R E S E A R C H
A R T I C L E
Volumetric MRI and MRS and Early
Motor Development of Infants
Born Preterm
Erlita Gadin, MD; Michele Lobo, PT, PhD; David A. Paul, MD; Kanik Sem; Karl V. Steiner, PhD; Amy Mackley, RNC;
Kert Anzilotti, MD; Cole Galloway, PT, PhD
Departments of Pediatrics and Neonatology (Drs Gadin and Paul and Ms Mackley) and Radiology (Dr Anzilotti),
Christiana Care Health System, Newark, Delaware; Departments of Physical Therapy (Drs Lobo and Galloway) and
Electrical & Computer Engineering (Dr Steiner and Mr Sem), University of Delaware, Newark, Delaware; Department of
Pediatrics (Drs Gadin and Paul), Thomas Jefferson University/Nemours Children’s Clinics, Wilmington, Delaware.
Purpose: To investigate the relationship between volumetric magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) in infants born less than 30 weeks gestation and early motor development
at 6 months adjusted age. Methods: Twenty infants born preterm and 4 born at term (control) underwent
MRI with volumetric analysis and MRS prior to neonatal intensive care unit discharge. Infants were assessed
using the Bayley Scale of Infant Development at 6 months adjusted age. Results: At 6 months, infants born
preterm with low motor scores had a reduction in their subcortical gray matter. No differences were detected
in other brain structures. N-acetylaspartate/choline correlated with white matter (R = 0.45, P = .03), gray matter (R = 0.43, P = .04), and cerebellar volume (R = 0.6, P = .002) but not with 6-month motor performance.
Conclusion: There is an association between diminished subcortical gray matter volume and low motor scores.
Our data suggest that volumetric MRI performed prior to hospital discharge may have some role in counseling
parents about potential motor delays. (Pediatr Phys Ther 2012;24:38–45) Key words: brain/growth & development, brain/metabolism, central nervous system/growth & development, child development/physiology,
comparison study, female, gestational age humans, longitudinal study, magnetic resonance imaging, magnetic resonance spectroscopy, male, newborn infant/growth and development, premature infant/growth &
development, prospective study, severity of illness index
INTRODUCTION
Advances in obstetrical and neonatal medicine have
improved the survival of premature infants, especially
those born at younger gestational ages. Infants born before 32 weeks gestation now represent more than 2% of all
live births and their survival rates exceed 85%.1 Follow-up
0898-5669/110/2401-0038
Pediatric Physical Therapy
C 2012 Wolters Kluwer Health | Lippincott Williams &
Copyright Wilkins and Section on Pediatrics of the American Physical Therapy
Association
Correspondence: David A. Paul, MD, 4745 Ogletown Stanton Rd, MAP
1, 217, Newark, DE 19713 (dpaul@christianacare.org).
Grant Support: NIH NICHD R01 HD051748-02; Clinical Trial
NCT00679471.
The authors declare no conflict of interest.
DOI: 10.1097/PEP.0b013e31823e069d
38
Gadin et al
studies have revealed high rates of neurodevelopmental
disability among infants born very preterm who survive.2
Identifying infants who are most at risk for subsequent
neurodevelopmental disability and who may benefit from
early intervention services is increasingly important. There
is evidence that early detection and early intervention
can help to ameliorate disabilities resulting from cerebral
injury.3
Magnetic resonance imaging (MRI) prior to hospital discharge may provide early detection of cerebral injury and allow families of neonates at high risk for developmental delay to seek early intervention. MRI studies have revealed that many infants born very prematurely have white-matter abnormalities, including signal
abnormalities, loss of volume, cystic abnormality, enlarged
ventricles, thinning of the corpus callosum, and delayed
myelination.4-6 Several investigations suggest that lesions
detected with advanced quantitative MRI technologies,
such as volumetric MRI, before hospital nursery discharge
Pediatric Physical Therapy
Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins and the Section on Pediatrics of the American Physical Therapy
Association. Unauthorized reproduction of this article is prohibited.
correlate with neurodevelopmental deficits assessed at 1
to 2 years of age.7-9 To date, studies using proton magnetic resonance spectroscopy (MRS) in prediction of neurodevelopmental outcome in infants born prematurely are
limited.
We hypothesized that volumetric MRI and proton
MRS, conducted prior to discharge from the neonatal intensive care unit (NICU) in infants born prematurely,
would aid in predicting motor impairment at 6 months
adjusted age.
METHODS
Subjects
The study included a cohort of infants born prematurely and recruited for volumetric MRI, evaluation of
long-term follow-up, and evaluation of early motor learning using a mobile paradigm. This analysis includes results
of the MRI analysis and the first developmental evaluation
at 6 months of age. Analyses of data using the mobile
paradigm are ongoing and will be reported at a future
date. Infants born prematurely at gestational ages less than
30 weeks, free of any significant congenital or chromosomal anomaly, and admitted to the NICU at Christiana
Hospital in Newark, Delaware, between November 2007
and December 2009 were eligible. A cohort of infants born
at term (gestational ages ≥37 weeks), who were admitted
to our NICU with minimal illness, were also recruited as a
comparison group. Exclusion criteria for recruited infants
born at term included major congenital anomalies, need
for mechanical ventilation, seizures, 5 minute Apgar score
less than 7, and clinically significant hypoglycemia. Infants
were enrolled into the study following informed written
parental consent as approved by the Christiana Care Institutional Review Board and the University of Delaware
Human Subjects Review Committee.
The best obstetric estimate of gestational age was used
to indicate pregnancy length, on the basis of last menstrual
period date or first trimester ultrasonographic results. Intrauterine growth restriction was defined as weight of less
than 10th percentile for gestational age. Bronchopulmonary
dysplasia was defined for those infants requiring supplemental oxygen at postmenstrual age of 36 weeks. For the
purposes of this study, infants with radiographic evidence
of intestinal dilation, ileus, or pneumatosis intestinalis
were defined as having necrotizing enterocolitis. Sepsis was
defined as any systemic bacterial infection documented by
a positive blood culture. At 1 month of age, all infants less
than 32 weeks gestation or with weight less than 1500 g
were evaluated for retinopathy of prematurity by pediatric
ophthalmologists. Subsequent examinations were determined by clinical findings. Head ultrasounds were done
routinely during the first week of life and at 1 month of
age. Ultrasounds were graded on the basis of the Papile
Classification.10 Severe intraventricular hemorrhage was
considered grade III-IV. Infants were considered to have
cystic periventricular leukomalacia if they had echolucent
cysts in the periventricular white matter.
Pediatric Physical Therapy
MRI and 1H-MRS Acquisition
Infants underwent MRI and MRS at 36 weeks postmenstrual age or just prior to hospital discharge if the
infants were physiologically ready for discharge prior to
36 weeks postmenstrual age. MRI scans were performed
without sedation. Before undergoing MRI, each infant was
fed and swaddled, and silicone earplugs were applied. All
infants’ heart rates and oxygen saturations, as measured by
pulse oximetry, were closely monitored during the scan.
We performed MRI and MRS using a 1.5-Tesla Siemens
Symphony MR unit. For the acquisition of the primary
MRI data, a spoiled gradient recalled sequence (1.25-mm
axial slices; flip angle, 45◦ ; repetition time, 1730 ms; echo
time, 3.49 ms; gap, 50%; field of view, 180 mm; matrix,
256 × 256) was applied. For MR spectroscopy data, a single voxel of 15 mm × 15 mm × 15 mm was centered in
the periventricular parietal region and a PRESS sequence
using a repetition time of 1500 ms and an echo time of 135
ms was performed. MRI scans were completed at Christiana Hospital and were digitally transferred to a workstation at the University of Delaware, in Newark, Delaware,
for volumetric analysis.
Volumetric MRI Analysis
Axial T1-weighted spoiled gradient recalled MRI
scans were imported into Amira 5.0 software (Visage
Imaging, Inc, Carlsbad, California) for manual segmentation and volume rendering. Prior to segmentation, images
were evaluated for usability. Images with excessive motion
artifacts were excluded from segmentation and volumetric
analysis. Tissue segmentation was performed by manually
segmenting low-intensity cerebrospinal fluid ventricular
spaces (right and left lateral ventricles, third ventricle, and
fourth ventricle) on the basis of pixel intensity and known
spatial neuroanatomic boundaries (Figure 1). Subcortical
gray matter was manually segmented in a similar manner. Subcortical gray matter was defined as structures with
higher signal intensity (consistent with gray matter tissue)
Fig. 1. Representation of 3-D brain segmentation reveals white
matter, gray matter, cerebellum, and ventricles.
MRI and Early Motor Development
39
Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins and the Section on Pediatrics of the American Physical Therapy
Association. Unauthorized reproduction of this article is prohibited.
medial to the external capsule, lateral to the midline, inferior to the anterior horn of the lateral ventricle, and superior to the third ventricle. These included the thalamus,
hypothalamus, globus pallidus, putamen, and claustrum.
The MRI scans did not readily differentiate the internal
capsule from surrounding gray matter tissue. Therefore,
subcortical gray matter volumes also included this white
matter structure. Larger structures, including cerebellum,
cortical gray matter, and cortical white matter, were identified and labeled last, on the basis of signal intensity and
spatial location. The total brain tissue volume was defined
as cerebrum plus cerebellum (excluding volume of ventricles). For a given structure, the 2-dimensional segmented
area was multiplied by the thickness of the slice, and the
resulting 3-dimensional volume was summed for each slice
containing the segmented structure, to yield the absolute
volume (in mL).
Metabolites of Interest on 1H-MRS
Magnetic resonance spectra are simply graphs of amplitude versus frequency in which the area under a “peak”
is proportional to concentration (Figure 2). For in vivo
brain tissue, the strongest metabolite signals and the common metabolites detectable at millimolar concentrations
by proton MRS are from N-acetylaspartate (NAA), creatine
(Cr), and choline (Cho).11 N-acetylaspartate is located almost exclusively in neurons and axons. This resonance has
been widely regarded as a marker for neuronal function.12
Disorders that reduce neuronal or axonal number and
density, impair neuronal function, or cause displacement
of neurons demonstrate reduced NAA. Creatine is converted to phosphocreatine, which is a high-energy dependent compound critical for maintaining cellular energydependent systems. The overall level of Cr is considered to
remain stable; therefore, Cr is used as a standard for com-
parison with other metabolites.13 Lastly, Cho is the precursor for acetylcholine and phosphatidylcholine, which is a
major constituent of the cell membrane. Changes in the
level of this metabolite are inherently linked to membrane
biochemistry. Choline elevations are regarded as a product
of myelin breakdown.12
Illness Severity
For objective measurement of illness severity, the
score for neonatal acute physiology (SNAP), was used. This
score is based on 26 routine clinical tests and vital signs.
The SNAP has been previously shown to directly correlate
with illness severity and mortality rate and a SNAP higher
than 15 correlates well with higher mortality rate.14
Developmental Follow-up at 6 Months
All infants were evaluated in their home environment
by a pediatric physical therapist (ML). At 6 months of
age adjusted for prematurity, the Bayley Scales of Infant
Development, Third Edition (BSID-III),15 was administered by 1 trained therapist. The sessions were video
recorded with 2 camera views. A second trained physical therapist blinded to infants’ birth and medical histories scored these assessments from video. The BSID-III
assesses development (at ages 1 to 42 months) across 5 domains: cognitive, language, motor, social-emotional, and
adaptive.15 Scaled scores (mean = 10, SD = 3), composite
scores (mean = 100, SD = 15), and percentile ranks for the
3 areas evaluated by item administration (cognitive, language, and motor) are provided. The cognitive composite
score is composed of findings from the cognitive scale. The
language composite score is composed of findings from
the receptive and expressive language scales. The motor
composite score is composed of findings from the fine
and gross motor scales. A low motor score was defined as
Fig. 2. Representative MRS spectrum.
40
Gadin et al
Pediatric Physical Therapy
Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins and the Section on Pediatrics of the American Physical Therapy
Association. Unauthorized reproduction of this article is prohibited.
performance 1.5 standard deviations below the standardized mean for the BSID-III score.
Data Analysis
Sample size for the study cohort was estimated a priori
on the basis of analysis of early motor learning as determined by a mobile paradigm (analysis for those data are
not presented in this article). Power calculation was based
on our previous publications with infants born with very
low birth weight, and up to 25% more variability than in
our previous work. Assuming 0.80 power and P < .05,
our calculations yielded estimates of 17 to 30 per group.
For statistical analysis, Pearson’s correlation, ANOVA, and
Mann-Whitney U tests were performed using Statistica version 7. Statistical significance was set at an alpha level
of 0.05.
RESULTS
Forty-five babies were recruited into this study.
Among these, 38 were born less than 30 weeks gestation
and 7 were born at term. Any infants lost to follow up,
missing MRI or MRS data sets, or whose MRI images were
unable to be segmented for volumetric analysis due to excessive motion artifact or poor quality were excluded from
statistical analysis. Among the infants born preterm, 26
had successful MRI and MRS acquisition and 20 had undergone their 6-month follow-up. When comparing the
infants born preterm we included in the study with those
excluded due to lack of MRI acquisition or loss to followup, no differences were found in birth weight (939 ± 238
vs 869 ± 268 g, P = .37) or gestational age (26.5 ± 1.7
vs 26.2 ± 1.8 weeks, P = .54), respectively. Among the
infants born at term, 4 successfully underwent MRI, MRS,
and the 6-month follow-up. We excluded 1 infant born at
term based on imaging findings of a large choroid plexus
cyst, which we felt could serve as a confounding variable.
Table 1 lists the Bayley-III composite and subscale
scores for the infants born prematurely and the infants
born at term. The cognitive composite score of the infants
born at term was significantly higher than the infants born
TABLE 1
Group Differences on the BSID-III Scale
Mean (SD)
Cognitive composite
Language composite
Receptive communication
Expressive communication
Motor composite
Fine motor
Gross motor
Preterm
(n = 20)
Term
(n = 4)
P
84.5 (13.9)
87.6 (10.8)
7.5 (2.7)
8.5 (2.5)
84.4 (14)
7.5 (2.9)
7.2 (2.4)
101.7 (7.6)
91.3 (7.4)
7 (2)
10 (1)
92 (1.7)
9.3 (1.2)
8 (1)
.05
.57
.76
.32
.36
.30
.58
Abbreviation: BSID-III, Bayley Scales of Infant Development, Third
Edition.
Pediatric Physical Therapy
prematurely. No differences were found in the motor and
language scores.
The infants born preterm when compared with the
infants born at term had smaller white matter volume
(146.5 ± 6.9 vs 107.7 ± 17.8 mL, P = .001) and gray
matter volume (114.6 ± 22.2 vs 144.1 ± 16 mL, P = .04).
They were also found to have smaller cerebellar volumes
(16.4 ± 5.2 vs 23 ± 1.9 mL, P = .04), subcortical gray
matter volume (17.7 ± 3.8 vs 23.9 ± 6 mL, P =.02), and
total brain volume (262.7 ± 27.2 vs 337.5 ± 12.1 mL,
P < .001) when compared with infants born at term. No
differences were found in ventricular volumes in the group
born prematurely (12.4 ± 32 vs 2.7 ± 0.3 mL, P = .61)
compared with the infants born at term.
The NAA/Cho ratio was higher in the infants born
at term than the infants born preterm (P = .046). No
differences were noted in the NAA/Cr or the Cho/Cr ratios
(data not shown). In investigating the relationship of the
metabolite ratios to brain volumes, we found NAA/Cho
to be positively correlated with white matter (R = 0.45,
P = .03), gray matter (R = 0.43, P = .04), and cerebellar
volumes (R = 0.6, P = .002), and thus, total brain volume
(R = 0.63, P = .001).
Among the infants born prematurely, 7 of 20 infants
had low motor scores. Table 2 shows the characteristics of
the infants born prematurely with low motor scores compared with those born prematurely with normal motor
TABLE 2
Characteristics of Infants Born Prematurely Based on BSID-III
Motor Socres
Gestational age, wk
Birth weight, g
Discharge weight, g
Maternal race/ethnicity
Non-Hispanic white
Non-Hispanic black
Hispanic
Other
Intrauterine growth
restriction, %
Multiple births, %
Antenatal steroids, %
SNAP
Necrotizing
enterocolitis, %
Sepsis, %
Severe intraventricular
hemorrhage, %
Cystic periventricular
leukomalacia, %
Retinopathy of
prematurity, %
Postnatal steroids, %
Length of
hospitalization, d
Preterm With
Normal Motor
Scores (n = 13)
Preterm With
Low Motor
Score (n = 7)
26.4 ± 1.3
956 ± 244
2768 ± 824
26.6 ± 2.4
921 ± 291
2813 ± 879
3 (23.1%)
6 (46.2%)
3 (23.1%)
1 (7.7%)
1 (7.7%)
4 (57.1%)
1 (14.3%)
0
2 (28.6%)
0
4 (30.8%)
11 (84.6%)
11.7 ± 6.6
2 (15.4%)
2 (28.6%)
6 (85.7%)
10.9 ± 7.2
1 (14.3%)
5 (38.5%)
0
5 (71.4%)
4 (57.1%)
2 (15.4%)
4 (57.1%)
8 (61.5%)
5 (71.4%)
0
80.8 ± 26.7
0
85.9 ± 37
Abbreviations: BSID-III, Bayley Scales of Infant Development, Third
Edition; SNAP, score for neonatal acute physiology.
MRI and Early Motor Development
41
Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins and the Section on Pediatrics of the American Physical Therapy
Association. Unauthorized reproduction of this article is prohibited.
scores. Infants with low motor scores had decreased
subcortical gray matter volume compared with infants
with normal motor scores (Table 3). No differences were
found in total brain, cortical white matter, cortical gray
matter, cerebellar or ventricular volumes between these
groups.
Infants born preterm with low motor scores had similar metabolite ratios as those infants born preterm with
normal motor scores (Table 4). No correlations were found
between metabolite ratios and individual brain volumes. In
addition, metabolite ratios were not noted to correlate with
the Bayley motor scores at 6 months.
DISCUSSION
The main finding of our study was that among infants
born prematurely, a reduction in subcortical gray matter
volume was associated with delayed motor performance
on the BSID-III at 6 months adjusted age. As in previous
studies,6,9,11 our data confirm a smaller global brain volume among infants born prematurely. In our study sample, premature birth was associated with reduction in total
brain volume due to a decrease in cerebral cortical gray
matter, cerebral cortical white matter, subcortical gray
matter, and cerebellar volume. A substantial number of
surviving infants born prematurely will experience future
neurodevelopmental challenges. Our data suggest that MR
volumetry may potentially assist clinicians in predicting,
before hospital discharge, infants at risk for low motor
scores at 6 months adjusted age.
TABLE 3
Brain Volumes of Infants Born Prematurely
Premature Infants
With Normal
Motor Scores
(n = 13)
Ventricles
Subcortical gray matter
Cortical gray matter
Cortical white matter
Cerebellum
Total brain
5.2
19.1
113.2
110.9
16
261.6
±
±
±
±
±
±
2.7
3.4
19.2
14.5
6.2
30
Premature Infants
With Low Motor
Scoresa
(n = 7)
P
25.6
15.3
117.2
101.8
17.1
264.6
±
±
±
±
±
±
54.0
3.4
28.4
22.7
3
23.4
.18
.03
.70
.28
.67
.82
a Low motor scores defined as below 1.5 SD from the mean at 6 months.
TABLE 4
Metabolite Ratios of Infants Born Prematurely With BSID-III Motor
Scores Above or Below 1.5 Standard Deviation From the Mean
at 6 Months
Preterm with normal
BSID-III motor score
Preterm with low
BSID-III motor score
ρ
NAA/Cr
Cho/Cr
NAA/Cho
0.87 ± 0.3
1.8 ± 1.5
0.5 ± 0.1
0.9 ± 0.4
1.9 ± 0.6
0.5 ± 0.2
0.66
0.83
0.67
Abbreviations: BSID-III, Bayley Scales of Infant Development, Third
Edition; Cho, choline; Cr, creatine; NAA, N-acetylaspartate.
42
Gadin et al
Our finding of reduced subcortical gray matter in
infants born preterm with low motor scores has potential
important clinical implications. The control of movement
and tone in the human nervous system is highly complex
and depends on many structures to be intact and provide
the right balance of signals to be operational.16 The subcortical gray matter includes the basal ganglia system, which
influences muscle power and tone by its effects on the corticospinal tract. A small proportion of our measurements
of the subcortical gray matter also included the internal
capsule, a white matter structure, which is important in
motor control. The observed reduction in the subcortical
gray matter volume may be indicative of changes in the
signals received and provided by the basal ganglia system.
The basal ganglia play an important role in motor behavior.
Extensive evidence indicates a role for the basal ganglia in
learning and memory. One prominent hypothesis is that
this brain region mediates a form of learning in which
stimulus-response associations or habits are acquired in
increments. Support for this hypothesis is provided by numerous neurobehavioral studies in different mammalian
species.17-23 Examples of stimulus-response learning before 6 months of age include reaching for and acting on
objects, or infants changing their spontaneous activity level
to demonstrate their needs to others. In terms of motor
control, if power and tone are atypical, infants’ earliest
spontaneous movements like kicking and arm flapping,
behaviors that teach infants about control of their bodies
and movements may be altered. This could affect development as these behaviors are building blocks for later skilled
behaviors such as reaching and walking.
In our study sample, 4 of the 7 infants born prematurely with low motor scores had severe intraventricular
hemorrhage and/or cystic periventricular leukomalacia on
head ultrasounds whereas only 2 of the 13 who had normal motor performance had cystic periventricular leukomalacia and none had severe intraventricular hemorrhage.
Similarly, infants with low motor scores had a high rate of
sepsis. Severe intraventricular hemorrhage, cystic periventricular leukomalacia, and sepsis are all known to be clinically associated with motor and cognitive deficits. From
our data we cannot determine if these morbidities may have
contributed to the observed reduction in subcortical gray
matter or had an independent effect on motor performance.
Clinical courses and long-term outcomes of infants born
preterm are highly variable, making prediction of these
outcomes difficult. Future studies with larger number of
infants will be needed to determine if morbidities such
as severe intraventricular hemorrhage, cystic periventricular leukomalacia, or sepsis are responsible for reduction in
subcortical gray matter in infants born preterm and further
delineate the role of volumetric MRI in routinely predicting
motor outcomes.
In addition to MRI, which provides clinicians with
anatomic information, MRS has the ability to quantify
regional brain metabolism. In our study sample, we did
not find an association between MR spectroscopy in the
periventricular parietal white matter and low motor scores.
Pediatric Physical Therapy
Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins and the Section on Pediatrics of the American Physical Therapy
Association. Unauthorized reproduction of this article is prohibited.
We cannot rule out the possibility that measurements of
metabolites in other brain regions would have yielded different results. In our study, the MR spectroscopy voxel
was placed in the periventricular parietal area to capture
potential loss of white matter secondary to diffuse (or noncystic) white matter damage, which is more commonly
found in infants born prematurely. The 3 metabolite ratios measured in our study were NAA/Cr, NAA/Cho, and
Cho/Cr. In early brain development, there is a normal decrease in Cho, which likely reflects incorporation of Cho
into macromolecules associated with myelination.24 At the
same time, NAA, which is primarily stored and synthesized
in neurons, increases as the brain develops. Reduction in
NAA likely reflects decreased neuronal viability, neuronal
function, or neuronal loss.24 In our study, there was a reduced NAA/Cho metabolite ratio in infants born premature
that did not correlate with motor outcome. The finding of
reduced NAA/Cho in infants born preterm may be representative of some degree of delayed myelination that was
not of sufficient magnitude to affect early motor function.
Alternatively, as infants born preterm are known to have
delayed myelination,16 this finding may also be representative of normal brain development in infants born preterm.
Numerous studies have found decreased NAA/Cr
and/or NAA/Cho ratios to be predictive of abnormal neuromotor outcome in newborns born at term with hypoxicischemic encephalopathy.25-28 Our findings are consistent
with a recent study which found NAA/Cr and/or NAA/Cho
useful in predicting outcome of neonates with asphyxia,
but not predictive of future development in infants born
prematurely.29 As MRS is an emerging technology, with
studies to date on infants born preterm looking at varied populations and brain regions, there is presently a
paucity of normal data for infants born preterm. Our data
are helpful in showing a reduction in NAA/Cho in infants
born preterm compared with term controls. The parietal
periventricular metabolite ratios of infants born preterm
measured in our study were similar to those measured in
the basal ganglia by Augustine et al.29 As with measurement of regional brain volumes in infants born preterm,
the establishment of normative metabolite ratio values are
needed to further aid clinicians before MRS is ordered
routinely.
Our study has several other important limitations.
We failed to find associations with metabolite ratios and
6-month Bayley scores. Our study sample size was not
calculated on the basis of analysis of volumetric MRI or
MRS. Small biochemical alterations secondary to prematurity may not have been detected due to the limited power of
the sample size. Detection of small differences in brain volume including white matter and ventricular volume in infants with low motor scores was also limited by the sample
size of this early cohort. Another notable limitation in our
study relates to the manual volumetric estimation of the
brain structures. In T1-weighted images from infants less
than 4 weeks of age, regions of unmyelinated white matter
have signal values lower than gray matter.30 This creates a
possibility for some misclassification of structures. In adPediatric Physical Therapy
dition, Bayley assessments were performed at 6 months
of age and may not correlate with later motor status. Although, the previous version of the Bayley was shown to
be reliable and valid, the Bayley III is relatively new and,
to date, limited evidence exists supporting its construct
and predictive validity. Finally, it should be noted that our
study investigated a sample of infants less than 30 weeks
gestation who were relatively stable, without a high rate
associated morbidities, and may not be generalizable to
other populations of infants born preterm including those
with greater illness severity or more advanced gestation.
CONCLUSIONS
Neurodevelopmental outcome remains difficult to
predict in infants born preterm. In our study sample, early
volumetric MRI studies identify reduction in regional brain
volume in infants born preterm. Infants born preterm with
Bayley scores less than 1.5 SD from the mean at 6 months of
age had a reduction in subcortical gray matter volume identified prior to hospital discharge. Proton MRS completed
at term equivalent age did not correlate with motor performance at 6 months adjusted age in infants born preterm.
Our data suggest that, with further study, volumetric MRI
may have some role in helping to counsel parents about
early motor development. Studies with larger numbers of
infants are now required to determine if volumetric MRI
would be superior to more traditional methods of counseling including using findings from head ultrasounds or
other clinical markers, such as sepsis, in predicting motor
outcomes.
REFERENCES
1. Horbar JD, Badger GJ, Carpenter JH, et al. Trends in mortality and
morbidity for very low birth weight infants. Pediatrics. 2002;110:
143-151.
2. Marlow N, Wolke D, Bracewell MA, Samara M. Neurologic and developmental disability at 6 years of age after extremely preterm birth.
N Engl J Med. 2005;352:9-19.
3. Blauw-Hosper CH, Hadders-Algra M. A systematic review of the effects of early intervention on motor development. Dev Med Child
Neurol. 2005;47(6):421-432.
4. Maalouf EF, Duggan PJ, Rutherford MA, et al. Magnetic resonance
imaging of the brain in a cohort of extremely preterm infants.
J Pediatr. 1999;135:351-357.
5. Inder TE, Wells SJ, Mogridge NB, Spencer C, Volpe JJ. Defining
the nature of the cerebral abnormalities in the premature infant: a
qualitative magnetic resonance imaging study. J Pediatr. 2003;143:
171-179.
6. Ajayi-Obe M, Saeed N, Cowan FM, Rutherford MA, Edwards AD.
Reduced development of cerebral cortex in extremely preterm infants.
Lancet. 2000:356:1162-1163.
7. Inder TE, Warfield SK, Wang H, Huppi PS, Volpe JJ. Abnormal cerebral structure is present at term in premature infants. Pediatrics.
2005;115:286-294.
8. Peterson BS, Anderson AW, Ehrenkranz R, et al. Regional brain
volumes and their later neurodevelopmental correlates in term and
preterm infants. Pediatrics. 2003;111:939-948.
9. Anderson PJ, Howard K, Bear M, et al. Relationship between regional
brain volumes at term equivalent age and cognitive functioning at
2 years in preterm children. Pediatr Res. 2004;55:3294A.
MRI and Early Motor Development
43
Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins and the Section on Pediatrics of the American Physical Therapy
Association. Unauthorized reproduction of this article is prohibited.
10. Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution
of subependymal and intraventricular hemorrhage: a study of infants
with birth weights less than 1,500 gm. J Pediatr. 1978;92(4):529-534.
11. Vigneron DB. Magnetic resonance spectroscopy imaging of human
brain development. Neuroimaging Clin N Am. 2006;16:75-85.
12. Moore GJ. Proton magnetic resonance spectroscopy in pediatric neuroradiology. Pediatr Radiol. 1998;28:805-814.
13. Govindaraju V, Young K, Maudsley AA. Proton NMR chemical
shifts and coupling constants for brain metabolites. NMR Biomed.
2000;13:129-153.
14. Maiya PP, Nagashree S, Shaik MS. Role of score for neonatal acute
physiology (SNAP) in predicting neonatal mortality. Indian J Pediatr.
2001;68:829-834.
15. Bayley N. Bayley Scales of Infant Development. 3rd ed. San Antonio,
TX: Pearson; 2006.
16. Volpe JJ. Neurology of the Newborn. 5th ed. Philadelphia: WB
Saunders; 2008.
17. Graybiel AM. The basal ganglia and chunking of action repertories.
Neurobiol Learn Mem. 1998;70:119-136
18. Jog MS, Kubota Y, Connolly CI, et al. Building neural representations
of habits. Science. 1999;286:1745-1749.
19. Kesner RP, Bolland BL, Dakis M. Memory for spatial locations, motor responses, and objects: triple dissociation among the hippocampus, caudate nucleus, and extrastriate visual cortex. Exp Brain Res.
1993;93:462-470.
20. Kimura M. Role of the basal ganglia in behavioral learning. Neurosci
Res. 1995;22:353-358.
21. Teng E, Stefanacci L, Squire LR, Zola SM. Contrasting effects
on discrimination learning after hippocampal lesions and conjoint hippocampal-caudate lesions in monkeys. J Neurosci. 2000;20:
3853-63.
44
Gadin et al
22. Butters N, Salmon D, Heindel WC. Specificity of the memory deficits
associated with basal ganglia dysfunction. Rev Neurol. 1994;150:
580-587.
23. Heindel WC, Butters N, Salmon DP. Impaired learning of a motor skill
in patients with Huntington’s disease. Behav Neurosci. 1988;102:1411150.
24. Shah DK, Anderson PJ, Carlin JB, et al. Reduction in cerebellar
volumes in preterm infants: relationship to white matter injury
and neurodevelopment at two years of age. Pediatr Res. 2006;60:
97-102.
25. Khong PL, Tse C, Wong IY, et al. Diffusion weighted imaging and proton magnetic resonance spectroscopy in perinatal hypoxic-ischemic
encephalopathy: association with neuromotor outcome at 18 months
of age. J Child Neurol. 2004;19:872-881.
26. Miller SP, Newton N, Ferriero DM, et al. Predictors of 30-month
outcome after perinatal depression: role of proton MRS and socioeconomic factors. Pediatr Res. 2002;52:71-77.
27. Barkovich AJ, Baranski K, Vigneron D, et al. Proton MR spectroscopy
for the evaluation of brain injury in asphyxiated, term neonates. Am
J Neuroradiol. 1999;20:1399-1405.
28. Groenendaal FR, Veenhoven RH, van der Grond J, et al. Cerebral lactate and N-acetyl-aspartate/choline ratios in asphyxiated full-term
neonates demonstrated in vivo using proton magnetic resonance
spectroscopy. Pediatr Res. 1994;35:148-151.
29. Augustine EM, Spielman Dm, Barnes PD, et al. Can magnetic resonance spectroscopy predict neurodevelopmental outcome in very low birth preterm infants? J Perinatol. 2008;28:611618.
30. Barkovich AJ, Kjos BO, Jackson DE JR, Norman D. Normal maturation of the neonatal and infant brain: MR imaging at 1.5T. Radiology.
1988;166:173-180.
Pediatric Physical Therapy
Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins and the Section on Pediatrics of the American Physical Therapy
Association. Unauthorized reproduction of this article is prohibited.