Keywords congenital heart disease - fetus - neonate - brain growth - neurodevelopment - communication
Despite the high survival rate of neonates undergoing cardiothoracic surgeries, many
babies with congenital heart disease (CHD) grow up to have neurodevelopmental delays
or disabilities later in life. When patients were assessed during school age, many
had abnormal neurologic examinations, as well as gross and fine motor abnormalities.[1 ]
[2 ] Ongoing research is exploring how neurodevelopmental outcomes in CHD patients may
be related to differential growth and development of the brain during the fetal and
neonatal period. One study found a structural neurodevelopmental delay of about 1 month
in CHD fetuses, whereas another group described abnormalities of fetal brain growth
and development using magnetic resonance imaging (MRI) volumetric analysis and MR
spectroscopy.[3 ]
[4 ]
Preliminary unpublished results from our longitudinal study of brain development in
fetuses, neonates, and children with CHD have demonstrated that children with CHD
are at risk for having expressive language delays. This is supported by historical
data in the literature.[1 ]
[2 ]
[5 ]
[6 ] Although our preliminary results and prior reports have found this to be a pervasive
finding for individuals with many different types of CHD (hypoplastic left heart syndrome,
transposition of the great arteries, tetralogy of Fallot, isolated ventricular septal
defect, etc.), the underlying pathogenic mechanisms have not yet been described.[1 ]
[5 ]
[6 ] We embarked upon identifying neuroanatomical abnormalities that might be predictive
of possessing such language delays. The two anatomic regions in the brain of particular
interest are the operculum and cerebellum. These two regions have recently been demonstrated
to share connectivity and cooperate in language coordination. Positron emission tomography
(PET), MRI, and functional MRI (fMRI) demonstrate the intimate interplay between these
regions during expressive language; additionally clinical correlates such as cerebellar
mutism reveal how crucial these functions are to daily communication.[7 ]
[8 ]
[9 ]
[10 ]
[11 ] Determining whether abnormalities exist in the very beginning and following the
longitudinal brain trajectory of the children with CHD will help clarify developmental
aberrations and optimize treatment plans.
The operculum includes areas of the brain essential to language and the motor components
of speech, and is composed of portions from the frontal, temporal, and parietal lobes.[12 ]
[13 ] The development of the operculum begins when the fetus is approximately 20 weeks.[14 ] At this time, the insular cortex is exposed. As growth of the frontal, temporal,
and parietal lobes progresses, the opercular opening over the insular cortex decreases,
resulting in closure of the operculum by the end of gestation.[15 ] An open operculum and exposed insular cortex have been associated with neurodevelopmental
delays and previously reported in neuroimaging studies of fetuses and neonates with
CHD.[1 ]
[3 ]
[16 ]
[17 ]
The cerebellum has long been accepted to play a crucial role in motor control, coordination,
and balance. However, it is now being demonstrated to be involved in higher cognitive
tasks such as learning and memory, attention, and language.[13 ]
[18 ] Language processing tasks, such as word generation, verbal fluency, and semantic
processing activate regions in the cerebellum.[19 ] The cerebellar vermis is essential for gross motor synchronization and balance,
and may be implicated in the speech deficits related to fine motor coordination loss
in CHD patients. Past studies, using sonographic or MRI data, have characterized the
growth of the cerebellar hemispheres and vermis during the fetal period.[20 ]
[21 ]
[22 ]
[23 ]
[24 ] Studies have found differential cerebellar growth in small for gestational age fetuses
and neonates, preterm infants, and fetuses with abnormal posterior fossae; however,
cerebellar growth in fetuses with CHD has not been examined.[18 ]
[25 ]
[26 ]
[27 ]
In this report of our initial experience, we aim to describe the structural neurodevelopment
of the operculum and cerebellum in CHD and non-CHD fetuses and neonates, using simple
easily available biometrics obtained from serial fetal and neonatal MRI. The same
imaging technique (single-shot fast spin echo [ssFSE]) was used to compare measurements
across time points (fetal and neonatal) translatable without confusion. Additionally,
we aim to determine whether there are any differences in the development of the operculum
and cerebellum of CHD fetuses and neonates compared with control fetuses and neonates
without CHD. We hypothesize that the internal opercular width will decrease before the external in normal controls, but both the internal and external opercular widths will remain
larger in the CHD brains. Additionally, the cerebellar measurements will be smaller
in the CHD individuals. Furthermore, we compare the neurodevelopmental scores with the anatomic measurements.
Materials and Methods
Patients
Pregnant mothers enrolled in the CHD cohort were approached for participation after
having a clinically indicated fetal ECHO through the Institute for Maternal-Fetal
Health. The non-CHD cohort comprised clinical and healthy controls. Clinical controls
included fetuses that did not have a diagnosis of CHD but had other abnormalities
including, but not limited to, suspected genitourinary, gastrointestinal, and limb
abnormalities. The fetuses assigned as clinical controls were enrolled retrospectively
once their clinically indicated fetal MRI was confirmed to have no central nervous
system abnormality and their neonatal outcome was confirmed to have no neurologic
concerns. The healthy controls, enrolled prospectively, were gravid women with uncomplicated
pregnancies who volunteered to participate in this research project, including having
fetal and postnatal MRIs of the brain and postnatal neurodevelopment evaluation. Only
English and Spanish-speaking mothers were eligible. If, at the time of consent, there
were confirmed fetal chromosomal abnormalities, suspected fetal structural brain malformation,
suspected fetal infection, or maternal refusal or contraindication for MRI procedure,
the patient was excluded. To be included in this analysis, a CHD fetus must have completed
all imaging time points and have participated in the neurodevelopmental assessment.
From January 2011 to June 2015, a total of 64 mothers were enrolled in the study.
There were 13 fetuses in the CHD cohort and 51 fetuses in the non-CHD cohort. Two
of the mothers in the CHD group did not have a fetal MRI and were excluded from this
study, making the final sample a total of 62 fetuses, with 11 CHD fetuses and 51 non-CHD
fetuses. After enrollment, two CHD patients were identified to have a chromosomal
abnormality and thus excluded.
Magnetic Resonance Imaging
Serial fetal (1.5T) and postnatal pre- and postoperative (3T) MRIs of the brain were completed in CHD patients. Comparable
successive cross-sectional imaging was performed in the non-CHD patients no more than
once during each the fetal and the neonatal periods, offering normal structural developmental models for which to relate the
CHD data. Fetal MRI was performed on a 1.5T system and the neonatal imaging on a 3T
system (Philips) with a neonatal head coil and neonatal incubator (if clinically necessary).
The following imaging sequences were acquired for fetal MRIs: an inclusion coil was
placed over the mother's abdomen and multiple single-shot T2 fast-spin echo images
were obtained using 3-mm thickness (0-mm gap) in at least two orthogonal planes with
a repetition time (TR)/echo time (TE) of 120/12,500 milliseconds, one signal acquired,
FOV_26–35 cm, a flip angle of 90 degrees, and a matrix of 196_195, 204_202, 112_92,
272_172, section thickness 2–3 mm, spacing_0. For neonatal MRIs, the following imaging
sequences were acquired: T2 in axial and sagittal planes (TE/TR_70/684–982 milliseconds,
FOV_15–16 cm, a flip angle of 90 degrees, matrix 120_98 or 112_92, section thickness,
3 mm, spacing_0. No sedation was used for fetal or postnatal imaging unless clinically
indicated by the discretion of the cardiothoracic intensive care team during the neonatal
MRIs.
Magnetic Resonance Imaging Brain Metrics
Fetal ssFSE and neonatal T2 MR images were used for manual linear cross-sectional
measurement post hoc. Gestational age was determined based on the most accurate overall
assessment by the obstetrician and perinatologist. Brain structures were measured
in three cross-sections as described by Garel.[22 ] In the axial plane at the level of the operculum, the following were used as landmarks
for the desired slice: the anterior horns and body of the lateral ventricles, third
ventricle, and thalamus. Three measurements of the operculum were taken on the left
and right side of the brain ([Fig. 1 ]).
Fig. 1 (A ) Operculum measurements, axial section measurements from same patients at fetal and
neonatal time points. (B ) Cerebellum measurements, axial section measurements from same patients at fetal
and neonatal time points. (C ) Cerebellar vermis, sagittal measurements from same patients at fetal and neonatal
time points. CHD, congenital heart disease.
Neurodevelopmental Assessment
CHD patients returned when they were 9 to 36 months old for developmental evaluation
with a pediatric neuropsychologist. Neurodevelopment was assessed in English or Spanish
using the Battelle Developmental Inventory, 2nd ed.
Statistical Analysis
Wilcoxon-Mann-Whitney test was used to determine whether the estimated gestational
age (EGA) populations mean rank differed among cohorts. Determining differences in
brain measurements among cohorts were evaluated longitudinally with a repeated measures
mixed-effects regression model. Mixed model random effect was at the patient level
utilizing an identity covariance structure. Nonlinear (NL) mixed-effects growth models,
accounting for repeated measurements, were fitted and assessed by maximum likelihood,
Akaike information criterion corrected for small sample size (AICc), and Bayesian
information criterion (BIC). In an effort to maintain the longitudinal aspects of
the data, mixed effects were used as the “Independence” assumption of simple linear
regression analysis did not hold. This type of generalized linear model provided for
adjusting for gestational age whereas simple bivariate tests did not. Furthermore,
this type of modeling also allows for handling of missing data. Spearman rho rank
correlation with Bonferroni correction was used to correlate neurodevelopmental assessment
scores with brain measurements in the fetal and postnatal pre- and postoperative periods.
Multivariate and correlation analysis were adjusted for gestational age at the time
of MRI scan. Missing data were handled with list-wise deletion in the correlation
analysis; that is, all observations with missing values were excluded from the analysis
to make all pairs identical and ensure a nonnegative definite correlation matrix.
Statistical significance for Bonferroni corrected correlation analysis was set at
p < 0.017, and all other statistical significance were set at p < 0.05. Regression models are presented as coefficient (95% confidence interval [CI]).
Continuous variables are presented as mean ± standard deviation (SD) or median (interquartile
range [IQR]) as appropriate. Data analysis and graphics were produced using SAS (Statistical
Software Package v 9.4, Cary, NC).
Results
Clinical Characteristics of the Patient Cohorts
Postmenstrual age (PMA) at birth of the entire fetal and neonatal cohort ranged from
19 to 38 weeks. The CHD cohort had an average PMA of 34 weeks at birth, whereas the
non-CHD cohort had a PMA of 29 weeks at birth. There was a statistically significant
difference in the PMA of each group (p < 0.01). The CHD cohort had six patients with hypoplastic left heart syndrome, two
with transposition of the great arteries, two with pulmonary atresia with intact ventricular
septum, one with each of the following: hypoplastic aortic arch, atrioventricular
canal, and tetralogy of Fallot. In the non-CHD cohort, 35 were normal healthy controls,
8 were diagnosed with congenital pulmonary adenomatoid malformation, and 8 with congenital
diaphragmatic hernia. There were no statistically significant differences between
the left- and right-side brain measurements. Two of the 11 CHD were identified postnatally
to have 22q11.2 deletion (DiGeorge's syndrome). These were removed from the final
analysis as this particular condition is known to have an impact on cerebellar and
opercular growth, as well as neurodevelopment.[28 ]
[29 ]
[30 ] (Interestingly, the opercular abnormalities are more pronounced in the fetal and
preoperative period if the 22q11.2 patients are included, [[Appendix ]]. This is consistent with the literature.[28 ]) The following were omitted in the operculum data as precise images were not available:
right operculum for one CHD fetus and seven non-CHD fetuses and left operculum for
three non-CHD fetuses. Clear measurement of the floor of the fourth ventricle was
not obtainable in the images of two non-CHD fetuses.
Comparison of Brain Metrics Measurements between CHD and non-CHD Cohorts
For fetuses and neonates with CHD, there was evidence of delayed internal closure
of bilateral opercula compared with normal controls. Also, there was bilateral lateral
ventricle enlargement in the CHD cohort. Additionally, cerebellar sagittal vermis
height was significantly smaller in the CHD fetuses and neonates. Measurements done
to demonstrate whether significant overall cerebral atrophy existed were normal in
the CHD group (nonsignificant differences between the CHD and control groups in brain
biparietal or bone biparietal diameters) ([Fig. 2 ], [Table 1 ]).
Table 1
Brain measurements in CHD cohort compared to non-CHD cohorts
Measurement (mm)
CHD β
95% CI
p
Operculum inside left
− 5.39
−8.66, −2.11
< 0.01
Operculum inside right
− 4.32
−7.78, −0.85
0.02
Operculum outside left
− 1.50
−4.62, 1.62
0.34
Operculum outside right
− 1.12
−4.22, 1.98
0.47
Operculum length left
0.62
−0.44, 1.68
0.24
Operculum length right
− 0.03
−0.89, 0.84
0.95
Cerebellum floor 4th ventricle
0.81
−0.53, 2.15
0.23
Cerebellum inferior vermis
− 0.52
−1.42, 0.38
0.25
Vermis height axial
0.27
−1.00, 1.54
0.67
Cerebellar hemisphere left
0.08
−0.87, 1.03
0.87
Cerebellar hemisphere right
− 0.29
−1.38, 0.80
0.59
Vermis height sagittal
− 1.94
−3.37, −0.52
0.01
Brain biparietal diameter
− 1.98
−5.27, 1.32
0.23
Bone biparietal diameter
− 1.03
−4.72, 2.66
0.58
Lateral ventricle left
1.58
0.19, 2.97
0.03
Lateral ventricle right
1.75
0.032, 0.24
0.01
Abbreviations: CHD, congenital heart disease; CI, confidence interval.
CHD-β slope compares to non-CHD babies' growth pattern. For example, for left operculum
inside width, after adjusting for gestational age at time of MRI, CHD patients' left
operculum inside width was 5.39 mm smaller compared to non-CHD patients (p < 0.01).
p is based on an analysis of mixed-effects repeated measures adjusting for gestational
age at time of MRI, and patient's between-subject and within-subject error.
Fig. 2 Growth curves of significant differences between congenital heart disease (CHD) and
controls. CI, confidence interval.
Growth Curve Characteristics for Patient Cohorts
For CHD fetuses and neonates, mixed linear growth curves best describe the measurements
focused on in this study (opercular and ventricle), with the exception of the vermis
where NL logistic and Gompertz growth curves fitted best. In contrast, normal healthy
control fetus and neonate brain measurements were best described with NL logistic
growth curves. The NL logistic and the Gompertz curves are both sigmoid curves used
to fit brain measurement growth across gestational ages. Initial growth of these functions
is approximately exponential, but unlike an exponential curve that continues to rise,
the growth slows into an s-shaped curve ([Table 2 ]).
Table 2
Growth curve analysis among cohorts
No CHD
CHD
−2 Log likelihood
AICc
BIC
−2 Log likelihood
AICc
BIC
Operculum inside left
Mixed linear
294.5
296.6
298.5
182.0
184.1
184.4
NL logistic growth curve
257.6
269.0
277.0
183.8
196.5
195.8
NL Gompertz growth curve
492.6
504.0
512.0
184.2
196.9
196.2
Operculum inside right
Mixed linear
272.8
274.9
276.7
176.4
178.6
178.8
NL logistic growth curve
248.6
260.1
267.5
177.3
190.2
189.3
NL Gompertz growth curve
275.2
286.7
294.1
266.2
279.1
278.2
Vermis height sagittal
Mixed linear
236.5
238.6
240.5
144.4
146.6
146.8
NL logistic growth curve
218.9
230.2
238.6
131.0
143.6
143.0
NL Gompertz growth curve
236.3
247.5
256.0
130.9
143.5
142.9
Lateral ventricle left
Mixed linear
198.0
200.0
201.9
152.2
154.4
154.6
NL logistic growth curve
187.9
199.2
207.4
142.5
155.1
154.5
NL Gompertz growth curve
302.7
314.0
322.1
201.7
214.3
213.7
Lateral ventricle right
Mixed linear
179.6
181.6
183.5
151.9
154.0
154.3
NL logistic growth curve
169.4
180.8
188.5
143.7
156.3
155.7
NL Gompertz growth curve
284.8
296.2
303.9
143.8
156.4
155.8
Abbreviations: AICc, Akaike's information criteria; BIC, Schwarz's Bayesian information
criteria (the lower the score, the better the curve fit).
Rows with the lowest values have been italicized.
Correlation with Neurodevelopmental Outcomes
When comparing the neurodevelopmental scores with the anatomic measurements, the cerebellar
inferior vermis width was significantly negatively correlated with expressive communication
in the CHD cohort. Decreases in scores of the adaptive developmental quotient correlated
with smaller measurements of the left cerebellar hemisphere. Additionally, the cerebellar
inferior vermis width was smaller and predicted a decrease in scores in the communication,
cognitive, personal-social and total developmental quotients ([Table 3 ]).
Table 3
Correlation of brain measurements and Battelle scores, significant scores only
Score (correlation, p value)
Fetal
Preoperative
Postoperative
Left cerebellar hemisphere
Brain biparietal diameter
Bone biparietal diameter
Right ventricle
Right cerebellar hemisphere
Brain biparietal diameter
Left ventricle
Cerebellum floor 4th ventricle
Cerebellum inferior vermis width
Self-care
−0.69
−0.64
−0.71
−0.78
−0.08
−0.86
−0.54
0.45
−0.77
0.06
0.08
0.05
0.02
0.86
0.01
0.21
0.37
0.07
Self-concept and social role
0.44
−0.65
−0.93
−0.83
−0.34
−0.51
−0.21
0.09
−0.83
0.28
0.08
<0.01
0.01
0.46
0.24
0.65
0.86
0.04
Expressive communication
−0.52
−0.57
−0.60
−0.77
0.09
−0.51
−0.18
0.21
−0.92
0.18
0.14
0.12
0.02
0.84
0.24
0.70
0.69
< 0.01
Fine motor
−0.49
0.04
0.13
−0.05
0.95
0.02
0.62
0.77
−0.23
0.22
0.93
0.75
0.91
<0.01
0.97
0.14
0.07
0.67
Attention and memory
−0.42
−0.56
−0.79
0.60
−0.37
−0.34
−0.71
−0.21
−0.88
0.30
0.15
0.02
0.11
0.42
0.46
0.08
0.69
0.02
Adaptive developmental quotient
−0.81
−0.69
−0.68
−0.69
−0.06
−0.86
−0.59
0.44
−0.80
0.02
0.06
0.06
0.06
0.89
0.01
0.16
0.38
0.06
Personal-social developmental quotient
−0.51
−0.63
−0.82
−0.80
−0.16
−0.49
−0.34
0.06
−0.93
0.20
0.10
0.01
0.02
0.74
0.26
0.46
0.90
< 0.01
Communication developmental quotient
−0.59
−0.56
−0.63
−0.73
0.15
−0.60
−0.30
0.21
−0.92
0.12
0.15
0.09
0.04
0.74
0.15
0.52
0.69
< 0.01
Motor developmental quotient
−0.49
−0.03
−0.01
−0.09
0.85
−0.13
0.85
0.91
−0.38
0.21
0.94
0.99
0.84
0.02
0.78
0.02
0.01
0.45
Cognitive developmental quotient
−0.53
−0.50
−0.76
−0.40
−0.32
−0.44
−0.61
0.05
−0.95
0.18
0.21
0.03
0.33
0.48
0.32
0.14
0.93
< 0.01
Total developmental quotient
−0.62
−0.53
−0.53
−0.67
0.26
−0.54
−0.19
0.29
−0.91
0.10
0.18
0.17
0.07
0.57
0.21
0.68
0.58
< 0.01
Adjusting for gestational age at time of MRI, p value is based on a Bonferroni adjustment. Significance is p < 0.017.
Discussion
This study is one of the first to demonstrate that the neonatal CHD language-communication
structures in the brain follow an abnormal trajectory and these aberrations correlate
with several domains of neurodevelopmental skills.
Operculum
There have been previous demonstrations on MRI preoperatively in a variety of CHD
lesions of the existence of open opercula with an approximate 17% incidence.[3 ]
[31 ] Additionally, autopsy data of hypoplastic left heart neonates found delayed opercularization.[32 ] Cortical maldevelopment has been demonstrated in this population as well.[33 ]
[34 ]
[35 ] Interestingly, one study of 18 hypoplastic left heart fetuses and 30 control fetuses
(25–37 weeks' gestation at MRI) demonstrated no significant difference in opercular
development between the two groups except for less asymmetry between the two sides
in the CHD group.[35 ] Having no difference between left and right coincides with our data and may be a
reflection of altered or decreased brain differentiation or specialization in the
CHD population. Although we observed a significant delay in the closure of the CHD
operculum, it was surprising that the presence of this anatomic deviation did not
correlate with any neurodevelopmental deficiencies. Perhaps with a larger sample size,
an effect may be visible.
Cerebellum
More than 70% of all the human brain neurons are found in the cerebellum, and for
many years, the cerebellum was considered to simply be involved in movement and coordination.[7 ]
[36 ] More recently, the cerebellum is being recognized to have many more important roles.
Neuroanatomical, imaging, and clinical correlates have provided evidence that nonmotor
language and cognitive functions also reside in the cerebellum, where critical temporal
orchestration may occur.[7 ]
[36 ]
[37 ] It is now known that fibers traversing through the thalamus, the pontine nuclei,
the red nucleus, and/or the inferior olive connect the prefrontal cortex to the language-dominant
opercular region and cerebellum.[7 ] Clinical and imaging correlations suggest that the vermis is also involved in language
processing.[7 ]
[37 ]
[38 ]
A condition referred to as cerebellar mutism syndrome occurs most commonly after a
child has surgery for a tumor in the posterior fossa. The condition results in temporary
loss of speech (4 days to 5 months).[10 ]
[37 ]
[39 ] Interestingly, the vermis has been a focus of prevention strategies for protecting
from cerebellar mutism as this specific structure is thought to play a role in speech
initiation.[10 ]
[39 ] Puget et al have demonstrated that the more extensive damage observed to the inferior
vermis correlates with the greater deficits.[40 ]
Our study as well as a prior study demonstrated cerebellar vermian growth deficiencies
in fetuses with CHD.[41 ] Additionally, this study contributed neonatal findings as well as neurodevelopmental
correlation. Continued study of this region and its impact on language and cognitive
functions will help clarify whether the caudocranial fiber development has gone awry
or the descending control mechanisms have maldeveloped.
Growth Curves
To our knowledge, this is the first study, although preliminary, to compare longitudinal
brain growth of certain structures of fetuses and neonates with CHD to normally growing
fetuses and neonates. There were significant differences demonstrated not only in
the measurements but also in the overall growth patterns that described their trajectories.
This is a unique vantage point of the impact that an abnormally developing heart can
have on brain development over an extended amount of time. Borzage et al developed
a growth curve from previously modified equations that would describe brain growth
throughout a lifetime.[42 ] Although we did not measure overall brain growth, the normal healthy control measurements
plotted on growth curves seemed to follow this general pattern.
The opercular growth deficiency was as predicted in the CHD population. Unfortunately,
there has not been a description of the opercular development in fetuses and neonates
who have CHD nor a previously dedicated growth curve for normal opercular growth.
There have been studies describing opercular growth in healthy neonates. These have
demonstrated differences between the right and left sides of the brain as well as
an impact that sex has on opercular development.[43 ]
[44 ] Our study for neither the CHD nor the normal healthy controls found a right- versus
left-side difference. This may have been due to our smaller sample size. Our sample
size also limited us in breaking down the population further into male versus female
to look for gender effect.
The ventricular size of the fetus and neonate in normal healthy individuals has been
described on growth curves that have a relatively linear appearance from 25 to 35
weeks of gestation.[45 ] Our normal healthy controls fall onto a growth curve that is very similar.
The cerebellar vermis measurements having been significantly different on one view
(vermis sagittal height) provides a specific view to follow serially. Tilea et al
have a sagittal vermis height growth curve for 26 to 40 weeks of gestation as measured
by fetal ultrasound of normal healthy fetuses.[46 ] Our values seem to correspond to this curve as well as other measurements obtained
by ultrasound and MRI as their 50th percentile at 36 weeks was approximately 20 mm
vermian height, as was ours on our normal controls.[23 ]
[46 ]
Conclusion
We are excited to present a few novel initial findings in our limited experience at
this interim analysis in our longitudinal CHD fetal and neonatal brain develop study.
We have demonstrated that CHD infants have delayed opercular closure, impaired cerebellar
vermis growth, and that the cerebellar vermis growth correlates with several neurodevelopmental
deficiencies.
Strengths of this study include that it is longitudinal, all measurements were done
by one individual (and verified by another), the controls encompassed a large gestational
age range, and that we were able to correlate anatomic measurements with neurodevelopment.
Limitations include manual measurements, a small sample size without age-matched controls,
difficulty in doing a timed analysis comparing two groups with only two time points
(for some data points), and use of clinical controls. Also, head circumference was
not available for comparison, and sex stratification analysis was not possible due
to the small sample size.
Focusing further studies on specific anatomic brain regions in the CHD population,
continuing to study patients to form a larger sample size, and developing targeted
rehabilitative strategies to prevent such neurodevelopmental delays are our future
goals.
