as seen in also in the majority of our patients, may reflect ineffective and energy-consuming processing at a maturational stage characterized by rapid formation of synapses. In the future, it will be important to implement event-related fMRI protocols to monitor the local hemodynamic changes time-locked with sensory stimulation.
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ACKNOWLEDGMENTS |
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This work was supported by grants from the BONFOR-Forschungskommission at the University Hospital Bonn.
We thank all parents for their cooperation and are very grateful to Professor F. Groenendaal (Utrecht, Netherlands) for fruitful discussions and technical advice.
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FOOTNOTES |
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Accepted Apr 15, 2008.
Address correspondence to Axel Heep, MD, University of Bonn, Department of Neonatology, Adenauerallee 119, D-53113 Bonn, Germany. E-mail: axel.heep{at}ukb.uni-bonn.de
The authors have indicated they have no financial relationships relevant to this article to disclose.
| What's Known on This Subject MRI provides indicators of structural brain changes predictive for long-term neurodevelopmental deficits in preterm infants. Structural MRI only allows inferring indirectly on functional states. There are initial observations using fMRI to study the sensorimotor system in the neonatal brain.
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| What This Study Adds Functional MRI was implemented in a clinical MRI setup in preterm children at term-equivalent age. Prototypical activation patterns in the primary sensorimotor cortex were identified and related to structural and early behavioral measures.
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