preterm infants are at a high risk of motor deficits in later life , with approximately fourteen percent of very preterm infants developing cerebral palsy ( cp ) , and up to forty percent of very preterm infants demonstrating mild motor deficits .
the mechanisms underlying such motor impairments have not yet been fully elucidated , but have been related to a number of factors , including abnormal cerebral development ( particularly in sensorimotor regions ) , conditions such as periventricular leukomalacia , peri - intraventricular hemorrhage , and/or stressors in the neonatal intensive care unit ( nicu ) environment .
new insights into the neural structures and mechanisms , underlying motor function in preterm - born infants , should help in the development of new diagnostic and prognostic tools and provide information on the immediate efficacy of early intervention therapies .
the corpus callosum is vital for communicating and integrating motor and somatosensory information between the hemispheres , and for bimanual motor coordination and function .
the maturation or structural development of the corpus callosum , that is , the organisation of axon fiber bundles and the degree of axonal myelination and microstructural integrity , can be studied using diffusion tensor imaging ( dti ) , particularly via the measures of fractional anisotropy ( fa ) and mean diffusivity ( md ) .
the interpretation of fa and md values is not entirely clear and largely depends on the underlying fiber architecture , including the degree of myelination , axon size , density , and organization [ 7 , 8 ] .
since the corpus callosum is a highly organized myelinated structure , with axons typically running in packed parallel bundles , a high fa value and low md value is suggestive of greater structural maturation . in imaging studies
, the infant corpus callosum is often segmented into six anatomical regions from anterior to posterior  the genu , rostral body , anterior midbody , posterior midbody , isthmus , and splenium .
thompson et al . found that very preterm infants had significantly reduced corpus callosum cross - sectional area , lower fa and higher md values compared to term infants , thus suggesting that corpus callosum development is altered in preterm - born infants compared to term - born infants .
a minority of studies have investigated the implications of this altered development by examining associations between corpus callosum maturation and neurodevelopment [ 1113 ]
investigated the relationship between dti measures of the genu and splenium ( the most anterior and posterior subregions of the corpus callosum , resp . )
taken at term age with neurological assessments ( amiel - tison scale , gross motor function classification system , and bayley scales of infant development ) performed at eighteen months in preterm - born children .
the maturation of the splenium ( as reflected by fa values ) was significantly lower in children with abnormal versus normal neurological assessments , indicating that splenium fa near term age could potentially be used to prognosticate subsequent neurodevelopment .
2002 study using dti to examine white matter tracts in children with cerebral palsy as a result of periventricular leukomalacia .
the tracts in the splenium , posterior corona radiate , and posterior internal capsule were markedly reduced in size in participants suffering from cerebral palsy compared to controls .
hence , it was suggested that interhemispheric tracts to or from the sensory cortex , in addition to motor tracts , may also play a role in motor impairment .
a strong positive association between the midsagittal surface area of the corpus callosum on t1-weighted magnetic resonance imaging ( mri ) scans and concomitant motor function in preterm - born children , studied at school age .
furthermore , iai et al . compared midsagittal corpus callosum t1-weighted mri measures in preterm - born children with spastic diplegia ( cp ) versus neurologically typical children . in the diplegic children ,
it was found that the ratios of the thickness of the splenium and of the midbody to the corpus callosum length were significantly reduced , compared to the ratios computed in neurologically typical children .
furthermore , the ratio for the splenium was highly correlated with the extent of motor impairment .
however , aside from these few studies , potential associations between corpus callosum structure and neuro - motor function in preterm - born neonates have not been reported .
outcomes from such investigations may prove clinically meaningful ; for example , they may inform development of early prognostic indicators , interventions , and/or markers to inform instigation of such interventions .
hence the primary aim of this study was to investigate and explore potential associations between dti measures of subregions of the corpus callosum and concomitant neurological measures in a small sample of preterm infants .
we hypothesized that a positive relationship would exist between corpus callosum maturation and concomitant neurological measures .
the participants were preterm infants born at gestational age between 28 and 32 weeks ( ga ) at the royal brisbane and women 's hospital ( rbwh ) with no post - natal medical issues or complications .
inclusion criteria were : infants that were born at a gestational age between 28 and 32 weeks , with a birth weight and length between the 10th and 90th percentiles for gestational age and who were determined to be medically stable .
exclusion criteria were as follows : the presence of abnormalities on brain ultrasound ( i.e. , intraventricular hemorrhage grades 3 or 4 , persistent periventricular flares , or periventricular cysts ) and the presence of major genetic disorders or malformations .
these criteria were set to ensure that the study participants were at low risk for an adverse outcome and were medically stable .  
this study was approved by the rbwh human research ethics committee and monash university human research ethics committee .
parents who agreed to their infant participation in the study signed a written consent form and were provided with a copy of the study protocol .   on reaching term - equivalent age ( 42 weeks ga ) , the infants underwent the hammersmith neonatal neurological examination ( hne )   at the rbwh performed by a single neonatologist .
the hne evaluates a number of motor and behavioral functions including posture and tone , tone patterns , reflexes , abnormal signs and orientation , and behavior .
when performed at around term age , it provides a summary score for each of these categories and a total hne score ( maximum score 32 ) which is the sum of these categories . as a follow - up analysis , a total  motor - specific  score ( maximum 20 )
was calculated by summing the scores from the posture and tone , tone patterns , and reflexes categories .
associations between the hne and motor - specific scores and dti measures were examined .  
the infants underwent neuroimaging at approximately term - equivalent age ( refer to table 1 ) .
the infants were scanned using a 3.0-t siemens tim trio scanner and were placed in an mri - compatible neonatal incubator with a dedicated head coil ( lammers medical , luebeck , germany ) .
they were swaddled and placed in a vacuum fixation beanbag designed to keep the infant still and supported in the scanner .
diffusion weighted images were acquired along 30 directions at a b - value of 1000  s / mm , along with one minimally diffusion weighted image ( b = 0 ) .
the image resolution of the scans was 1.75  1.75  mm in - plane , with a slice thickness of 2  mm .
other imaging parameters were as follows : tr / te 9300/130  ms , field of view 128  128 , 47 slices .
the mri parameters for the field map acquired were tr / te1/te2 488/4.9/7.4  ms , matrix size 64  64 , field of view 160  160  mm , slice thickness 2.6  mm with 0.65  mm slice gap , 29 slices , and flip angle 60 degrees .  
preprocessing of the imaging data involved correction for any head movement using rigid - body registration with subsequent adjustment of the b - matrix , skull stripping , as well as susceptibility distortion correction   and correction for intensity inhomogeneities .
additionally , images were visually examined for artifacts and distortions and infants whose images showed motion artifact on the minimally diffusion - weighted image were excluded from the dti analyses .  
fractional anisotropy ( fa ) , color fa , and md maps of the brain were calculated for each infant , with fa representing the degree of anisotropic diffusion and md representing the magnitude of diffusion .
alignment of images with the midsagittal plane was achieved using rigid - body registration of fa maps with the john hopkins university neonatal fa template .
care was taken in the manual delineation of the corpus callosum in order to minimize the number of voxels that were contaminated by partial volume effects .
for each infant , based on visual inspection , a corpus callosum region of interest was manually drawn onto the midsagittal slice of the color - fa maps .
four sets of masks were drawn for each infant , to ensure reproducibility of the masks .
for each infant , the four corpus callosum masks were then segmented into six regions  genu , rostral body , anterior midbody , posterior midbody , isthmus , and splenium  according to the neonatal segmentation schema provided by thompson et al .
an average was taken of the mean values of the regions from the four masks to provide six corpus callosum fa and md values for each infant .  
the infants ranged between 41 and 45 weeks ga at the time of dti assessment .
as it is known that fa values tend to increase rapidly with increasing ga , the fa values were adjusted for ga . using spss ( statistical package for the social sciences , version 14.0 ; ibm spss , chicago , il , usa )
, the correlations between clinical measures and corpus callosum dti measures were explored using a two - tailed spearman 's rho ( see tables 2 and 3 for the fa and md values used in the analysis ) .
correction for multiple comparisons was not performed given the exploratory nature of this study of a small sample as well as the number and nature of the variables analyzed .
table 1 provides a summary of the characteristics and assessments for these thirteen infants .   due to time constraints
furthermore , due to technical issues and motion artifacts , dti data from three infants was excluded from the analyses , leaving eight infants whose data was included in the correlation analyses .  
using spearman 's rho , associations were explored between the clinical and dti measures ( see tables 4 and 5 ) .
a highly significant positive correlation was found between the total hne scores and the anterior midbody fa measures ( rho = 0.929 ; p = 0.001 ) and similarly between the motor - specific scores and the anterior midbody fa measures ( rho = 0.857 ; p = 0.007 ) .
a statistically significant negative correlation was found between the total hne scores and the anterior midbody md measures ( rho = 0.714 ; p = 0.047 ) .
scatter plots illustrating these correlations are provided in figures 2 , 3 , and 4 .   in summary
, the total hne scores correlated significantly with both the anterior midbody fa and md measures . in addition a significant positive correlation was found between the motor - specific subscores of the hne assessment and anterior midbody fa measures .
overall neurological function , as well as specific motor function measures , correlated significantly with dti measures from the anterior midbody , but not from other regions of the corpus callosum .
these findings are consistent with studies investigating corpus callosum topography in primates and humans [ 26 , 27 ] .
the results from these studies suggest that , from a neuroanatomical perspective , axons in the midbody interconnect the premotor and primary motor cortical areas .
furthermore , the primary and secondary motor cortices and somatosensory regions are located in the precentral and postcentral cortices , which are in a similar spatial region to the corpus callosum midbody .
given that these somatosensory and motor regions , as well as the corpus callosum , are topographically organized , it is likely that interhemispheric axons which connect homologous regions of the left and right cortical regions pass through the corpus callosum midbody . in particular , these study findings suggest that such axons connecting ( frontal ) motor cortical regions likely constitute part of the anterior midbody .   both total hne and motor - specific scores correlated with greater maturation of the anterior midbody ( i.e. , higher fa and lower md values ) . it has been suggested that fa values in the corpus callosum are primarily a reflection of fiber density and organization , rather than myelination or axon diameter
in contrast , md values are believed to be more sensitive to ( pre-)myelination , with lower md values indicating advanced callosal myelination and microstructure [ 30 , 31 ] .
consequently , a relatively well - organized and ( pre-)myelinated corpus callosum ( e.g. , anterior midbody ) may be associated with more efficient transmission of interhemispheric neural signals , which thereby permits more optimal processing and integration of ( e.g. , motor - related ) information between the hemispheres .
this study appears to be one of the first studies to describe a strong correlation between the maturation of the anterior midbody and concomitant neurological function in preterm infants .
in contrast , a number of studies ( as described in section 4 ) demonstrated associations between splenium maturation and altered neurological function .
however , the infant cohorts used in these studies involved infants with demonstrated white - matter injury and periventricular leukomalacia ( pvl ) . a characteristic feature of pvl is thinning or altered maturation of the splenium ; hence , this may explain why a strong association was found between splenium maturation and altered neurological function in these infants .   in light of these findings
, intervention programs and management strategies directed towards enhancing the development of white matter should be investigated further , as this may aid in enhancing motor function and possibly other neurobehavioral functions for preterm infants .
an mri study performed by smith et al . demonstrated that stresses from the nicu environment correlated with decreased white matter maturation and interhemispheric communication in preterm infants , as assessed by dti and functional mri .
this study also reported that infants experiencing greater nicu - induced stress in the immediate postnatal period demonstrated poorer motor function at term - equivalent age .
als et al . performed a randomized control trial investigating the merits of a newborn individualized developmental care and assessment program ( nidcap ) in order to reduce stressors for preterm infants while in nicu .
they found improved white matter development ( assessed via dti ) , brain functional connectivity ( as measured by electroencephalography ) , and neurological function in the nidcap cohort of infants versus controls at term - equivalent age . a similar study performed by mcanulty et al . demonstrated that nidcap intervention had positive effects on preterm - born children 's neurobehavioral function at least until school age .
since the current findings indicate an association between anterior midbody development and neurological function , this may in part explain why interventions such as the nidcap , which are directed towards enhancing white matter development , resulted in improved neuromotor function .
the observed relationship between anterior midbody integrity and neurological function , if replicated and extended in larger studies , may inform future development of prognostic tools for neonates .
future studies should investigate whether such dti measures may demonstrate value in the prediction of neurodevelopmental , particularly motor outcomes at a later age .
conversely , in light of the strong correlation between hne scores and dti measures , it is possible that hne assessment may also prove to be a valuable prognostic marker , with the added advantage of being easy to perform at the bedside .
such markers might also ultimately prove informative for future interventional trial programs , for example for selection of inclusion criteria , or predicting or assessing response to a given intervention .
there are a number of limitations in the current study , particularly the small sample size and associated low statistical power .
in addition , the corpus callosum segmentation method employed was not necessarily optimal as current understanding of corpus callosum anatomical segmentation and tract topography in infants is limited , unlike in adult studies .
this would be likely improved by identification of callosal regions defined by dti tractography methods in infants . however
a positive association was observed between dti measures of structural maturation of the anterior midbody of the corpus callosum and neurological and motor function , in healthy preterm - born infants assessed at term - equivalent age .
future studies of larger samples may extend upon these preliminary findings and possibly investigate the value of corpus callosum dti measures as early prognostic markers for neurodevelopmental and motor outcomes .
 
 background . 
 the etiology of motor impairments in preterm infants is multifactorial and incompletely understood . whether corpus callosum development is related to impaired motor function 
 is unclear . 
 potential associations between motor - related measures and diffusion tensor imaging ( dti ) of the corpus callosum in preterm infants were explored . 
 methods . 
 eight very preterm infants ( gestational age of 2832 weeks ) underwent the hammersmith neonatal neurological examination and dti assessments at gestational age of 42 weeks . 
 the total hammersmith score and a motor - specific score ( sum of hammersmith motor subcategories ) were calculated . 
 six corpus callosum regions of interest were defined on the mid - sagittal dti slice  
 genu , rostral body , anterior midbody , posterior midbody , isthmus , and splenium . 
 the fractional anisotropy ( fa ) and mean diffusivity ( md ) of these regions were computed , and correlations between these and hammersmith measures were sought . results . 
 anterior midbody fa measures correlated positively with total hammersmith ( rho = 0.929 , p = 0.001 ) and motor - specific scores ( rho = 0.857 , p = 0.007 ) . 
 total hammersmith scores also negatively correlated with anterior midbody md measures ( rho = 0.714 , p = 0.047 ) . discussion . 
 these results suggest the integrity of corpus callosum axons , particularly anterior midbody axons , is important in mediating neurological functions . 
 greater callosal maturation was associated with greater motor function . 
 corpus callosum dti may prove to be a valuable screening or prognostic marker . 
1. Introduction
2. Participants and Methods
3. Results
4. Discussion
5. Conclusion