Diffusion tensor magnetic resonance histology reveals microstructural changes in the developing rat brain

doi:10.1016/j.neuroimage.2013.04.101

NeuroImage

Volume 79, 1 October 2013, Pages 329-339

https://doi.org/10.1016/j.neuroimage.2013.04.101 Get rights and content

Highlights

•
We track diffusion tensor changes in the rat brain throughout postnatal development.
•
We analyze diffusion tensor changes in white matter and gray matter structures.
•
We correlate diffusion tensor changes with tissue microstructural changes.

Abstract

The postnatal period is a remarkably dynamic phase of brain growth and development characterized by large-scale macrostructural changes, as well as dramatic microstructural changes, including myelination and cortical layering. This crucial period of neurodevelopment is uniquely susceptible to a wide variety of insults that may lead to neurologic disease. MRI is an important tool for studying both normal and abnormal neurodevelopmental changes, and quantitative imaging strategies like diffusion tensor imaging (DTI) allow visualization of many of the complex microstructural changes that occur during postnatal life. Diffusion tensor magnetic resonance histology (DT-MRH) provides particularly unique insight into cytoarchitectural changes in the developing brain. In this study, we used DT-MRH to track microstructural changes in the rat brain throughout normal postnatal neurodevelopment. We provide examples of diffusion tensor parameter changes in both white matter and gray matter structures, and correlate these changes with changes in cytoarchitecture. Finally, we provide a comprehensive database of image sets as a foundation for future studies using DT-MRH to characterize abnormal neurodevelopment in rodent models of neurodevelopmental disease.

Graphical abstract

Section snippets

Introduction and background

Early postnatal life is a crucial period of mammalian brain growth and development. During this period the neonate is exposed to the extrauterine environment for the first time and must learn to interact with others and process a wide variety of external stimuli (i.e. vision, olfaction, audition). These dramatic functional changes are accompanied by equally dramatic changes in brain structure including massive cell growth and macrostructural changes. Perhaps equally as important are the complex

Experimental animals

All experiments were done with the approval of the Duke University Institutional Animal Care and Use Committee. To ensure accurate sampling of postnatal brain development, we selected nine time-points temporally spaced to allow an approximately fixed percentage increase (~ 30%) in brain mass between samples based on previously published rat brain growth curves (Donaldson, 1915). The nine time-points selected for the atlas were p0, p2, p4, p8, p12, p18, p24, p40, and p80 (where “p” indicates

DT-MRH of postnatal rat brain development

Fig. 1 shows population-averaged (n = 5), directionally-encoded color FA maps from all nine time-points included in this study (p0 to p80) in the coronal plane. Pixel intensity indicates fractional anisotropy and color indicates orientation of the primary eigenvector (red = lateral/medial orientation, green = rostral/caudal and blue = dorsal/ventral). All coronal slices are taken from roughly the same anatomic location—through the rostral aspect of the hippocampal formation. On the right side of Fig. 1

Diffusion tensor changes reveal white matter maturation

A majority of white matter myelination in the rodent brain occurs during the early postnatal period, and the myelination process is virtually complete by the third postnatal week (Foran and Peterson, 1992). FA is a sensitive (though not specific) imaging biomarker for axonal organization and myelin integrity. The diffusion data collected for this study reveal dramatic microstructural changes during early postnatal development that correlate, both spatially and temporally, with known white

Conclusions

The data presented here represents the most comprehensive and highest-resolution diffusion tensor database of rat neurodevelopment to date. We have collected diffusion tensor data at unprecedented spatial- and temporal-resolution throughout postnatal neurodevelopment and used it to characterize the normal microstructural changes that occur during this crucial period of brain growth and differentiation. Further, we have correlated our findings with known microstructural developmental milestones

Acknowledgments

All work was performed at the Duke Center for In Vivo Microscopy, an NIH/NIBIB Biomedical Technology Resource Center (P41 EB015897). We are grateful to Sally Gewalt and James Cook for assistance with the imaging pipelines. We thank Dr. Yi Qi and Gary Cofer for assistance in specimen preparation and scanning. We thank John Lee and David Joseph Lee for assistance with labeling, and Sally Zimney for assistance in editing. Finally, we thank Neil Medvitz and Dr. Sara Miller at the Duke Electron

References (52)

A.L. Alexander et al.
Analysis of partial volume effects in diffusion-tensor MRI
Magn. Reson. Med.
(2001)
K.L. Allendoerfer et al.
The subplate, a transient neocortical structure: its role in the development of connections between thalamus and cortex
Annu. Rev. Neurosci.
(1994)
A.W. Anderson
Theoretical analysis of the effects of noise on diffusion tensor imaging
Magn. Reson. Med.
(2001)
V. Arsigny et al.
Log-Euclidean metrics for fast and simple calculus on diffusion tensors
Magn. Reson. Med.
(2006)
B. Avants et al.
Multivariate analysis of structural and diffusion imaging in traumatic brain injury
Acad. Radiol.
(2008)
P.J. Basser
Inferring microstructural features and the physiological state of tissues from diffusion-weighted images
NMR Biomed.
(1995)
P.J. Basser et al.
Microstructural and physiological features of tissues elucidated by quantitative-diffusion-tensor MRI
J. Magn. Reson. B
(1996)
K.H. Bockhorst et al.
Early postnatal development of rat brain: in vivo diffusion tensor imaging
J. Neurosci. Res.
(2008)
C. Bonnier et al.
Animal models of shaken baby syndrome: revisiting the pathophysiology of this devastating injury
Pediatr. Rehabil.
(2004)
E. Calabrese et al.
An ontology-based segmentation scheme for tracking postnatal changes in the developing rodent brain with MRI
NeuroImage
(2012)

E. Calabrese et al.

A quantitative magnetic resonance histology atlas of postnatal rat brain development with regional estimates of growth and variability

NeuroImage

(2013)

H. Chahboune et al.

Neurodevelopment of C57B/L6 mouse brain assessed by in vivo diffusion tensor imaging

NMR Biomed.

(2007)

G. Chanas-Sacre et al.

Radial glia phenotype: origin, regulation, and transdifferentiation

J. Neurosci. Res.

(2000)

N. Chuang et al.

An MRI-based atlas and database of the developing mouse brain

NeuroImage

(2011)

H.H. Donaldson

The Rat: Reference Tables and Data for the Albino Rat (Mus norvegicus albinus) and the Norway Rat (Mus norvegicus)

(1915)

J. Ellegood et al.

Brain abnormalities in a Neuroligin3 R451C knockin mouse model associated with autism

Autism Res.

(2011)

E.J. Field et al.

Electron microscopic observations on the development of myelin in cultures of neonatal rat cerebellum

J. Neurol. Sci.

(1969)

D.R. Foran et al.

Myelin acquisition in the central nervous system of the mouse revealed by an MBP-Lac Z transgene

J. Neurosci.

(1992)

R.T. Giberson et al.

Microwave processing techniques for electron microscopy: a four-hour protocol

Methods Mol. Biol.

(1999)

D.N. Guilfoyle et al.

Diffusion tensor imaging in fixed brain tissue at 7.0 T

NMR Biomed.

(2003)

Y. Jiang et al.

Microscopic diffusion tensor atlas of the mouse brain

NeuroImage

(2011)

G.A. Johnson et al.

Morphologic phenotyping with MR microscopy: the visible mouse

Radiology

(2002)

G.A. Johnson et al.

High-throughput morphologic phenotyping of the mouse brain with magnetic resonance histology

NeuroImage

(2007)

M. Kim et al.

Spatial resolution dependence of DTI tractography in human occipito-callosal region

NeuroImage

(2006)

P. Kochunov et al.

Regional spatial normalization: toward an optimal target

J. Comput. Assist. Tomogr.

(2001)

N. Kovacevic et al.

A three-dimensional MRI atlas of the mouse brain with estimates of the average and variability

Cereb. Cortex

(2005)

Cited by (20)

A multicontrast MR atlas of the Wistar rat brain
2021, NeuroImage
Citation Excerpt :
One of the strengths of this atlas is the combination possible since the volumes are registered. MR Histology is becoming much more routine in a wide range of studies in the rat brain (Calabrese et al., 2013, 2014; Johnson et al., 2014; Sills et al., 2004; Calabrese and Johnson, 2013; Antonsen et al., 2013; Sills et al., 2020). The new template and associated labels provided here will facilitate expanded applications.
Abstract We describe a multi-contrast, multi-dimensional atlas of the Wistar rat acquired at microscopic spatial resolution using magnetic resonance histology (MRH). Diffusion weighted images, and associated scalar images were acquired of a single specimen with a fully sampled Fourier reconstruction, 61 angles and b=3000 s/mm² yielding 50 um isotropic spatial resolution. The higher angular sampling allows use of the GQI algorithm improving the angular invariance of the scalar images and yielding an orientation distribution function to assist in delineating subtle boundaries where there are crossing fibers and track density images providing insight into local fiber architecture. A multigradient echo image of the same specimen was acquired at 25 um isotropic spatial resolution. A quantitative susceptibility map enhances fiber architecture relative to the magnitude images. An accompanying multi-specimen atlas (n=6) was acquired with compressed sensing with the same diffusion protocol as used for the single specimen atlas. An average was created using diffeomorphic mapping. Scalar volumes from the diffusion data, a T2* weighted volume, a quantitative susceptibility map, and a track density volume, all registered to the same space provide multiple contrasts to assist in anatomic delineation. The new template provides significantly increased contrast in the scalar DTI images when compared to previous atlases. A compact interactive viewer based on 3D Slicer is provided to facilitate comparison among the contrasts in the multiple volumes. The single volume and average atlas with multiple 3D volumes provide an improved template for anatomic interrogation of the Wistar rat brain. The improved contrast to noise in the scalar DTI images and the addition of other volumes (eg. QA,QSM,TDI ) will facilitate automated label registration for MR histology and preclinical imaging.
Structural and functional MRI of altered brain development in a novel adolescent rat model of quinpirole-induced compulsive checking behavior
2020, European Neuropsychopharmacology
Citation Excerpt :
We found increasing FA values in white matter tracts, between postnatal weeks five and ten. Previous studies also demonstrated an increase in FA values of white matter tracts during development in rats (Bockhorst et al., 2008; Calabrese and Johnson, 2013), which may continue during (early) adulthood (van Meer et al., 2012). Likewise, in humans, developmental increases in FA values of white matter tracts have been demonstrated to continue until the end of adolescence or the beginning of adulthood (Barnea-Goraly et al., 2005; Chen et al., 2016).
Obsessive-compulsive disorder (OCD) is increasingly considered to be a neurodevelopmental disorder. However, despite insights in neural substrates of OCD in adults, less is known about mechanisms underlying compulsivity during brain development in children and adolescents. Therefore, we developed an adolescent rat model of compulsive checking behavior and investigated developmental changes in structural and functional measures in the frontostriatal circuitry. Five-weeks old Sprague Dawley rats were subcutaneously injected with quinpirole (n = 21) or saline (n = 20) twice a week for five weeks. Each injection was followed by placement in the middle of an open field table, and compulsive behavior was quantified as repeated checking behavior. Anatomical, resting-state functional and diffusion MRI at 4.7T were conducted before the first and after the last quinpirole/saline injection to measure regional volumes, functional connectivity and structural integrity in the brain, respectively. After consecutive quinpirole injections, adolescent rats demonstrated clear checking behavior and repeated travelling between two open-field zones. MRI measurements revealed an increase of regional volumes within the frontostriatal circuits and an increase in fractional anisotropy (FA) in white matter areas during maturation in both experimental groups. Quinpirole-injected rats showed a larger developmental increase in FA values in the internal capsule and forceps minor compared to control rats. Our study points toward a link between development of compulsive behavior and altered white matter maturation in quinpirole-injected adolescent rats, in line with observations in pediatric patients with compulsive phenotypes. This novel animal model provides opportunities to investigate novel treatments and underlying mechanisms for patients with early-onset OCD specifically.
Volumetric development of the zebra finch brain throughout the first 200 days of post-hatch life traced by in vivo MRI
2018, NeuroImage
The first months of life are characterized by massive neuroplastic processes that parallel the acquisition of skills and abilities vital for proper functioning in later life. Likewise, juvenile songbirds learn the song sung by their tutor during the first months after hatching. To date, most studies targeting brain development in songbirds exclusively focus on the song control and auditory pathways. To gain a comprehensive insight into structural developmental plasticity of the entire zebra finch brain throughout the different subphases of song learning, we designed a longitudinal study in a group of male (16) and female (19) zebra finches. We collected T2-weighted 3-dimensional anatomical scans at six developmental milestones throughout the process of song learning, i.e. 20, 30, 40, 65, 90 and 120 days post hatching (dph), and one additional time point well after song crystallization, i.e. 200 dph. We observed that the total brain volume initially increases, peaks around 30–40 dph and decreases towards the end of the study. Further, we performed brain-wide voxel-based volumetric analyses to create spatio-temporal maps indicating when specific brain areas increase or decrease in volume, relative to the subphases of song learning. These maps informed (1) that most areas implicated in song control change early, i.e. between 20 and 65 dph, and are embedded in large clusters that cover major subdivisions of the zebra finch brain, (2) that volume changes between consecutive subphases of vocal learning appear highly similar in males and females, and (3) that only more rostrally situated brain regions change in volume towards later ages. Lastly, besides detecting sex differences in local tissue volume that align with previous studies, we uncovered two additional brain loci that are larger in male compared to female zebra finches. These volume differences co-localize with areas related to the song control and auditory pathways and can therefore be associated to the behavioral difference as only male zebra finches sing. In sum, our data point to clear heterochronous patterns of brain development similar to brain development in mammalian species and this work can serve as a reference for future neurodevelopmental imaging studies in zebra finches.
Functional correlates of central white matter maturation in perinatal period in rabbits
2014, Experimental Neurology
Citation Excerpt :
Maturation of DTI indices continues in rabbits during at least four postnatal weeks (D'Arceuil et al., 2005). Similar, rapid phase of FA change between P12 and P24 coincides with the onset of active myelination in rats (Calabrese and Johnson, 2013; Jito et al., 2008). In kittens, this period occurs between second and fourth weeks (Baratti et al., 1999).
Anisotropy indices derived from diffusion tensor imaging (DTI) are being increasingly used as biomarkers of central WM structural maturation, myelination and even functional development. Our hypothesis was that the rate of functional changes in central WM tracts directly reflects rate of changes in structural development as determined by DTI indices.
We examined structural and functional development of four major central WM tracts with different maturational trajectories, including internal capsule (IC), corpus callosum (CC), fimbria hippocampi (FH) and anterior commissure (AC). Rabbits were chosen due to perinatal brain development being similar to humans, and four time points were studied: P1, P11, P18 and adults. Imaging parameters of structural maturation included fractional anisotropy (FA), mean and directional diffusivities derived from DTI, and T2 relaxation time. Axonal composition and degree of myelination were confirmed on electron microscopy. To assess functional maturation, conduction velocity was measured in myelinated and non-myelinated fibers by electrophysiological recordings of compound action potential in perfused brain slices.
Diffusion indices and T2 relaxation time in rabbits followed a sigmoid curve during development similar to that for humans, with active changes even at premyelination stage. The shape of the developmental curve was different between the fiber tracts, with later onset but steeper rapid phase of development in IC and FH than in CC. The structural development was not directly related to myelination or to functional development. Functional properties in projection (IC) and limbic tracts (FH) matured earlier than in associative and commissural tracts (CC and AC).
The rapid phase of changes in diffusion anisotropy and T2 relaxation time coincided with the development of functional responses and myelination in IC and FH between the second and third weeks of postnatal development in rabbits. In these two tracts, MRI indices could serve as surrogate markers of the early stage of myelination. However, the discordance between developmental change of diffusion indices, myelination and functional properties in CC and AC cautions against equating DTI index changes as biomarkers for myelination in all tracts.
Diffusion MRI of the developing cerebral cortical gray matter can be used to detect abnormalities in tissue microstructure associated with fetal ethanol exposure
2013, NeuroImage
Citation Excerpt :
At time points similar to those studied here, rodent studies either confirm no change in axial diffusivity within the cerebral cortex (Larvaron et al., 2007), or report reductions in axial diffusivity with maturation (Bockhorst et al., 2008; Calabrese and Johnson, 2013; Huang et al., 2008). Regarding radial diffusivity, either increases similar to those seen here are reported (Bockhorst et al., 2008; Calabrese and Johnson, 2013), or no change in radial diffusivity is reported (Huang et al., 2008; Larvaron et al., 2007). Considering a loss of FA during early cortical development, an increase in radial diffusivity corresponds to an increase in complexity of dendritic arbors seen with maturation over this time period (Leigland and Kroenke, 2011).
Fetal alcohol spectrum disorders (FASDs) comprise a wide range of neurological deficits that result from fetal exposure to ethanol (EtOH), and are the leading cause of environmentally related birth defects and mental retardation in the western world. One aspect of diagnostic and therapeutic intervention strategies that could substantially improve our ability to combat this significant problem would be to facilitate earlier detection of the disorders within individuals. Light microscopy-based investigations performed by several laboratories have previously shown that morphological development of neurons within the early-developing cerebral cortex is abnormal within the brains of animals exposed to EtOH during fetal development. We and others have recently demonstrated that diffusion MRI can be of utility for detecting abnormal cellular morphological development in the developing cerebral cortex. We therefore assessed whether diffusion tensor imaging (DTI) could be used to distinguish the developing cerebral cortices of ex vivo rat pup brains born from dams treated with EtOH (EtOH; 4.5 g/kg, 25%) or calorie-matched quantities of maltose/dextrin (M/D) throughout gestation. Water diffusion and tissue microstructure were investigated using DTI (fractional anisotropy, FA) and histology (anisotropy index, AI), respectively. Both FA and AI decreased with age, and were higher in the EtOH than the M/D group at postnatal ages (P)0, P3, and P6. Additionally, there was a significant correlation between FA and AI measurements. These findings provide evidence that disruptions in cerebral cortical development induced by EtOH exposure can be revealed by water diffusion anisotropy patterns, and that these disruptions are directly related to cerebral cortical differentiation.
Tensor-valued and frequency-dependent diffusion MRI and magnetization transfer saturation MRI evolution during adult mouse brain maturation
2023, arXiv

View all citing articles on Scopus

View full text

Published by Elsevier Inc.

Diffusion tensor magnetic resonance histology reveals microstructural changes in the developing rat brain

Highlights

Abstract

Graphical abstract

Section snippets

Introduction and background

Experimental animals

DT-MRH of postnatal rat brain development

Diffusion tensor changes reveal white matter maturation

Conclusions

Acknowledgments

Analysis of partial volume effects in diffusion-tensor MRI

Magn. Reson. Med.

The subplate, a transient neocortical structure: its role in the development of connections between thalamus and cortex

Annu. Rev. Neurosci.

Theoretical analysis of the effects of noise on diffusion tensor imaging

Magn. Reson. Med.

Log-Euclidean metrics for fast and simple calculus on diffusion tensors

Magn. Reson. Med.

Multivariate analysis of structural and diffusion imaging in traumatic brain injury

Acad. Radiol.

Inferring microstructural features and the physiological state of tissues from diffusion-weighted images

NMR Biomed.

Microstructural and physiological features of tissues elucidated by quantitative-diffusion-tensor MRI

J. Magn. Reson. B

Early postnatal development of rat brain: in vivo diffusion tensor imaging

J. Neurosci. Res.

Animal models of shaken baby syndrome: revisiting the pathophysiology of this devastating injury

Pediatr. Rehabil.

An ontology-based segmentation scheme for tracking postnatal changes in the developing rodent brain with MRI

NeuroImage

A quantitative magnetic resonance histology atlas of postnatal rat brain development with regional estimates of growth and variability

NeuroImage

Neurodevelopment of C57B/L6 mouse brain assessed by in vivo diffusion tensor imaging

NMR Biomed.

Radial glia phenotype: origin, regulation, and transdifferentiation

J. Neurosci. Res.

An MRI-based atlas and database of the developing mouse brain

NeuroImage

The Rat: Reference Tables and Data for the Albino Rat (Mus norvegicus albinus) and the Norway Rat (Mus norvegicus)

Brain abnormalities in a Neuroligin3 R451C knockin mouse model associated with autism

Autism Res.

Electron microscopic observations on the development of myelin in cultures of neonatal rat cerebellum

J. Neurol. Sci.

Myelin acquisition in the central nervous system of the mouse revealed by an MBP-Lac Z transgene

J. Neurosci.

Microwave processing techniques for electron microscopy: a four-hour protocol

Methods Mol. Biol.

Diffusion tensor imaging in fixed brain tissue at 7.0 T

NMR Biomed.

Microscopic diffusion tensor atlas of the mouse brain

NeuroImage

Morphologic phenotyping with MR microscopy: the visible mouse

Radiology

High-throughput morphologic phenotyping of the mouse brain with magnetic resonance histology

NeuroImage

Spatial resolution dependence of DTI tractography in human occipito-callosal region

NeuroImage

Regional spatial normalization: toward an optimal target

J. Comput. Assist. Tomogr.

A three-dimensional MRI atlas of the mouse brain with estimates of the average and variability

Cereb. Cortex