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White matter structure in autism: preliminary evidence from diffusion tensor imaging.

BACKGROUND: Individuals with autism have severe difficulties in social communication and relationships. Prior studies have suggested that abnormal connections between brain regions important for social cognition may contribute to the social deficits seen in autism. METHODS: In this study, we used diffusion tensor imaging to investigate white matter structure in seven male children and adolescents with autism and nine age-, gender-, and IQ-matched control subjects. RESULTS: Reduced fractional anisotropy (FA) values were observed in white matter adjacent to the ventromedial prefrontal cortices and in the anterior cingulate gyri as well as in the temporoparietal junctions. Additional clusters of reduced FA values were seen adjacent to the superior temporal sulcus bilaterally, in the temporal lobes approaching the amygdala bilaterally, in occipitotemporal tracts, and in the corpus callosum. CONCLUSIONS: Disruption of white matter tracts between regions implicated in social functioning may contribute to impaired social cognition in autism.

Adolescent↗

Distribution of microtubule-associated protein MAP2-immunoreactive interstitial neurons in the parahippocampal white matter in subjects with schizophrenia.

OBJECTIVE: Evidence suggests that schizophrenia is a neurodevelopmental disorder that may involve abnormal connectivity between various cortical and subcortical brain areas. The parahippocampal gyrus is an area important for higher cognition in which a variety of cytoarchitectural, neuronal morphometric, and innervation abnormalities in schizophrenia have been reported. Previous studies have reported abnormal distributions of interstitial white matter neurons in prefrontal, parietal, and temporal neocortices, which suggests that schizophrenia may be related to prenatal disturbances in the cortical subplate, a transitory structure involved in the formation of connections in the developing cortex from which the interstitial white matter neurons derive. Abnormalities in the distribution of interstitial white matter neurons in the parahippocampal gyrus in schizophrenia may indicate an alteration in the migration of subplate neurons or in the pattern of programmed cell death that could lead to defective cortical circuitry and impaired cognition. METHOD: The authors used a monoclonal antibody against the microtubule-associated protein MAP2 to label interstitial white matter neurons in the anterior region of the parahippocampal gyrus from 41 individuals with schizophrenia and 15 comparison subjects. The distribution of MAP2-labeled neurons in relation to the gray matter/white matter boundary was determined by computer-assisted microscopy. RESULTS: The number of interstitial white matter neurons decreased with increasing white matter depth in both groups, but significantly more slowly in the schizophrenia group, with interstitial white matter neurons located deeper in white matter in schizophrenia subjects. CONCLUSIONS: These findings indicate there is an abnormality in the residua of the cortical subplate in the anterior region of the adult parahippocampal gyrus in schizophrenia subjects.

Adult↗

A diffusion tensor magnetic resonance imaging study of frontal cortex connections in very-late-onset schizophrenia-like psychosis.

OBJECTIVE: Onset of psychosis after the age of 60 may be associated with structural abnormalities within cerebral white matter. The authors looked within white-matter tracts, which mediate connectivity of the frontal lobes, in psychotic patients for evidence of loss of fiber integrity consistent with degenerative damage. METHODS: Fourteen patients with very-late-onset schizophrenia-like psychosis and an age-matched control group underwent diffusion tensor magnetic resonance imaging. Tract maps were constructed for each subject from the imaging data, and measurements of fractional anisotropy and mean diffusivity were made within the uncinate, superior longitudinal, and inferior occipito-frontal fasciculi, and the cingulum. RESULTS: There were no significant differences in fractional anisotropy, a measure of the ordering of axons within fiber tracts, nor in mean diffusivity, an orientationally-averaged measure of the bulk diffusivity within each voxel, between patients and control subjects. CONCLUSION: The lack of difference in fractional anisotropy and mean diffusivity measures between patients and controls argues against the presence of structural abnormalities within these tracts and the notion that a focal white-matter abnormality within the tracts investigated underpins the onset of psychosis.

Age of Onset↗

Functional and diffusion-weighted magnetic resonance imaging for visualization of the postthalamic visual fiber tracts and the visual cortex.

Diffusion-weighted magnetic resonance imaging (MRI) offers the possibility to study the course of the cerebral white matter tracts whereas functional MRI (fMRI) provides information about the specific functions of cortical areas. We evaluated the combination of fMRI and diffusion-weighted MRI to detect cortical visual areas with their corresponding visual fiber tracts in 15 healthy controls (age: 23 - 53 years, male : female = 8 : 7). We demonstrated activation within the primary visual cortex and white matter bundles connecting the lateral geniculate body and the striate cortex in all subjects investigated. Additional activation could be appreciated in some subjects within the lateral geniculate bodies (n = 2) and the motion-sensitive area V5 (n = 3). The combination of diffusion-weighted and functional imaging allows visualization of the origin, direction and functionality of large white matter tracts. This will prove helpful for imaging structural connectivity within the brain during functional imaging. Moreover, this technique might provide important information for neurosurgical patients presenting with space-occupying lesions close to the cortical and subcortical visual system since this technique can -- in contrast to diffusion tensor imaging -- easily be adopted into a neuronavigation system and can be performed on all MR scanners capable of diffusion-weighted imaging without specific post-processing programs.

Adult↗

Selective age-related degradation of anterior callosal fiber bundles quantified in vivo with fiber tracking.

The corpus callosum, the principal white matter structure enabling interhemispheric information transfer, is heterogeneous in its microstructural composition, heterotopic in its anteroposterior cortical connectivity, and differentially susceptible to aging. In vivo characterization of callosal features is possible with diffusion tensor imaging (DTI), a magnetic resonance imaging method sensitive to the detection of white matter's linear structure. We implemented a quantitative fiber tracking approach to examine age-related variation in regional microstructural characteristics [fractional anisotropy (FA) and apparent diffusion coefficient (ADC)] of callosal fibers in 10 younger (29 +/- 5 years) and 10 older (72 +/- 5 years) healthy adults. Fiber tracking was performed on 2.5 mm isotropic voxels collected at 3 T. Fiber targets comprised the midsagittal corpus callosum, divided into six regions based on known callosal anatomical projections. FA and ADC for each voxel of each fiber identified were determined; lower FA and higher ADC reflect degraded microstructural tissue integrity. Older subjects had lower FA (P < 0.002), higher ADC (P < 0.006), and fewer (P < 0.005) fibers than younger subjects. Group x region interactions indicated disproportionately lower FA (P = 0.0001) and higher ADC (P < 0.006) in the older than younger group in frontal fiber bundles relative to posterior bundles. As a test of the functional significance of the fiber bundle metrics, the older subjects were administered the Stroop Task, which showed significant correlations between regional fiber bundle integrity and performance. These results validate this quantitative fiber tracking approach and confirm the selective vulnerability of frontal white matter systems to normal aging, likely substrates of age-related declines in cognitive processes dependent on prefrontal circuitry integrity.

Adult↗

Association, commissural, and projection pathways and their functional deficit reported in literature.

This study demonstrates normal white matter structures of the supratentorial system revealed by diffusion tensor imaging. Their anatomic connections and functional significance are discussed in the context of the lesion-induced deficits reported in the literature, which may not fully represent the lesion-induced effects on the white matter function and may not be entirely specific to the tract discussed. Nevertheless, understanding the most common effects of lesions on the functional connectivity provides a framework that we can use in advanced neuroimaging studies, like diffusion tensor imaging, functional magnetic resonance imaging, and positron emission tomography, and in our daily clinical practice.

Brain↗

Diffusion tensor imaging (DTI) and proton magnetic resonance spectroscopy (1H MRS) in schizophrenic subjects and normal controls.

Several proton magnetic resonance spectroscopy (1H MRS) studies in schizophrenia have found reduced N-acetyl aspartate (NAA) concentrations in pre-frontal and temporal regions of the brain. Reductions in NAA may reflect abnormalities of neuronal structure (e.g. reduced neuronal density or viability) or abnormalities of neuronal function. Diffusion tensor imaging (DTI) measures diffusion anisotropy, an indicator of the structural integrity of a neuronal tract. Both techniques were used to examine the anatomical basis of pre-frontal dysfunction in schizophrenia. Ten patients with DSM-IV schizophrenia were compared with 10 healthy controls. 1H MRS and DTI were performed on a clinical MR system and analysed with a region of interest approach. NAA concentrations and diffusion anisotropy were measured in the same pre-frontal white matter region. Diffusion anisotropy was also measured in a control region (occipital white matter). 1H MRS revealed non-significant but consistently reduced NAA concentrations (by 10-15%) in the pre-frontal white matter in schizophrenic subjects. Diffusion anisotropy measures revealed no such differences between schizophrenics and controls. It is concluded that the abnormalities of 'connectivity' reported in brain-imaging studies of schizophrenia may not be attributable to structural abnormalities of white matter and that reduced NAA in the pre-frontal white matter may reflect abnormal function of structurally intact neurons.

Adult↗

Sex-dependent effects of schizophrenia: an MRI study of gyral folding, and cortical and white matter volume.

Alterations, sometimes sex-dependent, in volumes and gyral structure of areas of cerebral cortex have been reported in schizophrenia. Such changes imply an anomaly of connectivity. The gyrification, percentage of tissue volume attributed to white matter, cortical volume and white matter volume were measured from magnetic resonance images in males and females with (n = 61) and without (n = 42) schizophrenia. The frontal, temporal and an amalgam of occipital and parietal lobes were examined in both hemispheres. There was no effect of schizophrenia on the gyrification of the brain. For the volume of occipito-parietal white matter, females with schizophrenia had bilaterally lower volumes, while males with schizophrenia had greater volumes than controls. It is concluded that the changes in connectivity underlying the pathogenesis of schizophrenia are sex-specific and expressed in occipito-parietal white matter.

Adult↗

Functional and diffusion-weighted magnetic resonance images of space-occupying lesions affecting the motor system: imaging the motor cortex and pyramidal tracts.

OBJECT: During neurosurgical interventions, preservation of subcortical axons is as important as preservation of cortical neurons. The goal of this study was to assess the combined use of functional (f) and diffusion-weighted (DW) magnetic resonance (MR) imaging to assist in the preservation of the structure and function of the motor system. METHODS: The authors evaluated the combination of fMR imaging and DW MR imaging to detect cortical motor areas with their corresponding pyramidal tracts in 12 healthy volunteers and in 10 consecutive patients with various space-occupying lesions affecting the central motor system. Activation within the primary motor cortex (M1) and white matter bundles originating from this cortical region was demonstrated in 21 of the 22 individuals examined. Additional activation was exhibited along the course of white matter tracts at the level of the pons and. in the contralateral hemisphere, in the M1. Fiber tract displacement was visualized in all patients in white matter that had appeared normal on routine T1- and T2-weighted MR images. CONCLUSIONS: The combination of DW MR and fMR imaging allows visualization of the origin, direction, and functionality of large white matter tracts. This will prove helpful for imaging structural connectivity within the brain during functional imaging. Moreover, local relationships of cerebral tumors that encroach upon M1 and subcortical fiber tracts can be defined. This promises to decrease patient morbidity and to broaden the clinical applications of functional imaging.

Adult↗

MRI-Based topographic parcellation of human cerebral white matter and nuclei II. Rationale and applications with systematics of cerebral connectivity.

We describe a system for parcellation of the human cerebral white matter and nuclei, based upon magnetic resonance images. An algorithm for subdivision of the cerebral central white matter according to topographic criteria is developed in the companion manuscript. In the present paper we provide a rationale for this system of parcellation of the central white matter and we extend the system of cerebral parcellation to include principal subcortical gray structures such as the thalamus and the basal ganglia. The volumetric measures of the subcortical gray and white matter parcellation units in 20 young adult brains are computed and reported here as well. In addition, with the comprehensive system for cerebral gray and white matter structure parcellation as reference, we formulate a systematics of forebrain connectivity. The degree to which functionally specific brain areas correspond to topographically specific areas is an open empirical issue. The resolution of this issue requires the development of topographically specific anatomic analyses, such as presented in the current system, and the application of such systems to a comprehensive set of functional-anatomic correlation studies in order to establish the degree of structural-functional correspondence. This system is expected to be applied in both cognitive and clinical neuroscience as an MRI-based topographic systematics of human forebrain anatomy with normative volumetric reference and also as a system of reference for the anatomic organization of specific neural systems as disrupted by focal lesions in lesion-deficit correlations.

Adult↗

Imaging brain connectivity in children with diverse reading ability.

Reading is a complex cognitive skill that requires the coordination of multiple brain regions. Although functional neuroimaging studies highlight the cortical brain regions associated with a specific cognitive task like reading, they do not directly address the underlying neural connections necessary for efficient performance of this task. Adults with reading disability have demonstrated lower regional white matter connectivity, but it is not known whether this relationship between neuronal wiring and reading performance also holds in younger readers. Using diffusion tensor magnetic resonance imaging (DTI) that highlights the structural integrity of the brain wiring, we show that regional brain connectivity in the left temporo-parietal white matter correlates with a wide range of reading ability in children as young as 8-12 years old. Diffusion tensor tractography suggests that the posterior limb of the internal capsule is consistent with the location of the largest cluster of correlation between reading ability (Word Identification subtest) and fractional anisotropy. The maturation of the white matter may play a key role in the development of cognitive processes such as reading.

Anisotropy↗

Total length of nerve fibers in prefrontal and global white matter of chronic schizophrenics.

It has been suggested that the dysfunction of the prefrontal cortex in schizophrenics is due to dysfunctional connections between the prefrontal cortex and more posterior structures. The present study uses a recent stereological method that allows quantitation of the myelinated nerve fibers in the brain white matter. As especially the prefrontal region is of interest in schizophrenics, the prefrontal white matter was quantitated separately. The total length of nerve fibers in post-mortem brains was estimated from eight male chronic schizophrenics and nine male controls (age-range: 40-81 years). Samples were taken systematically and randomly from both the entire white matter and selectively from the prefrontal white matter. The biopsies were rotated randomly before sectioning to avoid bias due to the anisotropic nature of nerve fibers. The fibers were counted at light microscopic level at about 10,000 x magnification and the fiber diameter of each counted fiber was measured to get the size distribution of the fibers. The schizophrenics had a total of 129,000 km myelinated fibers in the white matter and 25,700 km in the prefrontal white matter, which was non-significantly different from a total of 137,000 km in the entire white matter and 27,600 km in the prefrontal white matter in controls. The size distribution of the fibers in schizophrenics was within normal limits compared to controls. Our results do not show a larger loss of nerve fibers in neither the white matter globally or in the prefrontal white matter of schizophrenics.

Adult↗

Contrast-enhanced, high-resolution, susceptibility-weighted magnetic resonance imaging of the brain: dose-dependent optimization at 3 tesla and 1.5 tesla in healthy volunteers.

OBJECTIVES: We sought to determine the optimal dose of a contrast agent with known high relaxivity on 1.5 and 3 Tesla scanners that would achieve the best compromise between image quality and scan time for the clinical application of contrast-enhanced susceptibility-weighted imaging (CE-SWI). METHODS: Pre- and postcontrast SWI was performed with different contrast agent doses (0.05, 0.1, and 0.2 mmol/kg gadobenate dimeglumine) at both 1.5 and 3 T in 6 healthy volunteers, resulting in 72 examinations. Venograms were created from minimum intensity projection reconstructions over specified deep white matter volumes to enhance the visual appearance of connected venous structures. Three independent radiologists blindly rated the visibility of the veins on a continuous scale of 1 to 10. A general linear model was used for statistical evaluation, with fixed effects of the contrast agent dose, the field strength, the rater and the patients as a random effect. RESULTS: With CE-SWI, we found significant differences in the visibility of the deep veins dependent on the contrast media dose (P=0.02). At 3 T, the visibility of deep venous vessels, with regard to susceptibility effect, image quality, and scan time reduction after a standard contrast agent dose 0.1 mmol/kg was significantly better than that achieved with 0.05 mmol/kg. The visibility was considered equal with 0.1 mmol/kg of the contrast agent to the precontrast images and a dose of 0.2 mmol/kg. At 1.5 T, no significant difference was found between the 4 contrast agent doses. We found no difference in the visibility of the veins with the shorter sequences at 3 T compared with the sequences at 1.5 T. CONCLUSIONS: Only a standard dose (0.1 mmol/kg) of gadobenate dimeglumine is required to achieve the optimum susceptibility effect and image quality at 3 T, together with a reduced scan time. This result can be attributed to the higher relaxivity of gadobenate dimeglumine, compared with conventional gadolinium chelates.

Adult↗

White matter imaging in holoprosencephaly in children.

PURPOSE OF REVIEW: Holoprosencephaly is a disorder of forebrain development characterized by a failure of the brain to separate into two hemispheres during early development. It is now clear that many cases of holoprosencephaly are caused by alterations in the genetic programmes that pattern the nervous system. Less is known about how a holoprosencephalic brain either forms or fails to form connections between various brain structures. RECENT FINDINGS: Abnormalities in the corpus callosum, corticospinal tract, medial lemniscus and cerebellar peduncles can be seen in holoprosencephaly. Diffusion tensor imaging has been and will continue to be an important tool for imaging white matter in the brain, and will be reviewed here. Furthermore, recent evidence suggests that holoprosencephaly can be associated with delays or abnormalities in myelination. The functional implications of white matter abnormalities in children with holoprosencephaly is only beginning to be understood. SUMMARY: Modern neuroimaging has led to a better appreciation of the variability seen in holoprosencephaly, an anomaly known to have multiple etiologies. Recent reviews of the biology of holoprosencephaly identify the condition as a defect in dorsoventral patterning. More detailed white and grey matter structure-function studies are likely to shed light on how a brain with drastically altered composition and connectivity does or does not organize itself to accomplish increasingly complex developmental functions.

Animals↗

Neurocorrelates of nocturnal enuresis in pre-adolescent children.

INTRODUCTION: Nocturnal enuresis (NE) is a common neurodevelopmental condition, yet its underlying neural mechanisms remain unclear. This study leverages the large-scale Adolescent Brain Cognitive Development (ABCD) dataset to identify structural and functional brain correlates associated with active symptoms and the resolution of bedwetting. METHODS: Using cross-sectional data from 3472 participants aged 9-10 years, children were categorized into three groups: active nocturnal enuresis (ANE, n = 225), history of nocturnal enuresis (HNE, n = 1171), and healthy control groups (CG, n = 2076). Multimodal neuroimaging protocol evaluated macrostructural properties via structural MRI (sMRI), microstructural white matter integrity via diffusion MRI (dMRI), and functional connectivity via resting-state fMRI (fMRI). Group differences were evaluated using linear models within an ANCOVA framework, adjusting for intracranial volume and handedness with False Discovery Rate (FDR) correction. RESULTS: Compared to controls, the ANE group exhibited a significant volume deficit in the right caudate, decreased sulcal depth in the left insula, and lower internal correlation within the Cingulo-Opercular Network (CON). Conversely, the dry HNE group demonstrated significant structural adaptations, including bilaterally larger putamen volumes and increased right caudate volume compared to the ANE group. The HNE group also showed increased microstructural density (decreased mean diffusivity) in the bilateral hippocampus and an increased cortical surface area in the left insula. Both NE groups demonstrated persistently reduced functional coupling within the CON. CONCLUSIONS: Nocturnal enuresis appears to be associated with a potential complex central signaling deficits. Reduced internal correlation within the CON across both active and former bedwetters indicates a potential for impairment in processing internal homeostatic bladder signals during sleep.

Humans↗

Neuronal ectopic masses induced by prenatal irradiation in the rat.

Ectopic neuronal masses below the subcortical white matter were seen in the brains of postnatal rats after 200 cGy irradiation at embryonic day 14. In contrast with the laminated organisation of the cortex located above the subcortical white matter, the ectopic masses were formed of confluent nodules composed of pyramidal and non-pyramidal neurons distributed at random, with no laminar organisation. Afferent and efferent fibres to/from the ectopic masses running together with fibres passing the subcortical white matter indicated that the ectopic masses were heavily connected to neighbouring structures. Examination of irradiated embryos revealed that the ectopic masses originated from ectopic periventricular rosettes, composed of germinal cells, which were formed shortly after irradiation. Neuronogenesis in these rosettes did not follow an inside-out gradient, as seen in the laminated cortex; however, early-generated neurons predominated in the external regions, whereas late-generated neurons were mainly located in the middle and internal regions of the ectopic masses.

Animals↗

Altered distribution of nicotinamide-adenine dinucleotide phosphate-diaphorase cells in frontal lobe of schizophrenics implies disturbances of cortical development.

Epidemiological and anatomical studies support the theory that disturbances of brain development may play a contributory role in the etiology of schizophrenia. Anatomical findings suggest that the normal pattern of neuronal migration during development of the cerebral cortex may be affected in the brains of schizophrenics, with the implication that cortical connectivity and associative function will be disrupted. In the present investigation in matched schizophrenic and control brains, we examined a particular population of neurons found in the prefrontal cortex and underlying white matter and characterized by histochemical staining for the enzyme nicotinamide-adenine dinucleotide phosphate-diaphorase. In normal brains, these neurons are found in highest numbers in the white matter immediately deep to layer VI of the cortex where they remain from the subplate, an early formed, but transitory structure that plays a key role in cortical development and connection formation. The dorsolateral prefrontal area of schizophrenics showed a significant decline in nicotinamide-adenine dinucleotide phosphate-diaphorase neurons in the superficial white matter and in the overlying cortex but a significant increase in these neurons in white matter deeper than 3 mm from the cortex. These findings are consistent with a disturbance of the subplate during development in which the normal pattern of programmed cell death is compromised and accompanied by a defect in the normal orderly migration of neurons toward the cortical plate. These are likely to have serious consequences for the establishment of a normal pattern of cortical connections leading to a potential breakdown of frontal lobe function in schizophrenics.

Adult↗

Genetic liability to schizophrenia or bipolar disorder and its relationship to brain structure.

Bipolar disorder and schizophrenia are highly heritable conditions that are associated with structural brain abnormalities. Although brain abnormalities are found in the well relatives of people with schizophrenia, the extent to which genetic liability relates to brain structure in either disorder is still unclear. This study sought to ascertain the effects of genetic liability to schizophrenia and bipolar disorder on white and grey matter volume in patients with these diagnoses and their well relatives. Seventy-one patients and 72 unaffected relatives were recruited for the study. Patients included those with schizophrenia from families affected by schizophrenia alone, those with bipolar disorder from families affected by bipolar disorder alone and those with bipolar disorder from families affected by both bipolar disorder and schizophrenia. Samples of unaffected relatives of each patient group were also recruited. Subjects underwent an MRI scan of the brain, which was analysed using optimised voxel-based morphometry (VBM). Grey and white matter volume was then related to a continuous measure of genetic liability based on a threshold-liability model. Genetic liability to schizophrenia was associated with decreased grey matter volume in dorso- (DLPFC) and ventrolateral prefrontal (VLPFC) cortices. The relationship remained after diagnostic status had been taken into account. Complementary white matter changes were also demonstrated. No relationship was demonstrated between a genetic liability to bipolar disorder and either white or grey matter volume. Genes that raise the likelihood of developing schizophrenia may exert their effects by diminishing grey matter volume in the DLPFC and VLPFC and their associated white matter connections. Genes for bipolar illness might have subtle effects on brain structure, which may need particularly large samples to detect.

Algorithms↗