PEDIATRICS Vol. 119 No. 4 April 2007, pp. 759-765 (doi:10.1542/peds.2006-2508)
ARTICLE |
Quantification of Deep Gray Matter in Preterm Infants at Term-Equivalent Age Using Manual Volumetry of 3-Tesla Magnetic Resonance Images
a Department of Pediatrics, Hammersmith Hospital, London, United Kingdom
b Imaging Sciences Department, Division of Clinical Sciences, Imperial College, London, United Kingdom
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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OBJECTIVE. Nonhypothesis-based MRI-analysis techniques including deformation-based morphometry and automated tissue segmentation have suggested that preterm infants at term-equivalent age have reduced tissue volume in the basal ganglia and thalami, which is most apparent among infants with supratentorial lesions. The aim of our study was to test this hypothesis by direct measurement of thalamic and lentiform nuclei volumes in preterm infants at term-equivalent age and term-born controls using manual volumetry.
DESIGN/METHODS. Forty preterm infants at term-equivalent age (median gestational age: 29.5 weeks; median birth weight: 1.3 kg) and 8 term-born controls were examined using a 3-T Philips (Best, Netherlands) system. T1-weighted volume images and T2-weighted fast-spin echo pseudovolumes were acquired. There was no significant difference in postmenstrual age at image acquisition between the 2 groups. ImageJ 1.34 (National Institutes of Health, Bethesda, MD) was used for manual segmentations.
RESULTS. The median thalamic and lentiform nuclei volumes for preterm infants at term-equivalent age were 13.6 and 3.07 cm3, respectively, significantly smaller than term-control volumes of 16.3 and 5.6 cm3, respectively. Ten preterm infants at term-equivalent age had supratentorial lesions (intraventricular hemorrhage, periventricular leukomalacia, or hemorrhagic parenchymal infarction), and the median thalamic and lentiform volumes for this group were 10.4 and 1.7 cm3, respectively. When this group was excluded, the remaining infants who had mild or moderate diffuse excessive high signal intensity in the white matter on T2-weighted images had a smaller, yet significant, volume reduction compared with controls. Tissue volumes were not related to weight and gestational age at birth.
CONCLUSIONS. Manual volumetry confirms that preterm infants at term-equivalent age have reduced thalamic and lentiform volumes compared with controls. This was most marked among infants with supratentorial lesions but was also seen among those with nonfocal white matter abnormalities.
Key Words: basal ganglia and thalamus • preterm infants • magnetic resonance volumetry
Abbreviations: WM—white matter • DEHSI—diffuse excessive high signal intensity • DBM—deformation-based morphometry • PAT—preterm at term-equivalent age • GA—gestational age
The increasing survival of premature infants is associated with an increased risk of cognitive and behavioral disorders.1,2 This leads to the investigation of the cortex, white matter (WM), basal ganglia, and cerebellum as putative neuroanatomical sites where abnormalities may contribute to these neurodevelopmental abnormalities.
WM disease, both cystic (diagnosed by MRI and cranial ultrasound imaging as periventricular leucomalacia) and noncystic (detected by MRI as diffuse excessive high signal intensity [DEHSI] on T2-weighted scans),3,4 have been the focus of much recent research because the incidence of WM disease (50%–70%)5 parallels the incidence of neurodevelopmental impairment.1 The basal ganglia and thalamus also were shown to have both diffuse and focal punctuate hyperechogenicity on ultrasound in preterm infants during the early neonatal period,6 although by term-equivalent age only 4% of infants have major persisting thalamic abnormality detected by conventional MRI.7
Some studies have suggested that WM disease may be linked to abnormalities in the basal ganglia and thalamus. Lin et al8 examined the relationship of WM disease and thalamic abnormality by manual delineation of the thalamic area on 2-dimensional MRIs in ex-preterm infants; the finding of a reduction in the ratio of area of the thalami to the cerebellum at 9 to 12 months in children with periventricular leucomalacia was compared with patient controls. However, this simple approach was potentially flawed because Lin et al did not measure tissue volumes, and comparison of thalamic areas with cerebellar areas were not ideal because the latter may be also compromised by the presence of WM injury.9 Recently, more advanced image analysis approaches have been applied. Boardman et al10 used deformation-based morphometry (DBM) to show that preterm at term-equivalent age (PAT) infants have reduced lentiform nuclei and thalamic volumes; this reduction was associated with both lower gestational age (GA) and the presence of noncystic WM disease. Inder et al,11 using an automatic segmentation technique, found a reduction in cortical, deep gray matter and WM volumes in PAT infants, although the deep gray matter reductions seen in this study were in a mixed group of infants with and without apparent WM injury.
Both DBM and automated segmentation techniques are nonhypothesis-driven methods that survey the whole brain to detect differences between 2 groups of patients, and the results clearly raise the specific hypothesis that PAT infants have smaller basal ganglia and thalami compared with term-born controls, which may be more severe in the presence of overt WM disease. Our study addresses this hypothesis.
Our study used manual volumetry to measure the volume of thalamic and lentiform nuclei in PAT infants and term-born controls to test the hypothesis that the size of these structures is reduced in PAT infants, particularly in the presence of overt WM disease.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Patient Characteristics
The preterm infants were recruited from the NICU at Hammersmith Hospital, and term-born control infants were recruited from the postnatal wards. Infants with congenital anomalies, metabolic disease, or congenital infections were excluded. The study was conducted with approval from Hammersmith Hospital Research Ethics Committee, and the infants were scanned after written parental consent was obtained. The preterm infants were <34 weeks' GA at birth and were scanned at term-equivalent age (37–44 weeks' GA). All neonates had standard neonatal management with serial cranial ultrasounds as part of their clinical care. Information about GA, birth weight, head circumference, chronic lung disease (defined as a need for supplemental oxygen at 36 weeks' GA), days to full enteral feeding, necrotizing enterocolitis, and sepsis were obtained from the clinical notes.
MRI Acquisition
MRIs were acquired on a 3-T Philips Intera system (Best, Netherlands). The preterm infants were sedated with chloral hydrate, and a trained neonatologist was present throughout scanning. Term-born controls were fed and swaddled, and the examination was conducted in natural sleep. All infants were monitored with pulse oximetry and electrocardiographic monitoring. Ear protection, consisting of silicon-based dental putty individually molded and fitted into the external ear- and minimuffs (Natus Medical, San Carlos, CA), was used to achieve 
30-dB sound attenuation. The infant's position was stabilized using a suction-evacuated pillow.12
The magnetic resonance sequence parameters were as follows: T1-weighted magnetization prepared rapid-acquisition gradient echo volumes: repetition time, 17 milliseconds; echo time, 4.6 milliseconds; field of view, 210 mm; matrix, 256 x 256; flip angle, 30°; number of acquisitions, 1; and voxel size, 0.86 x 0.86 x 0.8 mm; T2-weighted fast-spin echo pseudovolumes: repetition time, 8000 milliseconds; echo time, 160 milliseconds; field of view, 220 mm; matrix, 224 x 224; and flip angle, 90°. T1-weighted volume images were acquired in the sagittal plane and reformatted into transverse and coronal planes. T2-weighted images were acquired in the transverse plane.
Image Analysis
Images were visually assessed for normal anatomic appearance to the cerebral cortex, basal ganglia and thalami, WM, and cerebellum. The presence of overt focal lesions, such as cystic periventricular leucomalacia, hemorrhagic parenchymal infarction, and ventricular dilatation with or without residual intraventricular hemorrhage was noted. DEHSI was defined as high signal intensity in the WM on T2-weighted images and visually classified as mild, moderate, and severe: mild if there was increased signal intensity confined to a small region of the posterior periventricular WM; moderate if there was increased signal intensity in posterior and anterior periventricular region extending into the centrum semiovale; and severe if the high signal intensity extended from the periventricular area into the subcortical WM.
Thalamic and Lentiform Nuclei Quantification
ImageJ 1.34 (National Institutes of Health, Bethesda, MD) software was used for image processing and manual segmentation. The lentiform nuclei were measured by one observer (Mr Dutta) and the thalami by another (Dr Srinivasan). Intraobserver variability was calculated for each observer. Measurements were performed on all T1-weighted images, and in a subset of patients the thalamic measurements were performed on both T1- and T2-weighted images to check consistency between the 2 images. Each patient had a total of 100 image slices of which 40 slices contained deep gray matter structures. The start and end points for the anatomic position of each structure of interest were defined with the aid of a reference brain atlas.13
Putamina and Globi Pallidi
The lentiform nuclei are situated lateral to the caudate nuclei heads and thalami. Anteriorly, they are separated by the anterior limb of the internal capsule from the caudate nuclei and posteriorly from the thalami by the posterior limb. The external capsules form the lateral borders and separate them from the adjacent WM. Inferiorly, the segmentation included the nuclei accumbens, substantia innominata, and the amygdalae to the level of the anterior commissure. An example of the manual segmentation of the lentiform nuclei at several anatomic levels is given in Fig 1.
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Thalami
The thalami are composed of many nuclei, all of which were included in the segmentation. Each thalamus is situated between the head and the tails of the caudate nucleus. The third ventricle forms the medial border and the posterior limb of the internal capsule forms the lateral border; the lateral ventricle forms the posterior border, and the subthalamic nuclei along with the geniculate bodies form the inferior border. An example of the manual segmentation of the thalamus at several anatomic levels is also given in Fig 1.
Statistics
Statistical analysis was performed by using StatsDirect 2.0.1 (StatsDirect Ltd, Altrincham, United Kingdom). The data were tested for Normality by Shapiro-Wilk test before each analysis. Intraobserver variabilities for the thalamic and lentiform nuclei measurements were calculated by using an intraclass correlation coefficient. The correlation of thalamic volumes measured using T1- and T2-weighted sequences were tested by using simple linear regression and Bland-Altman analysis. A Mann-Whitney U test was used to compare the medians of volumes between individual groups, followed by the Kruskal-Wallis test to allow multiple comparison testing. Exploratory analysis with clinical variables was conducted using simple and multiple regressions.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Patient Characteristics
Forty preterm infants were recruited with a median GA of 29.5 weeks (range: 25–33 weeks), median birth weight of 1.3 kg (range: 0.6–2.3 kg), and median head circumference at birth of 27.2 cm (range: 22.5–34.5 cm). The preterm infants were scanned at term-equivalent age; the median GA at scan was 40 weeks' corrected (range: 37–44 weeks). Eight term-born control infants were scanned at a mean of 42.5 weeks (range: 38–45 weeks). The median weight at scan was 3.09 kg (range: 2–4.3 kg) for the PAT infants and 3.65 kg for the term-born controls (range: 3.3–4.7 kg). There was no significant difference in the postmenstrual age at scan or weight at scan between the 2 groups of infants. The median head circumference at scan for the PAT infants was 36.1 cm (range: 32.5–38.5 cm) and for the term-born controls was 36.2 cm (range: 35–38 cm).
Three preterm infants developed chronic lung disease, 2 needed inotropes, and 3 had significant patent ductus ateriosus, which was treated with ibuprofen. Seven preterm infants were diagnosed as suffering sepsis during their hospital admission by a positive blood culture or a clinical diagnosis accompanied by raised C-reactive protein and white cell counts; 3 infants had coagulase negative staphylococcus and 1 had enterobacter. The 2 infants had early culture negative sepsis, and the remaining infant had late onset culture negative sepsis. The preterm infants received total parenteral nutrition for a median of 4 days and achieved full enteral nutrition at a median of 6 days. One infant had suffered from necrotizing enterocolitis.
Intraobserver Correlation
Initial training was conducted by segmentation of the lentiform nuclei in 1 infant 50 times. Then, intraclass correlation for both the lentiform nuclei and thalamus were obtained by repeating the segmentation twice in 10 infants. The intraclass correlation coefficient from the repeated measurements for lentiform nuclei was 0.99 and for the thalamus was 0.96.
Comparison of Volumetry Using T1- and T2-Weighted Sequences
In a subset of 15 infants, the thalamic measurements were performed by using both T1- and T2-weighted images. Simple linear regression showed a significant correlation; and Bland-Altman analysis showed a mean difference of 1.6 cm3and limits of agreement of –5.2 to 2.8 cm3. The Bland-Altman plot for these measurements is given in Fig 2. The T1-weighted images were used in all additional analysis because these were true volume acquisition scans as opposed to T2 scans, which were acquired as pseudo volumes with overlapping slices.
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Thalamic and Lentiform Volumes
Term-born controls had a median thalamic volume of 16.3 cm3 and a median lentiform nuclei volume of 5.6 cm3. PAT infants had a median thalamic volume of 13.6 cm3 and a median lentiform nuclei volume of 3.07 cm3, which were significantly smaller compared with term-born controls infants (P < .0001). There was a wide range for the thalamic and lentiform nuclei volumes in PAT infants as shown in Fig 3, and additional analysis was conducted to determine whether the presence of supratentorial lesions explained this variance, together with an exploratory analysis of the effect of perinatal factors.
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Cerebral Lesions and Deep Gray Matter Volumes
Ten of the preterm infants had overt supratentorial lesions, such as intraventricular hemorrhage (3 infants), periventricular leucomalacia (3 infants), or hemorrhagic parenchymal infarction (4 infants). In 1 of the 3 infants who had hemorrhage, the hemorrhage extended into the basal ganglia and thalami. Infants with supratentorial lesions showed the most significant reduction in volume of both thalami and lentiform nuclei (Figs 4 and 5). The median thalamic volume and lentiform nuclei volumes in infants with lesions were 10.4 and 1.7 cm3, respectively. The median thalamic volume and lentiform nuclei volumes in infants without lesions were 14 and 3.07 cm3, respectively; these remaining infants had mild to moderate DEHSI on visual inspection of their T2-weighted images. Kruskal-Wallis analysis with pairwise comparisons (Dwass-Steel-Chritchlow-Fligner) showed significant differences between term controls and PAT infants without lesions (P = .0002), term controls versus PAT infants with lesions (P = .0015), and PAT infants with and without lesions (P < .0001). At a descriptive level, the severity of supratentorial lesion was related to the volume reduction; however, because there were only 10 infants with lesions, we were unable to make any statistical inference.
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Exploratory Analysis
Thalamic and lentiform nuclei volumes were not significantly related to any of the clinical variables: weight and GA at birth, postmenstrual age, weight at scan, and head circumference at birth and at scan. The effect of these variables on thalamic and lentiform volumes were initially tested by using simple regression analysis for each individual variable. To confirm the noncorrelation seen in the simple regression, a multiple regression analysis was performed with all the above-mentioned variables as covariates for the thalamic and lentiform volumes. When the infants were divided into 2 groups (<28 weeks [extreme preterm] and >28 weeks), there was still no significant difference. The deep gray matter volumes were not related to days of ventilation, chronic lung disease, days to full enteral feeding, necrotizing enterocolitis, or sepsis.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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This study supports the suggestion raised by nonhypothesis image analysis techniques that PAT infants show a reduction in lentiform nuclei and thalamic volume, and that the reduction is more pronounced in the presence of supratentorial lesions, predominantly focal WM.
DBM showed previously a reduction in the volume of the basal ganglia and thalamus, with no reduction in cortical or WM volumes. This reduction was only seen in the more preterm group and those with WM disease. This technique is a high dimensional registration technique that is highly sensitivity to local changes that are globally summated to reveal significant differences between patient groups.14 However, this approach to morphometric measurement provides a whole brain survey that is not based on any previous hypothesis, and formal statistical inference can be problematic. Our study effectively tests the hypothesis raised by the survey, confirming and clarifying the results.
Inder et al11 used automated segmentation to make another hypothesis-free survey and found reductions in the cortical, WM, and deep gray matter volumes in a mixed group of infants with and without WM lesions. The reduction in the deep gray matter volumes in this cohort depended on GA and was associated with more severe respiratory illness. Although automated segmentation is thought to be problematic in the neonatal brain because of the overlapping signal intensities from the different tissue types, our study provides confirmation of these deep gray matter results.
The deep gray matter has become an important focus of investigation because all the information to and from the cortex is relayed through and is modulated by the thalamus. Traditionally, basal ganglia dysfunctions were associated with a range of debilitating movement and psychiatric disorders in conditions, including Parkinson's disease,15 Huntington chorea,16 schizophrenia,17,18 attention-deficit disorder, Tourette syndrome,19 and various addictive behaviors. In neonates with hypoxic ischemic encephalopathy, the basal ganglia and thalamus are the main sites of injury in infants who develop predominantly motor impairments, such as cerebral palsy. However, when the lesions are severe, cognition is also affected. This led to an increasing recognition that the basal ganglia and thalamus may have an impact on normal cognition and affective functions.16,20
The basal ganglia and thalami are known to have very high metabolic rates and to be sensitive to hypoxic ischemic injury in infants.21 Hence, primary damage to the thalamus resulting in reduced size cannot be ruled out without the benefit of early imaging. This early imaging may need to include measures of tissue microstructure, provided by diffusion tensor imaging, because acute or subtle injury may not be visually detectable on conventional MRIs.
However, confirmation of the coherent reduction in the deep gray matter and WM damage suggests the possibility that WM injury might be a mechanism that leads to secondary damage and abnormal thalamocortical connectivity, resulting in a reduction in lentiform nuclei and thalamic volume. Lesions in the developing WM may be associated with a particular damage to the cortical subplate. There is animal evidence that injury to the subplate leads to thalamocortical disturbances.22 The subplate contains a transient set of neurons surrounded by a rich extracellular matrix and is maximally visible on MRI and histology23 during the second trimester when premature infants are undergoing intensive care. The subplate, with its neurons and extracellular matrix, forms a waiting zone for the thalamocortical afferents and efferents and receives guidance molecules that guide these fibers to the appropriate cortical regions. It is possible that diffuse WM disease includes injury to the subplate, maximizing the thalamocortical disturbances seen in preterm infants and causing a secondary reduction in deep gray matter volumes.
Abnormalities in the thalamus were shown in animal studies after lesions in the cerebral cortex. The subsequent axotomy leads to retrograde microglial-induced reduction in the number of thalamic neurons.24 The microglia are thought to mediate injury by excitotoxic glutaminergic mechanisms. The injury leads to a reduction in the thalamic volume and a relative increase in the cell density.25 Hence, in preterm infants the disturbances within the WM either focally, such as periventricular leukomalacia, or diffusely, such as DEHSI, may be associated with concomitant injury to the vulnerable cortical subplate, and these may precede and result in thalamic and basal ganglia abnormalities.
Some potential limitations of this study deserve consideration. First, diffuse WM injury (DEHSI) was identified by visual inspection and not by objective quantification of diffusion parameters. However, it has been shown by previous studies that infants with visually classified DEHSI have a reduction in fractional anisotropy and an increase in apparent diffusion coefficient in their WM.3,4,26 Second, there is some potential for confounding of the data by growth, because there was a nonsignificant trend of increased age in the term-born controls. It is known that cerebral and cerebellar volumes increase between 40 and 44 weeks' GA,27 hence there is a potential that the basal ganglia and thalami may also increase in volume during this period. However, no growth was detected over this time period in both the term-control infants and PAT infants, although the study was not powered to detect the growth issue and, therefore, cannot be formally excluded.
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CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Using manual techniques, we have shown that the volume of the lentiform and thalamic nuclei are reduced in preterm infants at term-equivalent age compared with term-born controls. Although preterm infants with overt supratentorial cerebral lesions have the most marked reduction in volume, significant reductions were also seen with milder diffuse WM changes consistent with DEHSI. These results support and extend the conclusions of studies using DBM and automatic segmentation.
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ACKNOWLEDGMENTS |
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We thank the Garfield Weston Foundation for continued support. Dr Srinivasan was funded by the March of Dimes (United States); Dr Counsell was funded by the United Kingdom Department of Health; Dr Boardman was funded by Medical Research Council, United Kingdom; and Ms Rutherford was funded by Health Foundation (United Kingdom).
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FOOTNOTES |
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Accepted Nov 15, 2006.
Address correspondence to A. David Edwards, FmedSci, Department of Pediatrics, Imperial College, Hammersmith Hospital, Du Cane Road, London W12 0NS, United Kingdom. E-mail: david.edwards{at}imperial.ac.uk
The authors have indicated they have no financial relationships relevant to this article to disclose.
This work was presented at the Pediatric Academic Society meeting; April 29–May 2, 2006; San Francisco, CA.
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