Fusion of white and gray matter geometry: a framework for investigating brain development.

We aimed to investigate whether DTI metrics and volumetric analysis could detect regional abnormalities in young Autism Spectrum Disorder (ASD) children. A sample of 22 pre-school children affected by ASD and a group of 10 age-matched controls underwent a conventional and advanced MRI protocol, including DTI and 3D T1- weighted imaging. Volumetric analysis revealed no significant differences between the ASD children and the controls, while the DTI results suggested an early involvement of both the cerebellum and the supratentorial grey matter (GM) in young ASD children, with fractional anisotropy (FA) emerging the most sensitive parameter.GM-FA changes correlated with Autism Diagnostic Observation Schedule-Generic (ADOS-G) and the Autism Diagnostic Interview-Revised (ADI-R). Further investigation in a larger sample is warranted in order to confirm a potential primary role of GM versus WM changes in the complex aetiopathogenesis of ASD.

Schizophrenia has been characterized as a neurodevelopmental disorder, with structural brain abnormalities reported at all stages. However, at present, it remains unclear whether gray and white matter abnormalities represent related or independent pathologies in schizophrenia. In this study, we present findings from an integrative analysis exploring the morphological relationship between gray and white matter in 45 schizophrenia participants and 49 healthy controls. We utilized mutual information (MI), a measure of how much information two variables share, to assess the morphological dependence between gray and white matter in three segments of the corpus callsoum, and the gray matter regions these segments connect: (1) the genu and the left and right rostral middle frontal gyrus (rMFG), (2) the isthmus and the left and right superior temporal gyrus (STG), (3) the splenium and the left and right lateral occipital gyrus (LOG). We report significantly reduced MI between white matter tract dispersion of the right hemispheric callosal connections to the STG and both cortical thickness and area in the right STG in schizophrenia patients, despite a lack of group differences in cortical thickness, surface area, or dispersion. We believe that this reduction in morphological dependence between gray and white matter may reflect a possible decoupling of the developmental processes that shape morphological features of white and gray matter early in life. The present study also demonstrates the importance of studying the relationship between gray and white matter measures, as opposed to restricting analyses to gray and white matter measures independently.

Despite the many neuroimaging studies that suggest gray matter volume reductions in schizophrenia, there is no compelling postmortem evidence to suggest neuronal loss, nor is there a distinctive or specific signature of gray matter abnormalities in schizophrenia. Instead, there appears to be no observed focal lesion that characterizes gray matter pathology in schizophrenia. This state of affairs has led to a movement away from conceptualizing schizophrenia as resulting from a single lesion, to conceptualizing schizophrenia as arising from abnormal communication between brain regions. Abnormal connectivity between brain regions is not a new concept, as Bleuler (1911) postulated such abnormalities. What is new, however, is an appreciation that brain regions that are not spatially proximal may be connected functionally into neural networks and that to understand altered neural connectivity we need to have a better understanding of the connections between brain regions which are made possible by white matter, the main infrastructure in the brain that makes possible long distance communication among neurons. Accordingly, a focus on white matter connections in the brain has become increasingly of interest in schizophrenia, particularly in the areas of imaging studies, postmortem studies, and new animal models of schizophrenia. This special issue focuses on schizophrenia and oligodendrocytes, the latter a class of neuroglia that give rise to myelin. The primary aim of this special issue is to understand and to clarify further white matter pathology in schizophrenia and how it may contribute to disconnectivity among brain regions, which results in the observed cognitive, behavioral, and clinical symptoms in this disorder. The first paper begins with a description of the theory that schizophrenia reflects a disorder of connectivity. The proposition put forth is that schizophrenia is, at least in part, the result of abnormal communication between brain regions that may be spatially distant but nonetheless functionally connected. As white matter is the main infrastructure for brain connectivity, this paper focuses on the use of a magnetic resonance imaging (MRI) technique called diffusion tensor imaging (DTI) to gain insight into the role of white matter abnormalities in schizophrenia. This paper also focuses on the functional implications of white matter abnormalities, particularly with regard to the possible role of myelin in modulating the transmission velocity of neural discharges. The paper ends with a speculative hypothesis about the relationship between gray matter and white matter abnormalities in schizophrenia. The second paper also focuses on altered neuronal connectivity. Here, however, the focus is on altered connectivity and impaired myelination in a postmortem study of schizophrenia and normal controls, where electron microscopy is used to study myelinated fibers and oligodendrocytes. This morphometric study examines myelinated fibers in the prefrontal cortex in both gray and white matter. Six types of abnormal fibers and ultrastructural alterations are described in the schizophrenia sample. The study reveals increased pathological fibers in gray matter in both young and elderly patients that are associated with positive symptoms, while in elderly patients, the frequency of pathological fibers in white matter is increased and these changes are associated with more negative symptoms. The key implication here is that altered myelinated fibers in white matter in schizophrenia likely follow alterations of myelinated fibers in gray matter that occur earlier in the course of illness. The third paper is a postmortem study on age-related changes in the number of oligodendrocytes in prefrontal cortex in schizophrenia, bipolar disorder and major depression. The study reveals an age-related increase in numerical density of oligodendrocytes in layer VI and adjacent white matter of BA9 and 10 that is seen only in normal controls and not in schizophrenia or in mood disorders. The absence of the normal age-related increase in oligodendrocytes in patients suggests that this aspect of normal brain development is dysregulated in schizophrenia and in mood disorders, and confirms postmortem and imaging data, further highlighting the fact that the absence of a normal age-related increase in oligodendrocytes is a key shared feature in these psychiatric populations. The fourth paper reviews white matter abnormalities in schizophrenia, including imaging and postmortem findings on the disconnectivity theory of schizophrenia, a major theme that underlies the three previous papers in this special issue. This paper then reviews some of the white matter diseases that commonly lead to psychotic symptoms and then reviews transgenic and mutant mouse models of schizophrenia. More specifically, genetic mouse models such as Plp1 transgenic mice and mutant mice heterogeneous for either NRG1 or its receptor erbB4, as well as Nogo-A- deficient mice are reviewed. This is followed by a focus on the myelin toxicity model of mice fed cuprizone. In the early stage (the second and third week) of the cuprizone feeding, mice show higher dopamine levels and lower norepinephrine levels in their prefrontal cortex, along with behavioral changes indicative of increased CNS activity. In the late stage (weeks 4–6), when demyelination and oligodendrocyte loss are obvious, mice display cognitive deficits as well as deficits in social interactions that are reminiscent of social withdrawal seen in patients with schizophrenia. Importantly, this cuprizone-feeding mouse may be used as an in vivo platform for psychopharmacological studies testing the effects of antipsychotic drugs on white matter alterations and associated behavioral changes, in addition to providing a new animal model of schizophrenia. The fifth and final paper of this special issue focuses on abnormal behavior and microstructural changes in juvenile mice that are repeatedly exposed to nonneurotoxic levels of amphetamine. These mice are compared with nonamphetamine treated mice. Oligodendrocyte numbers and three proteins expressed in mature oligodendrocytes are investigated in these young male mice at sacrifice. Treated mice showed higher locomotion and impaired spatial working memory, along with lowered Noga-A and GST-pi proteins, and lower MBP proteins, in frontal cortex and hippocampus and fewer mature oligodendrocytes in frontal cortex and corpus callosum, as well as lower MBP staining in frontal cortex, corpus callosum, and hippocampus, than untreated mice. These differences suggest that in wild-type mice late developing white matter is vulnerable to amphetamine and may lead to compromised white matter with increased dopamine in specific brain regions. Not only do these findings explain well the increased locomotion and impaired spatial working memory observed in amphetamine-treated mice, but also may serve as a principle for the amphetamine-treated mouse being used as a novel animal model of schizophrenia. To summarize, compared to the focus on gray matter and neurons, research on white matter and myelin/glial has been sparse in schizophrenia. In this special issue, neuroimaging findings are presented that suggest that myelin abnormalities in schizophrenia may underlie the white matter abnormalities observed using diffusion tensor imaging techniques. Data from postmortem studies also confirm the presence of oligodendrocyte and myelin abnormalities in schizophrenia as well as mood disorders. Oligodendrocytes provide protection and improve communication between brain regions and the oligodendroglia-producing myelin is approaching maturity in the same time frame as the onset of symptoms. Further, normal age-related white matter increases and related gray matter changes that likely predate the white matter changes are dysregulated in schizophrenia and may contribute to the clinical symptomatology of the disease. Finally, the recently developed animal models are not only of help in understanding connectivity abnormalities in schizophrenia but also provide novel platforms to test novel therapeutic approaches for schizophrenic patients. Treatments specifically targeting white matter, for example, may improve on the efficacy of those treatments currently in use. Martha E. Shenton Haiyun Xu Vahram Haroutunian George Bartzokis

There is increasing evidence that blood oxygenation level-dependent signaling in white matter (WM) reflects WM functional activity. Whether this activity is altered in schizophrenia remains uncertain, as does whether it is related to established alterations of gray matter (GM) or the microstructure of WM tracts. A total of 153 antipsychotic-naïve schizophrenia patients and 153 healthy comparison subjects were assessed by resting-state functional magnetic resonance imaging, diffusion tensor imaging, and high-resolution T1-weighted imaging. We tested for case-control differences in the functional activity of WM, and examined their relation to the functional activity of GM and WM microstructure. The relations between fractional anisotropy (FA) in WM and GM-WM functional synchrony were investigated as well. Then, we examined the associations of identified abnormalities to age, duration of untreated psychosis (DUP), and symptom severity. Schizophrenia patients displayed reductions of the amplitude of low-frequency fluctuations (ALFF), GM-WM functional synchrony, and FA in widespread regions. Specifically, the genu of corpus callosum not only had weakening in the synchrony of functional activity but also had reduced ALFF and FA. Positive associations were found between FA and functional synchrony in the genu of corpus callosum as well. No significant association was found between identified abnormalities and DUP, and symptom severity. The widespread weakening in the synchrony of functional activity of GM and WM provided novel evidence for functional alterations in schizophrenia. Regarding the WM function as a component of brain systems and investigating its alternation represent a promising direction for future research.

This thesis aimed to investigate the feasibility of two diffusion imaging techniques, Diffusion Tensor Imaging (DTI) and Diffusion Kurtosis Imaging (DKI), on detecting subtle physiological or pathological microstructural changes in normal-appearing neural tissues of human central nervous system. 
\n At first, ten patients with neuromyelitis optica (NMO) and twelve age- and gender-matched healthy subjects were recruited. DTI-derived indices including fractional anisotropy (FA), mean diffusivity (MD), axial and radial diffusivities were quantified in the lateral and dorsal columns of cervical spinal cord. Based on the regions of interest (ROIs) measurement, NMO patients showed reduced FA, increased MD and radial diffusivity compared to control subjects, while axial diffusivity did not show any significant difference. The three former DTI metrics also showed significant correlations with disability scores, and especially FA was found to be sensitive to mild NMO. Our results show that DTI-derived indices can quantitatively assess the white matter (WM) abnormalities with seemingly normal appearance in conventional MRI, and are associated with the level of clinical disability, suggesting that DTI may have great potential as a useful diagnostic tool in the clinical setting.
\n DKI is an extension of conventional DTI to probe the non-Gaussian diffusion property in biological tissues. Besides the four conventional DTI-derived metrics, DKI also provide three additional kurtosis metrics (mean kurtosis (MK), axial and radial kurtosis). In the second study, ROI-based analysis was used to characterize age-related microstructural changes in WM, cortical and subcortical gray matter (GM) of 27 healthy adults (21~59 yrs). Though the volumes of GM and WM were still preserved, DTI-derived metrics can detect the subtle changes in WM and GM. Meanwhile, MK and radial kurtosis significantly increased in both caudate nucleus and putamen while Thalamus showed little aging effect in the diffusivity and kurtosis metrics but significantly decreased only in FA. Our results demonstrated that DKI is sensitive to detect the age-related alterations in neural microstructures at the stage of early aging.
\n In addition, DKI has been applied to detect the pathological changes in the normal-appearing neural tissues of 18 patients with multiple sclerosis (MS), compared to 22 healthy controls. Diffuse WM abnormalities have been observed extensively in the brain, revealed by DKI-derived metrics. Though the volumetric and voxel-wise analysis revealed no significant changes in the volume of cortical GM, decreased FA and kurtoses with increased diffusivities in MS group were sensitive to disclose the subtle alterations in global and regional cortical GM tissues. Significant correlations have been found between FA in the global, frontal and temporal cortical GM in relapsing-remitting MS patients and their disability scores, suggesting FA as an important biomarker to monitor the disease progress in cortical GM. Moreover, elevated kurtosis indices in MS patients did not correlate with diffusivities in caudate nucleus, putamen and thalamus, suggesting these metrics may be vulnerable to different pathologic aspects of the disease.
\n In conclusion, DKI is sensitive to neural alterations during normal aging and in MS pathologies, and can provide complementary information to conventional MRI and DTI.

BackgroundSeveral studies have shown that patients with schizophrenia have low musical ability that correlates with poor cognitive functions and severe negative symptoms. Recently, using surface-based analysis, we reported that thinner cortical thickness in the left temporal, parietal, and inferior frontal regions is associated with lower musical ability in schizophrenia. Interestingly, thicker cortical thickness in the left supramarginal region correlates with lower musical ability in controls. Musical deficits such as congenital amusia was shown to contribute to white and grey matter pathophysiology in schizophrenia. We, therefore, sought to investigate diffusion tensor images (DTI) of patients with schizophrenia using an automated probabilistic tractography algorithm.MethodsTwenty-two right-handed patients with schizophrenia (12 males and 10 females, mean age = 45.9 years) and 20 right-handed healthy control subjects (13 males and 7 females, mean age = 42.8 years) consented to participate in this study. We measured musical ability, cognitive functions, and clinical assessments using the Montreal Battery for Evaluation of Amusia (MBEA), Brief Assessment of Cognition in Schizophrenia (BACS), and Positive and Negative Syndrome Scale (PANSS), respectively. We employed automatic probabilistic tractography DTI analysis using TRActs Constrained by UnderLying Anatomy (TRACULA) available in the Freesurfer software for the reconstruction of major tract bundles.ResultsWhole-tract diffusion characteristics in patients with schizophrenia and controls were significantly different. Fractional anisotropy (FA) was lower for patients with schizophrenia compared to controls in the left superior longitudinal fasciculus - parietal endings (slfp) (p < 0.001), left cingulum - angular bundle (cab) (p < 0.001), and corpus callosum - forceps minor (fminor) (p < 0.001). We found significant correlation between musical abilities and FA alterations in slfp in both controls and patients with schizophrenia. While lower musical ability corresponds to lower FA in slfp of controls (r = -0.572, p = 0.013), it is associated with higher FA in the slfp of patients with schizophrenia (r = 0.515, p = 0.021).DiscussionThis study shows that TRACULA can be used for the detection of decrements in several DTI tracts including the left slfp, left cab, and fminor in patients with schizophrenia. It revealed that while lower musical ability correlates with lower FA values in the left slfp in controls, it is associated with higher FA values in the same region in patients with schizophrenia. This contradictory finding in controls and patients with schizophrenia with regard to white matter pathology may reflect left supramarginal region malfunction resulting in cortical pathology in patients with schizophrenia. The data suggest that patients with schizophrenia may be more susceptible to changes in cortical thickness in the supramarginal region, and white matter alteration in the left slfp. Further study is needed to confirm the results. The characteristics of grey and white matter in the left parietal region which are relevant to musical ability may provide insight into pathological progression in patients with schizophrenia.

Structural MRI findings of abnormalities in the prefrontal cortex in schizophrenia and affective disorder have been inconsistent likely due to small, heterogeneous samples, the evaluation of prefrontal gray and white matter combined, and the fact that prefrontal cortex is typically not delineated into separate gyri (e.g., Shenton et al., 2001; Strakowski et al., 2002). We previously reported smaller prefrontal gray matter in first-episode schizophrenia relative to first-episode affective psychosis and controls (Hirayasu et al., 2001). One unresolved question in the literature is whether or not further volume reduction will be observed over time, the focus of this report. Prefrontal gray and white matter volumes were measured (see Fig. 1) in patients at the time of first hospitalization for schizophrenia (n=12, 3 females) or affective psychosis (n=10, 1 female, 9 bipolar, 1 unipolar), and psychiatrically well subjects (n=15, 1 female). Subjects were rescanned approximately 1.5 years later. Seven schizophrenia, six affective, and four comparison subjects were previously described solely at first scan (Hirayasu et al., 2001). Samples did not differ in age (28.1±8.4; 22.9±2.8; 25.4±4.5; F(2,34)=2.2, p=0.12) or WAIS Information scores (11.8±3.4; 12.2±3.1, 11.8±2.0; F(2.32)=0.6, p=0.9), nor in parental socioeconomic status (F(2.34)=2.32, p=0.11) or handedness (F(2.33)=1.6, p=0.22). BPRS scores were higher in schizophrenics (41.2±13.2) than affectives (33.8±8.0) (F(1,20)=5.71, p=0.027). Similar neuroleptics were prescribed for the patient groups (schizophrenics: 7 typical, 4 atypical, 1 none; affectives: 6 typical, 3 atypical, 1 none). Fig. 1 Prefrontal ROI definitions and volumes. (a) Coronal slice, (b) axial slice showing prefrontal gray and white matter, and (c) three. Three-dimensional reconstruction of the extent of gray and white matter boundaries. MR images were acquired with a 1.5-T ... Relative volumes [i.e., absolute volumes divided by intracranial contents (ICC)] were used in the analyses. Repeated-measures ANOVA was performed with diagnosis as the between-subjects factor and time and side as the within-subjects factors for gray and white matter separately. Prefrontal gray matter at time 1 was significantly different among groups (F2,30=5.56, p=0.009), with schizophrenics smaller than controls and affectives, who did not differ from each other. There was no interaction for group by time by side for prefrontal gray matter (F2,34=0.65, p=0.53). All groups showed larger gray matter on the left (F2,30=8.72, p=0.006). White matter volumes did not differ among groups (p>0.87), and all groups showed more white matter on the right (F1,30=39.20, p<0.001) and a reduction over time (F1,30=10.902, p=0.002), there was a trend for this effect to be larger on the right (F1,30=3.14, p=0.086) (%change over time for right white matter: schizophrenics 2.8%; affectives 6.5%; controls 2.1%). Neither removing the unipolar depression subject nor removing the females altered the results. There was no significant correlation between ROI volume change and medication dosage at time 1 for either patient group (Time 2 data came from out patients based on self-report and was for this reason not used). These data suggest that prefrontal cortical gray matter is selectively smaller at first hospitalization for schizophrenia relative to affective psychosis and controls, but this volume difference did not change over the relatively short post-first hospitalization time examined. Small gray matter volumes may be due to reduced dendritic arborization or increased neural density in prefrontal cortex in schizophrenia (Benes et al., 1992; Selemon et al., 1998). White matter, which was not different among groups, showed a decline with time in all groups, possibly consistent with normal aging (Good et al., 2001, although Bartzokis et al., 2001). Potential reasons for our not observing selective gray matter reductions point to several limitations of this study including the gender distribution, as females may have greater dorsolateral and orbitofrontal lobe involvement and males greater dorsomedial changes in schizophrenia (Gur et al., 2000); the use of large ROI, as sub-regions within the prefrontal cortex may change in volume at different rates (Gur et al., 1998; DeLisi et al., 1997); and lack of exact medication dosages and compliance histories during the intrascan interval cannot be ruled out as possible confounds. Although the sample size was small, the effect size was also small (Fig. 1) suggesting that even enlarging the sample would not result in a significant change in volume over time for either gray or white matter.

Purpose: The purpose of this study was to measure the apparent diffusion coefficient (ADC) and fractional anisotropy (FA) of normal adult brain tissue and tumors, and to compare the differences. Materials and Methods: Eight normal adults and ten patients in whom intracranial tumors had been diagnosed were included. Imaging was performed using a 1.5 T MR unit and a single-shot spin-echo EPI pulse sequence (TR/TE=4024/94 msec, 128 acquisition/256 reconstruction, 23 cm FOV, 5 mm thickness, 2 mm interslice gap, 4 NSA), six different direction gradients (x, y, z, xy, yz, xz), and 2 b-values (0, 1000). Isotropic ADC (D) was obtained from seven images per slice, and fractional anisotropy (FA) was calculated from the isotropic ADC and eigenvalues of three directions. A region of interest was drawn at frontal gray and white matter, periventricular white matter, the corpus callosum, internal capsule, caudate nucleus and center of the tumor mass, and for each region, fractional anisotropy readings were obtained. Results: In normal adults, the findings were as follows: frontal gray matter: D=0.810.06, FA=0.320.03; frontal white matter: D=0.790.04, FA=0.560.09, periventricular white matter: D=0.770.02, FA=0.51 0.04; corpus callosum: D=0.790.07, FA=0.820.07; internal capsule: D=0.730.04, FA=0.770.05; caudate nucleus: D=0.760.05, FA=0.350.05. High anisotropy was demonstrated in white matter, especially in the corpus callosum and internal capsule, and the degree of anisotropy was similar in gray and deep gray matter. For most brain tumors, isotropic ADC was similar to that of white matter, but fractional anisotropy was lower. A low-grade astrocytoma showed higher isotropic ADC and lower fractional anisotropy than normal white matter, and at the center of a meningioma, fractional anisotropy was high. Conclusion: For the classification of brain tumors and determination of the extent of disease, comparison between the apparent diffusion coefficient and fractional anisotropy is useful.

Impact of hemodynamic effects on diffusion-weighted fMRI signals

Background:Previous Diffusion Tensor Imaging (DTI) studies have demonstrated the temporal evolution of stroke injury in grey matter and white matter can be characterized by DTI indices. However, it still remains not fully understood how the DTI indices of white matter are altered progressively during the hyperacute (first 6 hours) and acute stage of stroke (≤ 1 week). In the present study, DTI was employed to characterize the temporal evolution of infarction and white matter injury after stroke insult using a macaque model with permanent ischemic occlusion.Methods and materials:Permanent middle cerebral artery (MCA) occlusion was induced in rhesus monkeys (n=4, 10-21 years old). The brain lesion was examined longitudinally with DTI during the hyperacute phase (2-6 hours, n=4), 48 hours (n=4) and 96 hours (n=3) post-occlusion.Results:Cortical infarction was seen in all animals. The Mean Diffusivity (MD) in lesion regions decreased substantially at the first time point (2 hours post stroke) (35%, p <0.05, compared to the contralateral side) and became pseudo-normalized at 96 hours. In contrast, evident FA reduction was seen at 48 hours (39%, p <0.10) post-stroke. MD reduction in white matter bundles of the lesion area was much less than that in the grey matter during the hyper-acute phase but significant change was observed 4 hours (4.2%, p < 0.05) post stroke . Also, MD pseudonormalisation was seen at 96 hours post stroke. There was a significant correlation between the temporal changes of MD in white matter bundles and those in whole lesion areas during the entire study period. Meanwhile, no obvious fractional anisotropy (FA) changes were seen during the hyper-acute phase in either the entire infarct region or white matter bundles. Significant FA alteration was observed in entire lesion areas and injured white matter bundles 48 and 96 hours post stroke. The stroke lesion in grey matter and white matter was validated by pathological findings.Conclusion:The temporal evolution of ischemic injury to the grey matter and white matter from 2 to 96 hours after stroke onset was characterized using a macaque model and DTI. Progressive MD changes in white matter bundles are seen from hyperacute phase to acute phase after permanent MCA occlusion and temporally correlated with the MD changes in entire infarction regions. MD reduction in white matter bundles is mild in comparison with that in the grey matter but significant and progressive, indicating it may be useful to detect early white matter degeneration after stroke.

Differentiation of absolute metabolite concentrations between gray and white matter in the occipital region of normal human brain was performed by in vivo localized single-voxel 1H magnetic resonance spectroscopy at 1.5 Tesla with long echo time (136 ms). With the combination of image segmentation between white and gray matter and cerebrospinal fluid, signal compensation of T1 and T2 effects, tissue water signal as the internal concentration reference, as well as compensation by different water contents in gray and white matters, it was determined that the levels of N-acetylaspartate (NAA), creatine and/or phosphocreatine (Cr), and choline-containing compounds (Cho) in gray matter were significantly higher than in white matter. The averaged NAA, Cr, and Cho concentrations in gray matter were 11.0, 9.7, and 1.9 mM/liter, respectively, in comparison with 7.5, 5.2, and 1.6 mM/liter in white matter. These results suggest that precise composition of white and gray matter and cerebrospinal fluid is necessary to avoid partial voluming effect in a single voxel and to accurately quantify the metabolite concentrations.

Patients with spina bifida (SB) have variable intellectual outcomes. The authors used diffusion tensor (DT) imaging to quantify whole-brain volumes of gray matter, white matter, and cerebrospinal fluid (CSF), and perform regional quantitative microstructural assessments of gray matter nuclei and white matter tracts in relation to intellectual outcomes in patients with SB. Twenty-nine children with myelomeningoceles and 20 age- and sex-matched children with normal neural tube development underwent MR imaging with DT image acquisition and assessments of intelligence. The DT imaging-derived metrics were the fractional anisotropy (FA), axial (parallel), and transverse (perpendicular) diffusivities. These metrics were also used to segment the brain into white matter, gray matter, and CSF. A region-of-interest analysis was conducted of the white and gray matter structures implicated in hydrocephalus. The amount of whole-brain gray matter was decreased in patients with SB, with a corresponding increase in CSF (p < 0.0001). Regional transverse diffusivity in the caudate nucleus was decreased (p < 0.0001), and the corresponding FA was increased (p < 0.0001), suggesting reduced dendritic branching and connectivity. Fractional anisotropy in the posterior limb of the internal capsule increased in the myelomeningocele group (p = 0.02), suggesting elimination of some divergent fascicles; in contrast, the FA in several white matter structures (such as the corpus callosum genu [p < 0.001] and arcuate fasciculus) was reduced, suggesting disruption of myelination. Diffusion tensor imaging-metrics involving gray matter volume and the caudate nucleus, but not other structures, predicted variations in IQ (r = 0.37-0.50; p < 0.05). Diffusion tensor imaging-derived metrics provide noninvasive neuronal surrogate markers of the pathogenesis of SB and predict variations in general intellectual outcomes in children with this condition.

To investigate the features of white matter myelin development in preterm infants using magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI). A total of 31 preterm infants with a gestational age of ≤32 weeks and a birth weight of <1 500 g were enrolled. According to head MRI findings, these infants were divided into preterm group with brain injury (12 infants) and preterm group without brain injury (19 infants). A total of 24 full-term infants were enrolled as control group. Head MRI and DTI were performed at a gestational age or corrected gestational age of 37-40 weeks. Fractional anisotropy (FA) and apparent diffusion coefficient (ADC) were measured for the same regions of interest in the three groups. The preterm group with brain injury showed a significantly lower FA value of the posterior limb of the internal capsule than the preterm group without brain injury and full-term control group (P<0.05). The preterm groups with and without brain injury showed significantly lower FA values of frontal white matter and lenticular nucleus than the full-term control group (P<0.05). The FA value of occipital white matter showed no significant differences among the three groups (P>0.05). Compared with the full-term control group, the preterm groups with and without brain injury showed significantly higher ADC values of the posterior limb of the internal capsule, lenticular nucleus, occipital white matter, and frontal white matter (P<0.05). After brain injury, preterm infants tend to develop disorder or delay of white matter myelination in the posterior limb of the internal capsule. At a corrected full-term gestational age, the preterm infants with and without brain injury have a lower grade of maturity in periventricular white matter and grey matter than full-term infants.

Apolipoprotein E (apoE) and cholesterol play a critical role in synapse and myelin maintenance and integrity and are thus appealing candidates in the pathogenesis of schizophrenia and bipolar disorder. To explore the role of these 2 molecules, we quantified cholesterol and apoE levels in prefrontal grey and white matter in patients with schizophrenia, bipolar disorder and healthy controls. Furthermore, we investigated the relations between apoE and cholesterol levels and the APOE genotype. We obtained dorsolateral prefrontal grey and white matter from the Stanley Medical Research Institute Brain Collection (schizophrenia n = 35, bipolar disorder n = 35 and controls n = 35). Cholesterol levels were quantified using high-pressure liquid chromatography, whereas apoE was measured by enzyme-linked immunosorbent assay. We found no significant differences in cholesterol or apoE levels among the groups. ApoE levels were higher in grey matter than in white matter in all groups; conversely, levels of cholesterol were higher in white matter than in grey matter. We observed a significant inverse correlation between apoE and cholesterol levels in both grey and white matter. Furthermore, in grey matter, apoE levels were significantly higher in APOE ε2 carriers compared with APOE ε3 or APOE ε4 carriers, with cholesterol levels following the opposite trend. LIMITATIONS of our study include our inability to control for potential confounding variables and the small numbers of APOE ε2 and ε4 carriers in each group. Although large amounts of cholesterol are present in white matter, apoE expression is limited. The APOE genotype may play a role in the regulation of both cholesterol and apoE levels in grey matter. The impact of APOE polymorphisms on lipid homeostasis in people with psychiatric disorders warrants further investigation.

For patients with focal epilepsy scheduled for surgery, including MRI-negative cases, (18)FDG-PET was shown to disclose hypometabolism in the seizure onset zone. However, it is not clear whether grey matter hypometabolism is informative of the integrity of the surrounding white matter cerebral tissue. In order to study the relationship between metabolism of the seizure onset zone grey matter and the integrity of the surrounding white matter measured by diffusion tensor imaging (DTI), we performed a monocentric prospective study (from 2006 to 2009) in 15 children with pharmacoresistant focal epilepsy, suitable for interictal (18)FDG-PET, T1-, T2-, FLAIR sequence MRI and DTI. Children had either positive or negative MRI (eight with symptomatic and seven with cryptogenic epilepsies, respectively). Seven children subsequently underwent surgery. Standardised uptake values of grey matter PET metabolism were compared with DTI indices (fractional anisotropy [FA], apparent diffusion coefficient [ADC], parallel diffusion coefficient [PDC], and transverse diffusion coefficient [TDC]) in grey matter within the seizure onset zone and adjacent white matter, using regions of interest automatically drawn from individual sulcal and gyral parcellation. Hypometabolism correlated positively with white matter ADC, PDC, and TDC, and negatively with white matter FA. In the cryptogenic group of children, hypometabolism correlated positively with white matter ADC. Our results demonstrate a relationship between abnormalities of grey matter metabolism in the seizure onset zone and adjacent white matter structural alterations in childhood focal epilepsies, even in cryptogenic epilepsy. This relationship supports the hypothesis that microstructural alterations of the white matter are related to epileptic networks and has potential implications for the evaluation of children with MRI-negative epilepsy.