Prominent White Matter Research Articles

Lipopolysaccharide-induced inflammation and perinatal brain injury

Both energy failure and infections are important risk factors for brain injury in term and preterm infants. In this review we focus on recent experimental studies that have examined the effects of lipopolysaccharide (LPS) exposure to the fetus or neonate and the interaction of LPS with other events. Intracerebral LPS injections induce a marked cerebral cytokine response and prominent white matter lesions. LPS administered intravenously to the fetus also induces gross lesions, which are mainly localised to the white matter and are accompanied by activation of inflammatory cells. Cerebral effects following fetal LPS exposure via more distant routes, such as intracervical, intrauterine or maternal LPS administration, are characterised by reductions in oligodendrocyte or myelin markers without macroscopic lesions being evident. Both antenatal and neonatal LPS exposures increase the sensitivity of the brain to subsequent hypoxic/ischaemic events, even in adulthood. These studies suggest that fetal inflammation is the strongest predictor of brain lesions.

Necrotizing Leukoencephalopathy Associated with Nonconvulsive Status Epilepticus and Periodic Short-Interval Diffuse Discharges: A Clinicopathological Study

We describe the clinical, neuroimaging and neuropathological features of an immunocompromised patient diagnosed as having refractory nonconvulsive status epilepticus (NCSE), and whose consecutive electroencephalograms (EEGs) revealed persistent periodic short-interval diffuse discharges (PSIDDs). Prominent subcortical white matter lesions in keeping with the diagnosis of multifocal necrotizing leukoencephalopathy may be neuropathological substrate of NCSE with persistent PSIDDs.

Pediatric diffusion tensor imaging: Normal database and observation of the white matter maturation in early childhood

Recent advances in diffusion tensor imaging (DTI) have made it possible to reveal white matter anatomy and to detect neurological abnormalities in children. However, the clinical use of this technique is hampered by the lack of a normal standard of reference. The goal of this study was to initiate the establishment of a database of DTI images in children, which can be used as a normal standard of reference for diagnosis of pediatric neurological abnormalities. Seven pediatric volunteers and 23 pediatric patients (age range: 0–54 months) referred for clinical MR examinations, but whose brains were shown to be normal, underwent anatomical and DTI acquisitions on a 1.5 T MR scanner. The white matter maturation, as observed on DTI color maps, was described and illustrated. Changes in diffusion fractional anisotropy (FA), average apparent diffusion constant (ADC ave), and T2-weighted (T2W) signal intensity were quantified in 12 locations to characterize the anatomical variability of the maturation process. Almost all prominent white matter tracts could be identified from birth, although their anisotropy was often low. The evolution of FA, shape, and size of the white matter tracts comprised generally three phases: rapid changes during the first 12 months; slow modifications during the second year; and relative stability after 24 months. The time courses of FA, ADC ave, and T2W signal intensity confirmed our visual observations that maturation of the white matter and the normality of its architecture can be assessed with DTI in young children. The database is available online and is expected to foster the use of this promising technique in the diagnosis of pediatric pathologies.

Dysmorphology and microstructural degradation of the corpus callosum: Interaction of age and alcoholism

Chronic alcohol abuse is a ubiquitous health and societal problem, with a growing prevalence in the older population. Alcoholism is a source of substantial deterioration in brain tissue and has been consistently observed in vivo and postmortem in white matter. To quantify the potential compounded effect of age and alcoholism, we used conventional structural MRI and diffusion tensor imaging (DTI) to examine the macrostructural and microstructural integrity of the corpus callosum, one of the most prominent white matter structures of the brain, in 131 adults, age 27–75 years. Compared with the 74 controls, the 40 alcoholic men and 17 alcoholic women, who were abstinent from alcohol for an average of 3 months, showed similar patterns and extents of callosal shrinkage, which was greatest in the genu and body and less prominent in the splenium. Microstructural integrity was measured with DTI as fractional anisotropy, an index of intravoxel orientational coherence of white matter fibers, and bulk mean diffusivity, an index of the amount of intravoxel water motility. The macrostructural shrinkage was accompanied by abnormalities in anisotropy and diffusivity of the microstructural environment of these callosal regions, indicative of disruption of structural constituents of local brain white matter. Correlational analyses revealed an age–alcohol interaction, where older alcoholics had smaller genu and splenium and higher diffusivity in these regions than younger alcoholics. Significant correlations between regional MRI and DTI measures and performance on working memory, visuospatial ability, and gait and balance provided evidence for the functional ramifications of the callosal abnormalities in the alcoholics. Thus, despite abstinence from alcohol, the interaction of age and recent alcoholism history exerted a compounded untoward effect on callosal macrostructure and microstructure.

Beyond localization: from hodology to function.

A century on, Campbell's largely forgotten 1905 monograph on the localization of cerebral function has a distinctly contemporary feel. Although his map of cortical fields has been eclipsed by Brodmann's later contribution, Campbell's project went beyond cytoarchitectonic cartography, attempting to integrate clinical, anatomical and physiological evidence to provide a guide to function. A key component of Campbell's integrative, functional anatomical approach was hodology--the pattern of white matter connections between cortical areas--foreshadowing a recently developed functional anatomical technique: diffusion tensor tractography. Here, we revisit Campbell's model of the human visual system using tractography to illustrate prominent white matter connections within the occipital lobe and from occipital to frontal, parietal and temporal regions. Campbell used his integrative approach to support the view that vision consisted of a "visuo-sensory" and a "visuo-psychic" stage, combining hodological, cytoarchitectonic, physiological and clinicopathological evidence to locate the former within the calcarine cortex and the latter within the cortical field surrounding it. Speaking directly to contemporary debates surrounding the neurobiology of conscious vision and providing a framework with which to shape future developments in tractography, Campbell's integrative functional anatomical approach is as relevant today as it was 100 years ago.

S.16.02 Erythropoietin and neurodegeneration

Periventricular leukomalacia (PVL) is the predominant pathology in premature infants, characterized by prominent cerebral white matter injury, and commonly caused by hypoxia–ischemia and inflammation. Activated microglia trigger white matter damage and play a major role in the development of PVL. Erythropoietin (EPO) and its derivative carbamylated erythropoietin (CEPO) have been shown to be neuroprotective in several brain disease models. Here we investigated whether EPO and CEPO could provide protection in mouse models of PVL induced by hypoxia–ischemia or hypoxia–ischemia-inflammation. We administered EPO or CEPO to mice with PVL, and found that both EPO and CEPO treatments decreased microglia activation, oligodendrocyte damage and myelin depletion. We also noted improved performance in neurological function assays. Inhibited disease progression in PVL mice by EPO or CEPO treatment was associated with decreased poly-(ADP-ribose) polymerase-1 (PARP-1) activity. PARP-1 activity was increased dramatically in activated microglia in untreated mice with PVL. Furthermore, we demonstrated that the neuroprotective properties of EPO and CEPO were diminished after PARP-1 gene depletion. The therapeutic doses of EPO and CEPO used in this study did not interfere with normal oligodendrocyte maturation and myelination. Together, our data demonstrate that EPO and CEPO are neuroprotective in cerebral white matter injury via a novel microglial PARP-1 dependent mechanism, and hold promise as a future treatment for PVL and other hypoxic–ischemic/inflammatory white matter diseases.

Asymmetry analysis of cingulum based on scale-invariant parameterization by diffusion tensor imaging.

Current analysis of diffusion tensor imaging (DTI) is based mostly on a region of interest (ROI) in an image dataset, which is specified by users. This method is not always reliable, however, because of the uncertainty of manual specification. We introduce an improved fiber-based scheme rather than an ROI-based analysis to study in DTI datasets of 31 normal subjects the asymmetry of the cingulum, which is one of the most prominent white matter fiber tracts of the limbic system. The present method can automatically extract the quantitative anisotropy properties along the cingulum bundles from tractography. Moreover, statistical analysis was carried out after anatomic correspondence specific to the cingulum across subjects was established, rather than the traditional whole-brain registration. The main merit of our method compared to existing counterparts is that to find such anatomic correspondence in cingulum, a scale-invariant parameterization method by arc-angle was proposed. It can give a continuous and exact description on any segment of cingulum. More interestingly, a significant left-greater-than-right asymmetry pattern was obtained in most segments of cingulum bundle (-50-25 degrees), except in the most posterior portion of cingulum (25-50 degrees).

Apoptosis in oligodendrocytes is associated with axonal degeneration in P301L tau mice

Transgenic mice overexpressing human tau with the P301L mutation develop neurofibrillary tangles, extensive gliosis, adult-onset motor abnormalities, and neuronal loss in affected brain regions. We investigated the mechanism of neuronal cell death in this model of tauopathy. There was no evidence of neuronal apoptosis at any age; however, a population of oligodendorocytes was immunopositive for TUNEL and activated caspase-3. EM confirmed that these oligodendrocytes were undergoing apoptosis. These data suggest that classical apoptosis is not a major mechanism of neuronal cell death associated with the tau dysfunction in this mouse model; however, prominent white matter pathology in the spinal cord suggests that axonal degeneration in dying neurons causes oligodendrocytes to undergo apoptosis. It is unknown if loss of oligodendrocytes either through apoptosis or through the formation of intracellular tau lesions further contributes to the neurodegeneration seen in these mice.

Fiber tract-based atlas of human white matter anatomy.

Two- and three-dimensional (3D) white matter atlases were created on the basis of high-spatial-resolution diffusion tensor magnetic resonance (MR) imaging and 3D tract reconstruction. The 3D trajectories of 17 prominent white matter tracts could be reconstructed and depicted. Tracts were superimposed on coregistered anatomic MR images to parcel the white matter. These parcellation maps were then compared with coregistered diffusion tensor imaging color maps to assign visible structures. The results showed (a). which anatomic structures can be identified on diffusion tensor images and (b). where these anatomic units are located at each section level and orientation. The atlas may prove useful for educational and clinical purposes.

Cingulate fasciculus integrity disruption in schizophrenia: a magnetic resonance diffusion tensor imaging study

Background Evidence suggests that a disruption in limbic system network integrity and, in particular, the cingulate gyrus (CG), may play a role in the pathophysiology of schizophrenia; however, the cingulum bundle (CB), the white matter tract furnishing both input and output to CG, and the most prominent white matter fiber tract in the limbic system, has not been evaluated in schizophrenia using the new technology of diffusion tensor imaging (DTI). Methods We used line scan DTI to evaluate diffusion in the CB in 16 male schizophrenia patients and 18 male control subjects, group-matched for age, parental socioeconomic status, and handedness. We acquired 4-mm-thick coronal slices through the entire brain. Maps of fractional anisotropy (FA) were generated to quantify diffusion within the left and right CB on eight slices that included the central portion of the CB. Results Results showed group differences, bilaterally, in area and mean FA for CB, where patients showed smaller area and less anisotropy than controls. For patients, decreased left CB correlated significantly with attention and working memory measures as assessed by the Wisconsin Card Sorting Test. Conclusions These data provide strong evidence for CB disruptions in schizophrenia, which may be related to disease-related attention and working memory abnormalities.

Abnormal white matter integrity in schizophrenia and schizoaffective disorder revealed by diffusion tensor imaging

Evidence suggests that a disruption in limbic system network integrity and, in particular, the cingulate gyrus (CG), may play a role in the pathophysiology of schizophrenia; however, the cingulum bundle (CB), the white matter tract furnishing both input and output to CG, and the most prominent white matter fiber tract in the limbic system, has not been evaluated in schizophrenia using the new technology of diffusion tensor imaging (DTI).We used line scan DTI to evaluate diffusion in the CB in 16 male schizophrenia patients and 18 male control subjects, group-matched for age, parental socioeconomic status, and handedness. We acquired 4-mm-thick coronal slices through the entire brain. Maps of fractional anisotropy (FA) were generated to quantify diffusion within the left and right CB on eight slices that included the central portion of the CB.Results showed group differences, bilaterally, in area and mean FA for CB, where patients showed smaller area and less anisotropy than controls. For patients, decreased left CB correlated significantly with attention and working memory measures as assessed by the Wisconsin Card Sorting Test.These data provide strong evidence for CB disruptions in schizophrenia, which may be related to disease-related attention and working memory abnormalities.

Sex differences in brain maturation during childhood and adolescence.

Brain development during childhood and adolescence is characterized by both progressive myelination and regressive pruning processes. However, sex differences in brain maturation remain poorly understood. Magnetic resonance imaging was used to examine the relationships between age and sex with cerebral gray and white matter volumes and corpus callosal areas in 118 healthy children and adolescents (61 males and 57 females), aged 6-17 years. Gender groups were similar on measures of age, handedness, socioeconomic status and Full Scale IQ. Significant age-related reductions in cerebral gray and increases in white matter volumes and corpus callosal areas were evident, while intracranial and cerebral volumes did not change significantly. Significant sex by age interactions were seen for cerebral gray and white matter volumes and corpus callosal areas. Specifically, males had more prominent age-related gray matter decreases and white matter volume and corpus callosal area increases compared with females. While these data are from a cross-sectional sample and need to be replicated in a longitudinal study, the findings suggest that there are age-related sex differences in brain maturational processes. The study of age-related sex differences in cerebral pruning and myelination may aid in understanding the mechanism of several developmental neuropsychiatric disorders.

Cluster analysis and patterns of findings on cranial magnetic resonance imaging of the elderly: the Cardiovascular Health Study.

To characterize patterns of findings on cranial magnetic resonance imaging (MRI) of the elderly using a statistical technique called cluster analysis. The Cardiovascular Health Study is a population-based, longitudinal study of 5888 people 65 years and older. Of these, 3230 underwent cranial MRI scans, which were coded for presence of infarcts and grades for white matter, ventricles, and sulci. Cluster analysis separated participants into 5 clusters based solely on patterns of MRI findings. Participants comprising each cluster were contrasted with respect to cardiovascular risk factors and clinical manifestations. One cluster was low on all the MRI findings (normal) and another was high on all of them (complex infarcts). Another cluster had evidence for infarcts alone (simple infarcts), whereas the last 2 clusters lacked infarcts, one having enlarged ventricles and sulci (atrophy) and the other having prominent white matter changes and enlarged ventricles (leukoaraiosis). Factors that distinguished these clusters in a discriminant analysis were age, sex, several measures of hypertension, internal carotid artery wall thickness, smoking, and prevalent claudication before the MRI. The atrophy group had the highest percentage of men and the normal group had the lowest. Cognitive and motor performance also differed across clusters, with the atrophy cluster performing better than may have been expected. These MRI patterns identified participants with different vascular disease risk factors and clinical manifestations. Results of these exploratory analyses warrant consideration in other populations of elderly people. Such patterns may provide clues about the pathophysiology of structural brain changes in the elderly.

Brain development, IX: human brain growth.

Back to table of contents Previous article Next article Images In NeuroscienceFull AccessBrain Development, IXHuman Brain GrowthJAY GIEDD, M.D., JAY GIEDDSearch for more papers by this author, M.D., Bethesda, Md.Published Online:1 Jan 1999https://doi.org/10.1176/ajp.156.1.4AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail Although brain development is most dynamic in utero, several processes affecting brain structure, such as myelination and arborization, persist throughout the childhood and adolescent years (top figure). Magnetic resonance imaging is well-suited for studies of childhood brain development because it uses no ionizing radiation, allowing not only scans of healthy children but even repeated scans of the same individual. Such longitudinal studies, now underway, will be critical for characterizing the nonlinear developmental curves of childhood.Although total brain volume is about 95% of its adult size by the age of 5 years, various subcomponents of the brain do undergo age-related changes. In general, white matter—an indication of myelination—increases with age, while gray matter decreases with age. The brain’s most prominent white matter structure, the corpus callosum, increases about 1.8% per year between ages 3 and 18 years. The bottom figure demonstrates growth of the corpus callosum, the sideways C-shaped white structure in the center of the brain, by showing longitudinal scans of a healthy girl at ages 3 and 9 years. The corpus callosum integrates the activity of the left and right cerebral hemispheres, and increases in corpus callosum size may reflect increased aptitude for higher-order cognitive abilities.Images are courtesy of Dr. Giedd. Time Course of Critical Events in the Determination of Human Brain Morphometry FiguresReferencesCited byDetailsCited ByBiological hypotheses, risk factors, and biomarkers of schizophreniaProgress in Neuro-Psychopharmacology and Biological Psychiatry, Vol. 120Cyberbullying involvement and short sleep duration among adolescentsSleep Health, Vol. 8, No. 2Central and Peripheral Explorations by Metabolomics to Study Neurodevelopmental Disorders30 September 2022Nonmedical use of prescription opioids, psychological distress, and suicidality among adolescents9 September 2020 | Social Psychiatry and Psychiatric Epidemiology, Vol. 56, No. 5FutureTox IV Workshop Summary: Predictive Toxicology for Healthy Children8 February 2021 | Toxicological Sciences, Vol. 180, No. 2Energy drink consumption, psychological distress, and suicidality among middle and high school studentsJournal of Affective Disorders, Vol. 268American Journal of Physical Anthropology, Vol. 171, No. S70Human Brain Mapping, Vol. 40, No. 4Neuroscience, Vol. 399Spatial and spectral trajectories in typical neurodevelopment from childhood to middle ageNetwork Neuroscience, Vol. 3, No. 2Frontiers in Neurology, Vol. 10Neuroscience & Biobehavioral Reviews, Vol. 83Frontiers in Neuroendocrinology, Vol. 44International Journal of Environmental Research and Public Health, Vol. 15, No. 1Reprint of “Adolescent cortical thickness pre- and post marijuana and alcohol initiation”Neurotoxicology and Teratology, Vol. 58Neurobiology of Disease, Vol. 92Neurotoxicology and Teratology, Vol. 57From neural development to cognition: unexpected roles for chromatin9 April 2013 | Nature Reviews Genetics, Vol. 14, No. 5, Vol. 16International Journal of Psychophysiology, Vol. 89, No. 2Human Brain Mapping, Vol. 33, No. 1Child's Nervous System, Vol. 27, No. 2NeuroImage, Vol. 49, No. 3Neuropsychopharmacology, Vol. 35, No. 1Journal of Addictive Diseases, Vol. 29, No. 2Neuroscience & Biobehavioral Reviews, Vol. 33, No. 6Journal of the American Academy of Child & Adolescent Psychiatry, Vol. 47, No. 11The Brain and Behavior: Limitations in the Legal Use of Functional Magnetic Resonance Imaging6 January 2021 | American Journal of Law & Medicine, Vol. 33, No. 2-3NeuroImage, Vol. 28, No. 2Neuroscience, Vol. 135, No. 1Schizophrenia Research, Vol. 73, No. 2-3Magnetic Resonance Imaging, Vol. 22, No. 3The American Journal of Clinical Nutrition, Vol. 77, No. 6Developmental Psychobiology, Vol. 41, No. 2Developmental Psychobiology, Vol. 39, No. 3CNS Spectrums, Vol. 6, No. 1International Forum of Psychoanalysis, Vol. 10, No. 3-4Development of Sex Differences in Spatial Memory31 August 2016 | Perceptual and Motor Skills, Vol. 89, No. 1Journal of Psychiatric Research, Vol. 33, No. 6 Volume 156Issue 1 January 1999Pages 4-4 Metrics PDF download History Published online 1 January 1999 Published in print 1 January 1999

Brain abnormalities in the elderly: frequency and predictors in the United States (the Cardiovascular Health Study). Cardiovascular Health Study Collaborative Research Group.

Characterize brain abnormalities in elderly people using cranial magnetic resonance imaging (MRI). Comprehensive lists of people 65 years and older living in the United States of America were used to obtain a representative sample of 5,888 community-dwelling participants who underwent extensive standardized evaluations. A subset of 3,660 underwent MRI. Without clinical information, neuroradiologists evaluated each scan. Enlarged ventricles and sulci and prominent white matter changes were relatively common, even in a subset of the healthiest participants. Infarcts 3 mm or greater were present in 31% of all participants and 28% of those without a history of stroke. Most infarcts were clinically silent, small, and in the basal ganglia. Among those without a history of stroke, white matter changes were common but mostly of a mild degree. These changes were independently related to greater age, silent stroke, higher systolic blood pressure, lower forced expiratory volume in one second and income less than $50,000 per year. Changes were also associated with dysfunction, especially of cognition and the lower extremities. MRI abnormalities are common in elderly people. Cautious interpretation is appropriate because participants are healthier than the general population and the study's design is cross-sectional.

Panencephalitic Creutzfeldt-Jakob disease in a Chinese family Unusual presentation with PrP codon 210 mutation and identification by PCR-SSCP

A point mutation at codon 210 ( GTT to ATT) of the prion protein gene on chromosome 20 was found in a 48-year-old CJD-affected woman of a Chinese family. This affected woman had an early onset and long-duration form of CJD. Serial magnetic resonance image (MRI) analysis of this woman showed severe brain atrophy, prominent diffuse white matter degeneration, and subsequent mineralization of basal ganglia and thalamus. MR spectroscopy ( 1H) analysis elucidated the absence of peaks of choline, creatine and N-acetylaspartate. Using polymerase chain reaction and single-strand conformational polymorphism (PCR-SSCP) techniques, presymptomatic diagnosis of the second son of this woman showed that he has a similar codon mutation of prion gene as his mother.

Multifocal inflammatory leukoencephalopathy with 5-fluorouracil and levamisole.

A cerebral demyelinating disease developed in 3 patients during adjuvant therapy with 5-fluorouracil and levamisole for adenocarcinoma of the colon. None of the patients had evidence of metastatic disease or prior neurological disease. The duration of chemotherapy before onset of neurological symptoms ranged from 15 to 19 weeks. The total dose of 5-fluorouracil was 9.7 to 15.7 gm. The total dose of levamisole was 2.7 to 3.75 gm. Two patients presented with a subacute (2-3 weeks) progressive decline in mental status and ataxia. The third patient had two unexplained episodes of loss of consciousness. In each, magnetic resonance imaging with gadolinium demonstrated prominent multifocal enhancing white matter lesions. Cerebral biopsy was performed stereotaxically in 2 patients. The morphological features were those of active demyelinating disease. The myelin loss was associated with numerous dispersed as well as vasocentric macrophages, sparing of axons, and perivascular lymphocytic inflammation. Electron microscopy confirmed the light microscopic findings. All 3 patients improved after cessation of chemotherapy and a short course of corticosteroid therapy. Our patients represent the first reported examples of an inflammatory leukoencephalopathy associated with the administration of 5-fluorouracil and levamisole. This syndrome may represent the pathological basis for 5-fluorouracil neurotoxicity, although we cannot completely exclude the role of levamisole.

Neuroimaging Findings in Alexander's Disease

We present the findings from magnetic resonance imaging, computed tomographic scan, and single photon emission computed tomography of the brain in a 2-year-old girl with Alexander's disease. Computed tomographic scans showed prominent low-density white matter throughout the cerebral hemispheres. Magnetic resonance imaging showed increased T2 signal from the cerebral white matter but not the cerebellum or brain stem. Single photon emission computed tomography revealed diminished cerebral metabolism, particularly in the frontal regions, as compared with the cerebellum.

Prominent white matter lesions develop in Mongolian gerbils treated with 100% normobaric oxygen after global brain ischemia

Carotid arteries were occluded bilaterally for 15 min in two groups of Mongolian gerbils. The first group received 100% oxygen during the first 3 h of reperfusion. During that period, room air was given to the second group. After 3 h, both groups received room air. Brains of gerbils that died within 14 days after occlusion were removed, fixed in formalin and embedded in paraffin. Gerbils that survived 15-28 days were perfused with formalin before their brains were removed and embedded in paraffin. Adjacent, serially cut sections were stained with luxol fast blue (LFB)-H&E, cresyl violet, according to the Bodian method, or immunocytochemically with antisera raised against myelin basic protein (MBP) and glial fibrillary acidic protein (GFAP). In brain sections of gerbils receiving 3 h of 100% oxygen, there were circumscribed white matter lesions in the corpus striatum, lateral thalamus, mesencephalon and posterior limb of the internal capsule. Myelin sheaths were swollen, fragmented and were less intensely stained by MBP antiserum. MBP and LFB-stained myelin fragments were present extracellularly and in macrophages. Many axons in these areas appeared undamaged. Previously described ischemic changes were found in gray matter and some areas of white matter in both groups. However, neurons in the deeper laminae of the cerebral cortex appeared to be better preserved in gerbils given oxygen. The results suggest that hyperoxia, if present immediately after transient brain ischemia, may damage myelin more severely than other cellular elements.

Cerebral Pathology and Neuropsychological Effects Differential Effects of Cranial Radiation as a Function of Age

Cranial radiation therapy (CRT) has been associated with an increased incidence of neuropsychological impairments and pathologic changes in the CNS among children. However, findings regarding a causal relationship between CRT and neurobehavioral impairments and the differential impact of CRT as a function of treatment age have been equivocal. Inconsistent findings may be attributed to the current research focus on description of impairments to the neglect of a larger theoretical framework and the failure of investigators to integrate findings from the various disciplines involved in assessing CRT effects. Two theories regarding the etiology of CRT effects on neuropsychological functions have been proposed. The myelination hypothesis suggests that CRT effects are attributable to direct effects on myelin synthesis. Findings indicating that the child is in a state of particular vulnerability to teratogens due to the rapid growth phase of myelin during the first 48 months of life provide the basis for this hypothesis. The myelination hypothesis predicts a differential effect for CRT as a function of age/maturation. The vascular hypothesis proposes that CRT effects are due to pathological changes in vascular tissues. Results indicating prominent white matter changes among some CRT recipients provide the basis for this hypothesis. The vascular hypothesis predicts no age effect or an inverse age effect; it places more emphasis on the relationship between indices of cerebral blood flow and neuropsychological test performance. Two basic mechanisms underlying the effects of CRT are outlined to provide a theoretical framework on which future research may be based.(ABSTRACT TRUNCATED AT 250 WORDS)