Differential developmental trajectories of magnetic susceptibility in human brain gray and white matter over the lifespan

As indicated by several recent studies, magnetic susceptibility of the brain is influenced mainly by myelin in the white matter and by iron deposits in the deep nuclei. Myelination and iron deposition in the brain evolve both spatially and temporally. This evolution reflects an important characteristic of normal brain development and ageing. In this study, we assessed the changes of regional susceptibility in the human brain in vivo by examining the developmental and ageing process from 1 to 83 years of age. The evolution of magnetic susceptibility over this lifespan was found to display differential trajectories between the gray and the white matter. In both cortical and subcortical white matter, an initial decrease followed by a subsequent increase in magnetic susceptibility was observed, which could be fitted by a Poisson curve. In the gray matter, including the cortical gray matter and the iron‐rich deep nuclei, magnetic susceptibility displayed a monotonic increase that can be described by an exponential growth. The rate of change varied according to functional and anatomical regions of the brain. For the brain nuclei, the age‐related changes of susceptibility were in good agreement with the findings from R2^* measurement. Our results suggest that magnetic susceptibility may provide valuable information regarding the spatial and temporal patterns of brain myelination and iron deposition during brain maturation and ageing. Hum Brain Mapp 35:2698–2713, 2014. © 2013 Wiley Periodicals, Inc .     

The effect of hypointense white matter lesions on automated gray matter segmentation in multiple sclerosis

Previous imaging studies assessing the relationship between white matter (WM) damage and matter (GM) atrophy have raised the concern that Multiple Sclerosis (MS) WM lesions may affect measures of GM volume by inducing voxel misclassification during intensity‐based tissue segmentation. Here, we quantified this misclassification error in simulated and real MS brains using a lesion‐filling method. Using this method, we also corrected GM measures in patients before comparing them with controls in order to assess the impact of this lesion‐induced misclassification error in clinical studies. We found that higher WM lesion volumes artificially reduced total GM volumes. In patients, this effect was about 72% of that predicted by simulation. Misclassified voxels were located at the GM/WM border and could be distant from lesions. Volume of individual deep gray matter (DGM) structures generally decreased with higher lesion volumes, consistent with results from total GM. While preserving differences in GM volumes between patients and controls, lesion‐filling correction revealed more lateralised DGM shape changes in patients, which were not evident with the original images. Our results confirm that WM lesions can influence MRI measures of GM volume and shape in MS patients through their effect on intensity‐based GM segmentation. The greater effect of lesions at increasing levels of damage supports the use of lesion‐filling to correct for this problem and improve the interpretability of the results. Volumetric or morphometric imaging studies, where lesion amount and characteristics may vary between groups of patients or change over time, may especially benefit from this correction. Hum Brain Mapp, 2012. © 2011 Wiley Periodicals, Inc.     

Origin and dynamics of oligodendrocytes in the developing brain: Implications for perinatal white matter injury

Infants born prematurely are at high risk to develop white matter injury (WMI), due to exposure to hypoxic and/or inflammatory insults. Such perinatal insults negatively impact the maturation of oligodendrocytes (OLs), thereby causing deficits in myelination. To elucidate the precise pathophysiology underlying perinatal WMI, it is essential to fully understand the cellular mechanisms contributing to healthy/normal white matter development. OLs are responsible for myelination of axons. During brain development, OLs are generally derived from neuroepithelial zones, where neural stem cells committed to the OL lineage differentiate into OL precursor cells (OPCs). OPCs, in turn, develop into premyelinating OLs and finally mature into myelinating OLs. Recent studies revealed that OPCs develop in multiple waves and form potentially heterogeneous populations. Furthermore, it has been shown that myelination is a dynamic and plastic process with an excess of OPCs being generated and then abolished if not integrated into neural circuits. Myelination patterns between rodents and humans show high spatial and temporal similarity. Therefore, experimental studies on OL biology may provide novel insights into the pathophysiology of WMI in the preterm infant and offers new perspectives on potential treatments for these patients.     

Patterns of regional gray matter and white matter atrophy in cortical multiple sclerosis

We investigated the patterns of regional distribution of focal lesions, white matter (WM) and gray matter (GM) atrophy in patients with cortical (cort) MS in comparison to classical (c) MS patients. Nine cort-MS, nine c-MS and nine age-matched healthy controls (HC) underwent a brain MRI exam, including FLAIR and high-resolution T1-weighted scans. MS patients underwent neurological and neuropsychological assessment. Between-group differences of GM and WM volumes and their correlations with neuropsychological performances were assessed with voxel-based morphometry. FLAIR and T1 lesion probability maps (LPMs) were also obtained. Performance at neuropsychological tests was worse in cort-MS than in c-MS patients. Compared to HC, MS patients had a distributed pattern of GM and WM atrophy. No GM/WM area was more atrophic in c-MS vs cort-MS patients. Compared to c-MS, cort-MS patients experienced GM atrophy of frontal–temporal–parietal areas and cingulate cortex and WM atrophy of the cingulum bundle, bilateral cerebral peduncles, right inferior longitudinal fasciculus and left superior longitudinal fasciculus. FLAIR and T1 LPMs did not differ between c-MS vs cort-MS patients. A higher susceptibility to neurodegenerative processes in key brain regions known to be related to cognitive functions is likely to underlie the clinical manifestations of cort-MS.     

Music impacts brain cortical microstructural maturation in very preterm infants: A longitudinal diffusion MR imaging study

Preterm birth disrupts important neurodevelopmental processes occurring from mid-fetal to term-age. Musicotherapy, by enriching infants’ sensory input, might enhance brain maturation during this critical period of activity-dependent plasticity. To study the impact of music on preterm infants’ brain structural changes, we recruited 54 very preterm infants randomized to receive or not a daily music intervention, that have undergone a longitudinal multi-shell diffusion MRI acquisition, before the intervention (at 33 weeks’ gestational age) and after it (at term-equivalent-age). Using whole-brain fixel-based (FBA) and NODDI analysis (n = 40), we showed a longitudinal increase of fiber cross-section (FC) and fiber density (FD) in all major cerebral white matter fibers. Regarding cortical grey matter, FD decreased while FC and orientation dispersion index (ODI) increased, reflecting intracortical multidirectional complexification and intracortical myelination. The music intervention resulted in a significantly higher longitudinal increase of FC and ODI in cortical paralimbic regions, namely the insulo-orbito-temporopolar complex, precuneus/posterior cingulate gyrus, as well as the auditory association cortex. Our results support a longitudinal early brain macro and microstructural maturation of white and cortical grey matter in preterm infants. The music intervention led to an increased intracortical complexity in regions important for socio-emotional development, known to be impaired in preterm infants.     

Joint contributions of cortical morphometry and white matter microstructure in healthy brain aging: A partial least squares correlation analysis

Cortical atrophy and degraded axonal health have been shown to coincide during normal aging; however, few studies have examined these measures together. To lend insight into both the regional specificity and the relative timecourse of structural degradation of these tissue compartments across the adult lifespan, we analyzed gray matter (GM) morphometry (cortical thickness, surface area, volume) and estimates of white matter (WM) microstructure (fractional anisotropy, mean diffusivity) using traditional univariate and more robust multivariate techniques to examine age associations in 186 healthy adults aged 20–94 years old. Univariate analysis of each tissue type revealed that negative age associations were largest in frontal GM and WM tissue and weaker in temporal, cingulate, and occipital regions, representative of not only an anterior‐to‐posterior gradient, but also a medial‐to‐lateral gradient. Multivariate partial least squares correlation (PLSC) found the greatest covariance between GM and WM was driven by the relationship between WM metrics in the anterior corpus callosum and projections of the genu, anterior cingulum, and fornix; and with GM thickness in parietal and frontal regions. Surface area was far less susceptible to age effects and displayed less covariance with WM metrics, while regional volume covariance patterns largely mirrored those of cortical thickness. Results support a retrogenesis‐like model of aging, revealing a coupled relationship between frontal and parietal GM and the underlying WM, which evidence the most protracted development and the most vulnerability during healthy aging.     

Prefrontal gray and white matter volumes in healthy aging and Alzheimer disease

OBJECTIVES: To quantify the contribution of gray and white matter volumes to total prefrontal volume in healthy aging. To determine if prefrontal tissue volumes distinguish healthy aging from Alzheimer disease (AD). DESIGN: Volumes of total prefrontal cortex, prefrontal gray matter, and prefrontal white matter were compared among young healthy elderly (YHE) (n = 14; mean age, 70 years), old healthy elderly (OHE) (n = 14; mean age, 90 years), and subjects with AD (n = 14; mean age, 70 years) by analysis of variance. Additionally, Pearson correlations were performed between volumes and age. RESULTS: Old healthy elderly and subjects with AD had significantly less total prefrontal volume (approximately 15% less in both groups) and prefrontal white matter volume (approximately 30% less and 20% less in the OHE and AD groups, respectively) than YHE, but there were no differences between the OHE and AD groups. There was a significant difference in gray-white matter volume ratio with OHE having a higher ratio than YHE. Subjects with AD did not differ from YHE or OHE in this ratio. There were significant negative correlations between age and total prefrontal volume and age and prefrontal white matter volume in the healthy subjects. CONCLUSIONS: In the very old, the decline of white matter volume is disproportionately greater than the decline of gray matter volume. In subjects with AD both gray and white matter loss contribute to the decline of prefrontal volume. This is demonstrated by the gray-white matter ratio that does not differ between YHE and subjects with AD. Thus, it is likely that AD is different from accelerated aging.     

Mapping brain size and cortical gray matter changes in elderly depression.

BACKGROUND: In elderly depression, volumetric brain imaging findings suggest abnormalities of the frontal lobe, particularly the orbitofrontal cortex, and the hippocampus. No studies to date have mapped cortical abnormalities over the entire brain surface in major depression. Here, we conducted detailed spatial analyses of brain size and gray matter within the cortical mantle in elderly patients with major depression. METHODS: High-resolution, three-dimensional, structural magnetic resonance imaging data and cortical pattern matching methods were used in 24 depressed elderly patients and 19 group-matched controls to measure local brain size and proportions of gray matter at thousands of homologous cortical surface locations. RESULTS: Prominent brain size reductions were observed in the depressed subjects in the orbitofrontal cortex bilaterally. Cortical gray matter measurements revealed significant gray matter increases in the orbitofrontal cortex, adjacent to focal trend level significant decreases of gray matter in the same region. Depressed patients also exhibited significant gray matter increases in parietal cortices, as well as the left temporal cortex. CONCLUSIONS: Complex cortical changes may contribute to the brain size reduction of the orbitofrontal cortex and to the gray matter abnormalities detected in orbitofrontal cortex and temporoparietal cortices, thereby providing a potentially new window into the pathophysiology of elderly depression.     

Relationships between gray matter,body mass index,and waist circumference in healthy adults

Obesity and overweight are often defined by the body mass index (BMI), which associates with metabolic and cardiovascular disease, and possibly with dementia as well as variations in brain volume. However, body fat distribution and abdominal obesity (as measured by waist circumference) is more strongly correlated with cardiovascular and metabolic risk than is BMI. While prior studies have revealed negative associations between gray matter tissue volumes and BMI, the relationship with respect to waist circumference remains largely unexplored. We therefore investigated the effects of both BMI and waist circumference on local gray matter volumes in a group of 115 healthy subjects screened to exclude physical or mental disorders that might affect the central nervous system. Results revealed significant negative correlations for both BMI and waist circumference where regional gray matter effects were largest within the hypothalamus and further encompassed prefrontal, anterior temporal and inferior parietal cortices, and the cerebellum. However, associations were more widespread and pronounced for waist circumference than BMI. Follow‐up analyses showed that these relationships differed significantly across gender. While associations were similar for both BMI and waist circumference for males, females showed more extensive correlations for waist circumference. Our observations suggest that waist circumference is a more sensitive indicator than BMI, particularly in females, for potentially determining the adverse effects of obesity and overweight on the brain and associated risks to health. Hum Brain Mapp, 2013. © 2011 Wiley Periodicals, Inc.     

Early cortical gray matter loss and cognitive correlates in non-demented Parkinson's patients

BackgroundWhereas the motor dysfunction in Parkinson's disease (PD) has been related to deficits in basal ganglia (BG) structures, neural correlates of cognitive changes remain to be fully defined. This study tested the hypothesis that cognitive changes in non-demented PD may be related to cortical gray matter (GM) loss.MethodsHigh-resolution T1-weighted magnetic resonance images of the brain and comprehensive cognitive function tests were acquired in 40 right-handed, non-demented PD subjects and 40 matched controls. GM changes were assessed using voxel-based morphometry (VBM) in FSL. VBM and cognitive results were compared between PD and controls, and correlation analyses were performed between those brain areas and cognitive domains that showed significant group differences.ResultsPD patients demonstrated significant GM reduction localized predominantly in frontal and parieto-occipital regions. Patients also showed reduced performance in fine motor speed and set-shifting compared to controls. Fine motor speed and set-shifting were associated with GM volume in the frontal cortex in controls, whereas these domains were associated primarily with occipital GM regions in PD patients.ConclusionsNon-demented PD subjects demonstrate cortical structural changes in frontal and parieto-occipital regions compared to controls. The association between typically recognized “frontal lobe” function and occipital lobe volume suggested a compensatory role of occipital lobe to primary fronto-striatal pathology in PD. Further longitudinal study of these changing structure–function relationships is needed to understand the neural bases of symptom progression in PD.     

Development of superficial white matter and its structural interplay with cortical gray matter in children and adolescents

Healthy human brain undergoes significant changes during development. The developmental trajectory of superficial white matter (SWM) is less understood relative to cortical gray matter (GM) and deep white matter. In this study, a multimodal imaging strategy was applied to vertexwise map SWM microstructure and cortical thickness to characterize their developmental pattern and elucidate SWM‐GM associations in children and adolescents. Microscopic changes in SWM were evaluated with water diffusion parameters including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) in 133 healthy subjects aged 10–18 years. Results demonstrated distinct maturational patterns in SWM and GM. SWM showed increasing FA and decreasing MD and RD underneath bilateral motor sensory cortices and superior temporal auditory cortex, suggesting increasing myelination. A second developmental pattern in SWM was increasing FA and AD in bilateral orbitofrontal regions and insula, suggesting improved axonal coherence. These SWM patterns diverge from the more widespread GM maturation, suggesting that cortical thickness changes in adolescence are not explained by the encroachment of SWM myelin into the GM‐WM boundary. Interestingly, age‐independent intrinsic association between SWM and cortical GM seems to follow functional organization of polymodal and unimodal brain regions. Unimodal sensory areas showed positive correlation between GM thickness and FA whereas polymodal regions showed negative correlation. Axonal coherence and differences in interstitial neuron composition between unimodal and polymodal regions may account for these SWM‐GM association patterns. Intrinsic SWM‐GM relationships unveiled by neuroimaging in vivo can be useful for examining psychiatric disorders with known WM/GM disturbances. Hum Brain Mapp 35:2806–2816, 2014. © 2013 Wiley Periodicals, Inc .     

Mapping the neuroanatomical impact of very preterm birth across childhood

Those born very preterm (VPT; <32 weeks gestational age) have an increased risk in developing a wide range of cognitive deficits. In early‐to‐late childhood, brain structure has been shown to be altered in VPT compared to full‐term (FT) children; however, the results are inconsistent. The current study examined subcortical volumes, cortical thickness, and surface area in a large cohort of VPT and FT children aged 4–12 years. Structural magnetic resonance imaging (MRI) was obtained on 120 VPT and 146 FT children who returned up to three times, resulting in 176 VPT and 173 FT unique data points. For each participant, Corticometric Iterative Vertex‐based Estimation of Thickness was used to obtain global measurements of total brain, cortical grey and cortical white matter volumes, along with surface‐based measurements of cortical thickness and surface area, and Multiple Automatically Generated Templates (MAGeT) brain segmentation tool was used to segment the subcortical structures. To examine group differences and group–age interactions, mixed‐effects models were used (controlling for whole‐brain volume). We found few differences between the two groups in subcortical volumes. The VPT children showed increased cortical thickness in frontal, occipital and fusiform gyri and inferior pre–post–central areas, while thinning occurred in the midcingulate. Cortical thickness in occipital regions showed more rapid decreases with age in the VPT compared to the FT children. VPT children also showed both regional increases, particularly in the temporal lobe, and decreases in surface area. Our results indicate a delayed maturational trajectory in those born VPT.     

精神分裂症早期的脑白质和灰质信号强度下降

目的分析精神分裂症早期阶段脑灰质和脑白质结构的变化。方法对25例早期阶段(病程小于6个月)的首发未用药的精神分裂症患者和28名正常对照的脑部进行磁共振T1加权成像,所得图像以统计参数图软件包进行预处理,再对两组脑灰质密度和白质信号强度进行t检验。结果患者组左侧岛叶区(x=34,y=18,z=-2,体素集合数=163)、左枕叶(x=14,y=-66,z=14,体素集合数=76)、右侧额叶(x=46,y=44,z=8,体素集合数=74)白质信号强度较正常对照组降低(t=-3.78,P=0.007;t=-3.36,P=0.02;t=3.26,P=0.03);右侧枕叶(x=10,y=-84,z=8,体素集合数=64)脑灰质信号强度比正常对照组降低(t=3.12,P=0.03)。结论精神分裂症早期阶段即存在脑实质结构异常,以白质为著。     

Distinct patterns of progressive gray and white matter degeneration in amyotrophic lateral sclerosis

Progressive cerebral degeneration in amyotrophic lateral sclerosis (ALS) remains poorly understood. Here, three‐dimensional (3D) texture analysis was used to study longitudinal gray and white matter cerebral degeneration in ALS from routine T1‐weighted magnetic resonance imaging (MRI). Participants were included from the Canadian ALS Neuroimaging Consortium (CALSNIC) who underwent up to three clinical assessments and MRI at four‐month intervals, up to 8 months after baseline (T ₀). Three‐dimensional maps of the texture feature autocorrelation were computed from T1‐weighted images. One hundred and nineteen controls and 137 ALS patients were included, with 81 controls and 84 ALS patients returning for at least one follow‐up. At baseline, texture changes in ALS patients were detected in the motor cortex, corticospinal tract, insular cortex, and bilateral frontal and temporal white matter compared to controls. Longitudinal comparison of texture maps between T ₀ and T _max (last follow‐up visit) within ALS patients showed progressive texture alterations in the temporal white matter, insula, and internal capsule. Additionally, when compared to controls, ALS patients had greater texture changes in the frontal and temporal structures at T _max than at T ₀. In subgroup analysis, slow progressing ALS patients had greater progressive texture change in the internal capsule than the fast progressing patients. Contrastingly, fast progressing patients had greater progressive texture changes in the precentral gyrus. These findings suggest that the characteristic longitudinal gray matter pathology in ALS is the progressive involvement of frontotemporal regions rather than a worsening pathology within the motor cortex, and that phenotypic variability is associated with distinct progressive spatial pathology.

In this study, we use MRI texture analysis to detect progressive cerebral degeneration in amyotrophic lateral sclerosis (ALS). Here, we demonstrate distinct spatiotemporal patterns of degeneration related to clinical phenotypes in patients with ALS.     

A forward application of age associated gray and white matter networks

To capture patterns of normal age-associated atrophy, we previously used a multivariate statistical approach applied to voxel based morphometry that identified age-associated gray and white matter covariance networks (Brickman et al. [2007]: Neurobiol Aging 28:284-295). The current study sought to examine the stability of these patterns by forward applying the identified networks to an independent sample of neurologically healthy younger and older adults. Forty-two younger and 35 older adults were imaged with standard high-resolution structural magnetic resonance imaging. Individual images were spatially normalized and segmented into gray and white matter. Covariance patterns that were previously identified with scaled subprofile model analyses were prospectively applied to the current sample to identify to what degree the age-associated patterns were manifested. Older individuals were also assessed with a modified version of the Mini Mental State Examination (mMMSE). Gray matter covariance pattern expression discriminated between younger and older participants with high optimal sensitivity (100%) and specificity (90.5%). While the two groups differed in the degree of white matter pattern expression (t (75) = 5.26, P < 0.001), classification based on white matter expression was relatively low (sensitivity = 80% and specificity = 61.9%). Among older adults, chronological age was significantly associated with increased gray matter pattern expression (r (32) = 0.591, P < 0.001) but not with performance on the mMMSE (r (31) = -0.314, P = 0.085). However, gray matter pattern expression was significantly associated with performance on the mMMSE (r (31) = -0.405, P = 0.024). The findings suggest that the previously derived age-associated covariance pattern for gray matter is reliable and may provide information that is more functionally meaningful than chronological age.     

Genetic influences of cortical gray matter in language-related regions in healthy controls and schizophrenia

Individuals with schizophrenia show a broad range of language impairments, including reading difficulties. A recent structural MRI (sMRI) study linked these difficulties to structural abnormalities in language-related regions (Leonard et al., 2008). Similar regions have been implicated in primary reading disability (RD). Major hypotheses of RD implicate abnormal embryonic neuronal migration in the cortex, and genetic linkage and association studies have identified a number of candidate RD genes that are associated with neuronal migration (Paracchini et al., 2007). Interestingly, evidence suggests at least some individuals with schizophrenia also show impaired neuronal migration in the cortex (Akbarian et al., 1996). Thus the aim of this study was to examine the link between RD-related genes and gray matter volumes in healthy controls and schizophrenia. We used parallel independent component analysis (parallel-ICA) to examine the relationship between gray matter volumes extracted using voxel-based morphometry (VBM) and 16 single nucleotide polymorphisms (SNPs) spanning FOXP2 and four RD-related genes, DCDC2, DYX1C1, KIAA0319 and TTRAP. Parallel-ICA identified five sMRI-SNP relationships. Superior and inferior cerebellar networks were related to DYX1C1 and DCDC2/KIAA0319 respectively in both groups. The superior prefrontal, temporal and occipital networks were positively related to DCDC2 in the schizophrenia, but not the control group. The identified networks closely correspond to the known distribution of language processes in the cortex. Thus, reading and language difficulties in schizophrenia may be related to distributed cortical structural abnormalities associated with RD-related genes.     

Cortical gray and white matter volume in unmedicated schizotypal and schizophrenia patients

Magnetic resonance imaging (MRI) studies have revealed fronto-temporal cortical gray matter volume reductions in schizophrenia. However, to date studies have not examined whether age- and sex-matched unmedicated schizotypal personality disorder (SPD) patients share some or all of the structural brain-imaging characteristics of schizophrenia patients. We examined cortical gray/white matter volumes in a large sample of unmedicated schizophrenia-spectrum patients (n = 79 SPD, n = 57 schizophrenia) and 148 healthy controls. MRI images were reoriented to standard position parallel to the anterior–posterior commissure line, segmented into gray and white matter tissue types, and assigned to Brodmann areas (BAs) using a postmortem-histological atlas. Group differences in regional volume of gray and white matter in the BAs were examined with MANOVA. Schizophrenia patients had significantly reduced gray matter volume widely across the cortex but more marked in frontal and temporal lobes. SPD patients had reductions in the same regions but only about half that observed in schizophrenia and sparing in key regions including BA10. In schizophrenia, greater fronto-temporal volume loss was associated with greater negative symptom severity and in SPD, greater interpersonal and cognitive impairment. Overall, our findings suggest that increased prefrontal volume in BA10 and sparing of volume loss in temporal cortex (BAs 22 and 20) may be a protective factor in SPD which reduces vulnerability to psychosis.     

Cerebellar white matter pathways are associated with reading skills in children and adolescents

Reading is a critical life skill in the modern world. The neural basis of reading incorporates a distributed network of cortical areas and their white matter connections. The cerebellum has also been implicated in reading and reading disabilities. However, little is known about the contribution of cerebellar white matter pathways to major component skills of reading. We used diffusion magnetic resonance imaging (dMRI) with tractography to identify the cerebellar peduncles in a group of 9‐ to 17‐year‐old children and adolescents born full term (FT, n = 19) or preterm (PT, n = 26). In this cohort, no significant differences were found between fractional anisotropy (FA) measures of the peduncles in the PT and FT groups. FA of the cerebellar peduncles correlated significantly with measures of decoding and reading comprehension in the combined sample of FT and PT subjects. Correlations were negative in the superior and inferior cerebellar peduncles and positive in the middle cerebellar peduncle. Additional analyses revealed that FT and PT groups demonstrated similar patterns of reading associations within the left superior cerebellar peduncle, middle cerebellar peduncle, and left inferior cerebellar peduncle. Partial correlation analyses showed that distinct sub‐skills of reading were associated with FA in segments of different cerebellar peduncles. Overall, the present findings are the first to document associations of microstructure of the cerebellar peduncles and the component skills of reading. Hum Brain Mapp 36:1536–1553, 2015. © 2014 Wiley Periodicals, Inc.