Cerebral Cortical Gray Matter Research Articles

A novel missense variant in the RELN gene in sheep with lissencephaly and cerebellar hypoplasia.

Lissencephaly and cerebellar hypoplasia (LCH) represents a spectrum of congenital developmental malformations of the cerebral cortex and cerebellum, mostly occurring as inherited conditions caused by variants in an increasingly recognized number of genes. LCH has been identified in three Dorset-cross lambs with congenital neurological signs in Australia. Lambs were unable to walk and had reduced vision, and one lamb developed a hypermetric gait and intention tremors. Grossly, the lambs had diffuse pachygyria with reduction in white matter, mild bilateral ventriculomegaly of the lateral ventricles, and a markedly hypoplastic cerebellum. Histologically, there was disorganization of neurons within the cerebral cortex and hippocampus. The cerebellar vermis had disorganized, thin, and hypocellular gray matter with frequent ectopic Purkinje cells, while identifiable folia were largely absent within the hemispheres. Luxol fast blue stain and glial fibrillary acidic protein, neuronal nuclear protein, synaptophysin, and neuron-specific enolase immunohistochemistry confirmed the thickened, disorganized cerebral cortical gray matter and reduced white matter. Within the cerebellum, immunohistochemistry demonstrated marked dysplasia. Whole-genome sequencing analysis and prediction of variant effects identified a missense variant of interest in the candidate gene reelin (RELN; NC_040255.1:g.50288685C>T; NM_001306121.1:c.7088G>A; NP_001293050.1:p.(R2363H)) with a deleterious Sorting Intolerant from Tolerant (SIFT) score. Sanger sequencing identified that the variant segregated with LCH disease in the 3 affected individuals, their sire, and 6 unaffected flock members. The NP_001293050.1: p.(R2363H) substitution is predicted to decrease the stability of the protein (ΔΔG = -1.55 kcal/mol). Pathological and genetic findings are consistent with previously described phenotypes of RELN variants in Churra sheep, dogs, and humans.

The Combination of Presurgical Cortical Gray Matter Volumetry and Cerebral Perfusion Improves the Efficacy of Predicting Postoperative Cognitive Impairment of Elderly Patients.

Postoperative cognitive dysfunction (POCD) is a common complication of the central nervous system in elderly surgical patients. Structural MRI and arterial spin labelling (ASL) techniques found that the grey matter volume and cerebral perfusion in some specific brain areas are associated with the occurrence of POCD, but the results are inconsistent, and the predictive accuracy is low. We hypothesised that the combination of cortical grey matter volumetry and cerebral blood flow yield higher accuracy than either of the methods in discriminating the elderly individuals who are susceptible to POCD after abdominal surgery. Participants underwent neuropsychological testing before and after surgery. Postoperative cognitive dysfunction (POCD) was defined as a decrease in cognitive score of at least 20%. ASL-MRI and T1-weighted imaging were performed before surgery. We compared differences in cerebral blood flow (CBF) and cortical grey matter characteristics between POCD and non-POCD patients and generated receiver operating characteristic curves. Out of 51 patients, 9 (17%) were diagnosed with POCD. CBF in the inferior frontal gyrus was lower in the POCD group compared to the non-POCD group (p < 0.001), and the volume of cortical grey matter in the anterior cingulate gyrus was higher in the POCD group (p < 0.001). The highest AUC value was 0.973. The combination of cortical grey matter volumetry and cerebral perfusion based on ASL-MRI has improved efficacy in the early warning of POCD to elderly abdominal surgical patients.

Magnetic resonance imaging pattern recognition of metabolic and neurodegenerative encephalopathies in dogs and cats.

Metabolic/neurodegenerative encephalopathies encompass a wide list of conditions that share similar clinical and magnetic resonance imaging (MRI) characteristics, challenging the diagnostic process and resulting in numerous tests performed in order to reach a definitive diagnosis. The aims of this multicentric, retrospective and descriptive study are: (I) to describe the MRI features of dogs and cats with metabolic/neurodegenerative encephalopathies; (II) to attempt an MRI recognition pattern classifying these conditions according to the involvement of grey matter, white matter or both; and (III) to correlate the MRI findings with previous literature. A total of 100 cases were recruited, comprising 81 dogs and 19 cats. These included hepatic encephalopathy (20 dogs and three cats), myelinolysis (five dogs), intoxications (seven dogs and one cat), thiamine deficiency (two dogs and seven cats), hypertensive encephalopathy (three dogs and two cats), neuronal ceroid lipofuscinosis (11 dogs and one cat), gangliosidosis (three dogs and two cats), fucosidosis (one dog), L-2-hydroxyglutaric aciduria (13 dogs and one cat), Lafora disease (11 dogs), spongiform leukoencephalomyelopathy (one dog) and cerebellar cortical degeneration (four dogs and two cats). None of the hepatic encephalopathies showed the previously described T1-weighted hyperintensity of the lentiform nuclei. Instead, there was involvement of the cerebellar nuclei (8/23), which is a feature not previously described. Dogs with myelinolysis showed novel involvement of a specific white matter structure, the superior longitudinal fasciculus (5/5). Thiamine deficiency affected numerous deep grey nuclei with novel involvement of the oculomotor nuclei (3/9), thalamic nuclei, subthalamus and cerebellar nuclei (1/9). Cats with hypertensive encephalopathy had a more extensive distribution of the white matter changes when compared to dogs, extending from the parietal and occipital lobes into the frontal lobes with associated mass effect and increased brain volume. Lysosomal storage disease showed white matter involvement only, with neuronal ceroid lipofuscinosis characterised by severe brain atrophy when compared to gangliosidosis and fucosidosis. All patients with L-2-hydroxyglutaric aciduria had a characteristic T2-weighted hyperintense swelling of the cerebral and cerebellar cortical grey matter, resulting in increased brain volume. Lafora disease cases showed either normal brain morphology (5/11) or mild brain atrophy (6/11). Dogs with cerebellar cortical degeneration had more marked cerebellar atrophy when compared to cats. This study shows the important role of MRI in distinguishing different metabolic/neurodegenerative encephalopathies according to specific imaging characteristics.

A study of the correlation between gray matter atrophy in multiple sclerosis and impairment of cognitive function domains

Objective: To quantify cerebral cortical and deep gray matter atrophy in patients with multiple sclerosis (MS) and explore its correlation with impairment in domains of cognitive function. Methods: Twenty patients with MS and 16 healthy controls (HC) matched for age, sex, and education level were included. Using FreeSurfer software, based on 3D-MRI technology, the differences in cortical thickness and deep gray matter volume between the two groups were comparatively analyzed. A neuropsychological scale that included six domains of cognitive function was scored on both study groups to analyze the correlation between cortical thickness and volume of deep gray matter in MS patients with impairment in cognitive function domains. Results: Impairment in domains of cognitive function: cognitive impairment was present in 60% MS patients in this study, mainly manifesting as impairment of verbal memory, verbal fluency, visuospatial memory, and information processing speed function (all P<0.05). Of these, the majority had impaired visuospatial memory function (55.0%), and the least number of patients had impaired information processing speed (15.0%). Changes in cortical thickness: compared with the HC group, the MS group showed that cortical atrophy was mainly concentrated in the frontoparietal region, including significant thinning of cortical thickness in the left inferior parietal gyrus, right superior frontal gyrus, and the right superior parietal gyrus (all P<0.05). Among them, atrophy of the left inferior parietal gyrus was significantly positively correlated with the impairment of verbal memory, verbal fluency, and information processing speed (all P<0.05). There was a significant positive correlation between the right superior frontal gyrus atrophy and verbal memory, verbal fluency, and visuospatial memory impairment (all P<0.05). Changes in deep gray matter volume: compared with the HC group, deep gray matter volume in the MS group decreased significantly in the bilateral thalamus, bilateral putamen, bilateral pallidum (all P<0.01), and right nucleus accumbens (P<0.05). Among them, left thalamus atrophy was significantly positively correlated with visuospatial memory impairment (r=0.45, P=0.046), and left putamen atrophy was both significantly positively correlated with visuospatial memory (r=0.45, P=0.047) and information processing speed impairment (r=0.50, P=0.026). Conclusions: Early structural brain changes in MS are dominated by gray matter atrophy. Deep gray matter is more prominent than cortical atrophy.

Cardiovascular disease risk exacerbates brain aging among Hispanic/Latino adults in the SOL-INCA-MRI Study.

Cardiovascular disease (CVD) risk factors are highly prevalent among Hispanic/Latino adults, while the prevalence of MRI infarcts is not well-documented. We, therefore, sought to examine the relationships between CVD risk factors and infarcts with brain structure among Hispanic/Latino individuals. Participants included 1,886 Hispanic/Latino adults (50-85 years) who underwent magnetic resonance imaging (MRI) as part of the Study of Latinos-Investigation of Neurocognitive Aging-MRI (SOL-INCA-MRI) study. CVD risk was measured approximately 10.5 years before MRI using the Framingham cardiovascular risk score, a measure of 10-year CVD risk (low (<10%), medium (10- < 20%), and high (≥20%)). MR infarcts were determined as present or absent. Outcomes included total brain, cerebral and lobar cortical gray matter, hippocampal, lateral ventricle, and total white matter hyperintensity (WMH) volumes. Linear regression models tested associations between CVD risk and infarct with MRI outcomes and for modifications by age and sex. Sixty percent of participants were at medium or high CVD risk. Medium and high CVD risk were associated with lower total brain and frontal gray matter and higher WMH volumes compared to those with low CVD risk. High CVD risk was additionally associated with lower total cortical gray matter and parietal volumes and larger lateral ventricle volumes. Men tended to have greater CVDRF-related differences in total brain volumes than women. The association of CVD risk factors on total brain volumes increased with age, equal to an approximate 7-year increase in total brain aging among the high-CVD-risk group compared to the low-risk group. The presence of infarct(s) was associated with lower total brain volumes, which was equal to an approximate 5-year increase in brain aging compared to individuals without infarcts. Infarcts were also associated with smaller total cortical gray matter, frontal and parietal volumes, and larger lateral ventricle and WMH volumes. The high prevalence of CVD risk among Hispanic/Latino adults may be associated with accelerated brain aging.

Fractal dimension of the cortical gray matter outweighs other brain MRI features as a predictor of transition to dementia in patients with mild cognitive impairment and leukoaraiosis.

The relative contribution of changes in the cerebral white matter (WM) and cortical gray matter (GM) to the transition to dementia in patients with mild cognitive impairment (MCI) is not yet established. In this longitudinal study, we aimed to analyze MRI features that may predict the transition to dementia in patients with MCI and T2 hyperintensities in the cerebral WM, also known as leukoaraiosis. Sixty-four participants with MCI and moderate to severe leukoaraiosis underwent baseline MRI examinations and annual neuropsychological testing over a 2 year period. The diagnosis of dementia was based on established criteria. We evaluated demographic, neuropsychological, and several MRI features at baseline as predictors of the clinical transition. The MRI features included visually assessed MRI features, such as the number of lacunes, microbleeds, and dilated perivascular spaces, and quantitative MRI features, such as volumes of the cortical GM, hippocampus, T2 hyperintensities, and diffusion indices of the cerebral WM. Additionally, we examined advanced quantitative features such as the fractal dimension (FD) of cortical GM and WM, which represents an index of tissue structural complexity derived from 3D-T1 weighted images. To assess the prediction of transition to dementia, we employed an XGBoost-based machine learning system using SHapley Additive exPlanations (SHAP) values to provide explainability to the machine learning model. After 2 years, 18 (28.1%) participants had transitioned from MCI to dementia. The area under the receiving operator characteristic curve was 0.69 (0.53, 0.85) [mean (90% confidence interval)]. The cortical GM-FD emerged as the top-ranking predictive feature of transition. Furthermore, aggregated quantitative neuroimaging features outperformed visually assessed MRI features in predicting conversion to dementia. Our findings confirm the complementary roles of cortical GM and WM changes as underlying factors in the development of dementia in subjects with MCI and leukoaraiosis. FD appears to be a biomarker potentially more sensitive than other brain features.

Differential reductions in the capillary red-blood-cell flux between retina and brain under chronic global hypoperfusion.

It has been hypothesized that abnormal microcirculation in the retina might predict the risk of ischemic damages in the brain. Direct comparison between the retinal and the cerebral microcirculation using similar animal preparation and under similar experimental conditions would help test this hypothesis. We investigated capillary red-blood-cell (RBC) flux changes under controlled conditions and bilateral-carotid-artery-stenosis (BCAS)-induced hypoperfusion, and then compared them with our previous measurements performed in the brain. We measured capillary RBC flux in mouse retina with two-photon microscopy using a fluorescence-labeled RBC-passage approach. Key physiological parameters were monitored during experiments to ensure stable physiology. We found that under the controlled conditions, capillary RBC flux in the retina was much higher than in the brain (i.e., cerebral cortical gray matter and subcortical white matter), and that BCAS induced a much larger decrease in capillary RBC flux in the retina than in the brain. We demonstrated a two-photon microscopy-based technique to efficiently measure capillary RBC flux in the retina. Since cerebral subcortical white matter often exhibits early pathological developments due to global hypoperfusion, our results suggest that retinal microcirculation may be utilized as an early marker of brain diseases involving global hypoperfusion.

Patients with chronic mild or moderate traumatic brain injury have abnormal longitudinal brain volume enlargement more than atrophy

Introduction Many studies have found brain atrophy in patients with traumatic brain injury (TBI), but most of those studies examined patients with moderate or severe TBI. A few recent studies in patients with chronic mild or moderate TBI found abnormally large brain volume. Some of these studies used NeuroQuant®, FDA-cleared software for measuring MRI brain volume. It is not known if the abnormal enlargement occurs before or after injury. The purpose of the current study was to test the hypothesis that it occurs after injury. Methods 55 patients with chronic mild or moderate TBI were compared to NeuroQuant® normal controls ( n &gt; 4000) with respect to MRI brain volume change from before injury (time 0 [t0], estimated volume) to after injury (t1, measured volume). A subset of 36 patients were compared to the normal controls with respect to longitudinal change of brain volume after injury from t1 to t2. Results The patients had abnormally fast increase of brain volume for multiple brain regions, including whole brain, cerebral cortical gray matter, and subcortical regions. Discussion This is the first report of extensive abnormal longitudinal brain volume enlargement in patients with TBI. In particular, the findings suggested that the previously reported findings of cross-sectional brain volume abnormal enlargement were due to longitudinal enlargement after, not before, injury. Abnormal longitudinal enlargement of the posterior cingulate cortex correlated with neuropathic headaches, partially replicating a previously reported finding that was associated with neuroinflammation.

Gray Matter Matters: A Longitudinal Magnetic Resonance Voxel-Based Morphometry Study of Primary Progressive Multiple Sclerosis.

Background: Multiple Sclerosis (MS) lesions in white matter (WM) are easily detected with conventional MRI which induce inflammation thereby generating contrast. WM lesions do not consistently explain the extent of clinical disability, cognitive impairment, or the source of an exacerbation. Gray matter (GM) structures including the cerebral cortex and various deep nuclei are known to be affected early in Primary Progressive Multiple Sclerosis (PPMS) and drive disease progression, disability, fatigue, and cognitive dysfunction. However, little is known about how rapidly GM lesions develop and accumulate over time.Objective: The purpose of this study is to analyze the degree and rate of progression in 25 patients with PPMS using voxel-based automated volumetric quantitation.Methods: This is a retrospective single-center study which includes a cohort of 25 patients with PPMS scanned utilizing NeuroQuant® 3 dimensional voxel-based morphometry (3D VBM) automated analysis and database and restudied after a period of ~1 year (11–14 months). Comparisons with normative data were acquired for whole brain, forebrain parenchyma, cortical GM, hippocampus, thalamus, superior and inferior lateral ventricles. GM volume changes were correlated with their clinical motor and cognitive scores using Extended Disability Status Scales (EDSS) and Montreal Cognitive Assessments (MoCA).Results: Steep reductions occurred in cerebral cortical GM and deep GM nuclei volumes which correlated with each patient's clinical and cognitive impairment. The median observed percentile volume losses were statistically significant compared with the 50th percentile for each GM component. Longitudinal assessments of an unselected sample of one dozen patients involved in the PPMS study showed prominent losses occurring mainly in cortical GM and hippocampus which were reflected in their EDSS and MoCA. The longitudinal results were compared with a similar sample of patients having Relapsing MS (RMS) whose GM values were largely in normal range, annualized volume GM changes were much less, while WM hyperintensities were in abnormal range in half the unselected cases.Conclusions: Knowledge of the degree and rapidity with which cortical atrophy and deep GM volume loss develops clarifies the source of progressive cognitive and clinical decline in PPMS.

Sex-Based Differences in Cortical and Subcortical Development in 436 Individuals Aged 4–54 Years

Abstract Sex-based differences in brain development have long been established in ex vivo studies. Recent in vivo studies using magnetic resonance imaging (MRI) have offered considerable insight into sex-based variations in brain maturation. However, reports of sex-based differences in cortical volumes and thickness are inconsistent. We examined brain maturation in a cross-sectional, single-site cohort of 436 individuals (201 [46%] males) aged 4–54 years (median = 16 years). Cortical thickness, cortical surface area, subcortical surface area, volumes of the cerebral cortex, white matter (WM), cortical and subcortical gray matter (GM), including the thalamic subnuclei, basal ganglia, and hippocampi were calculated using automatic segmentation pipelines. Subcortical structures demonstrated distinct curvilinear trajectories from the cortex, in both volumetric maturation and surface-area expansion in relation to age. Surface-area analysis indicated that dorsal regions of the thalamus, globus pallidus and striatum, regions demonstrating structural connectivity with frontoparietal cortices, exhibited extensive expansion with age, and were inversely related to changes seen in cortical maturation, which contracted with age. Furthermore, surface-area expansion was more robust in males in comparison to females. Age- and sex-related maturational changes may reflect alterations in dendritic and synaptic architecture known to occur during development from early childhood through to mid-adulthood.

Patients with chronic mild or moderate traumatic brain injury have abnormal brain enlargement

ABSTRACTIntroduction: Much less is known about brain volume abnormalities in patients with chronic mild or moderate traumatic brain injury (TBI) compared with patients with more severe injury. Commercially available software methods including NeuroQuant® are being used increasingly to assess MRI brain volume in patients with TBI.Methods: 50 patients with mild or moderate TBI were compared to the NeuroQuant® normal control database (n = thousands) with respect to MRI brain volume.Results: The patients had many areas of abnormal enlargement and fewer areas of atrophy, including abnormally small cerebral white matter (CWM) limited to the first 10 months after injury. Examination of correlations within the patient group between CWM volume and volumes of the abnormally enlarged regions showed multiple significant negative correlations, indicating that CWM atrophy correlated with enlargement of the other regions.Discussion: The finding of many regions of abnormal brain enlargement was relatively new, although a couple of previous studies of patients with mild TBI found similar but more limited findings. The cause of the abnormal enlargement was unknown, but possibilities included: (1) hyperactivity and hypertrophy; or (2) chronic neuro-inflammation and edema.Abbreviations: ADNI: Alzheimer’s Disease Neuroimaging Initiative; CWM: cerebral white matter; GM: cerebral cortical gray matter; ICC: intraclass correlations coefficient; IFT: infratentorial; MRI: magnetic resonance imaging; mTBI: mild TBI; NQ: NeuroQuant®; SCN: subcortical nuclei; t0: time of injury; t1: time of first NeuroQuanted MRI scan after injury; t2: time of second NeuroQuanted MRI scan after injury; TBI: traumatic brain injury; VBR: ventricle-to-brain ratio; WBP: whole-brain parenchyma.

Ultrastructural Remodeling of the Neurovascular Unit in the Female Diabetic db/db Model—Part III: Oligodendrocyte and Myelin

Obesity, insulin resistance, and type 2 diabetes mellitus are associated with diabetic cognopathy. In this study, we tested the hypothesis that neurovascular unit(s) (NVU), oligodendrocytes, and myelin within cerebral cortical grey matter and deeper transitional zone regions between the cortical grey matter and white matter may be abnormal. The monogenic (Leprdb) female diabetic db/db [BKS.CgDock7m +/+ Leprdb/J] (DBC) mouse model was utilized for this ultrastructural study. Upon sacrifice (20 weeks of age), left-brain hemispheres of the DBC and age-matched non-diabetic wild type control C57BL/KsJ (CKC) mice were immediately immersion-fixed. We found prominent remodeling of oligodendrocytes with increased nuclear chromatin condensation and volume and increased numbers of active myelination sites of the cytoplasm in transition zones. Marked dysmyelination with outer myelin lamellae sheath splitting, separation, and ballooning with aberrant mitochondria in grey matter and similar myelin remodeling changes with marked disarray with additional axonal collapse in transitional zones in DBC as compared to CKC models.

Altered Brain Fraction Amplitude of Low Frequency Fluctuation at Resting State in Patients With Early Left and Right Bell’s Palsy: Do They Have Differences?

Purpose: Bell’s palsy refers to acute idiopathic unilateral facial nerve palsy. It is a common disorder of the main motor pathway to the facial muscles. This study aimed to investigate the abnormal fraction amplitude of low frequency fluctuation (fALFF) of the brain in patients with early left and right Bell’s palsy.Materials and Methods: Sixty-seven patients (left 33, right 34) and 37 age- and sex-matched healthy controls underwent resting-state functional magnetic resonance imaging (R-fMRI) examination. The fALFF values were measured from all subjects and were compared among the left palsy, right palsy, and control groups. Then, correlations between the Toronto Facial Grading System (TFGS) scores of the patients and the fALFF values of abnormal brain regions were analyzed.Results: Significant group differences in fALFF values among the three groups were observed mainly in the cerebral cortical, subcortical, and deep gray matter regions. Compared with the right Bell’s palsy group, the left Bell’s palsy group showed significantly decreased fALFF values in the left temporal pole of the superior temporal gyrus (TPOsup), right supramarginal, left and right middle cingulate cortex (MCC), left superior frontal gyrus (SFG), and left precentral gyrus (PreCG), and increased fALFF values were observed in the right SFG and PreCG. Furthermore, altered fALFF values correlated positively with the TFGS scores in the left superior TPO, bilateral MCC, and right PreCG, and correlated negatively with the TFGS scores in the right SFG of the left Bell’s palsy group. Altered fALFF values correlated positively with the TFGS scores in the bilateral MCC and right PreCG and correlated negatively with the TFGS scores in the left superior TPO and SFG of the right Bell’s palsy group.Conclusion: Regulatory mechanisms seem to differ between patients with left and right early Bell’s palsy. The severity of the disease is associated with these functional alterations.

Ultrastructural Remodeling of the Neurovascular Unit in the Female Diabetic db/db Model–Part II: Microglia and Mitochondria

Obesity, insulin resistance, and type 2 diabetes mellitus are associated with diabetic cognopathy. This study tested the hypothesis that neurovascular unit(s) (NVU) within cerebral cortical gray matter regions may depict abnormal cellular remodeling. The monogenic (Leprdb) female diabetic db/db [BKS.CgDock7m +/+Leprdb/J] (DBC) mouse model was utilized for this ultrastructural study. Upon sacrifice (20 weeks), left-brain hemispheres of the DBC and age-matched nondiabetic control C57BL/KsJ (CKC) mice were immediately immersion-fixed. We observed an attenuation/loss of endothelial blood–brain barrier tight/adherens junctions and pericytes, thickened basement membranes, adherent red and white blood cells, neurovascular unit microbleeds and pathologic remodeling of protoplasmic astrocytes. In this second of a three-part series, we focus on the observational ultrastructural remodeling of microglia and mitochondria in relation to the NVU in leptin receptor deficient DBC models. This study identified novel ultrastructural core signature remodeling changes, which consisted of invasive activated microglia, microglial aberrant mitochondria with nuclear chromatin condensation and adhesion of white blood cells to an activated endothelium of the NVU. In conclusion, the results implicate activated microglia in NVU uncoupling and the resulting ischemic neuronal and synaptic damage, which may be related to impaired cognition and diabetic cognopathy.

The effects of breastfeeding versus formula-feeding on cerebral cortex maturation in infant rhesus macaques

Breastfeeding is positively associated with several outcomes reflecting early brain development and cognitive functioning. Brain neuroimaging studies have shown that exclusively breastfed children have increased white matter and subcortical gray matter volume compared to formula-fed children. However, it is difficult to disentangle the effects of nutrition in breast milk from other confounding factors that affect brain development, particularly in studies of human subjects. Among the nutrients provided by human breast milk are the carotenoid lutein and the natural form of tocopherol, both of which are selectively deposited in brain. Lutein is the predominant carotenoid in breast milk but not in most infant formulas, whereas infant formulas are supplemented with the synthetic form of tocopherol. In this study, a non-human primate model was used to investigate the effects of breastfeeding versus formula-feeding, as well as lutein and natural RRR-α-tocopherol supplementation of infant formula, on brain maturation under controlled experimental conditions. Infant rhesus macaques (Macaca mulatta) were exclusively breastfed, or were fed infant formulas with different levels and sources of lutein and α-tocopherol. Of note, the breastfed group were mother-reared whereas the formula-fed infants were nursery-reared. Brain structural and diffusion MR images were collected, and brain T2 was measured, at two, four and six months of age. The mother-reared breastfed group was observed to differ from the formula-fed groups by possessing higher diffusion fractional anisotropy (FA) in the corpus callosum, and lower FA in the cerebral cortex at four and six months of age. Cortical regions exhibiting the largest differences include primary motor, premotor, lateral prefrontal, and inferior temporal cortices. No differences were found between the formula groups. Although this study did not identify a nutritional component of breast milk that could be provided to infant formula to facilitate brain maturation consistent with that observed in breastfed animals, our findings indicate that breastfeeding promoted maturation of the corpus callosum and cerebral cortical gray matter in the absence of several confounding factors that affect studies in human infants. However, differences in rearing experience remain as a potential contributor to brain structural differences between breastfed and formula fed infants.

Ultrastructural Remodeling of the Neurovascular Unit in the Female Diabetic db/db Model—Part I: Astrocyte

Obesity, insulin resistance, and type 2 diabetes mellitus are associated with cognitive impairment, known as diabetic cognopathy. In this study, we tested the hypothesis that neurovascular unit(s) (NVU) within cerebral cortical gray matter regions display abnormal cellular remodeling. The monogenic (Leprdb) female diabetic db/db (BKS.CgDock7m +/+Leprdb/J; DBC) mouse model was utilized for this ultrastructural study. Upon sacrifice (at 20 weeks of age), left-brain hemispheres of the DBC and age-matched non-diabetic wild-type control C57BL/KsJ (CKC) mice were immediately immersion-fixed. We found attenuation/loss of endothelial blood–brain barrier tight/adherens junctions and pericytes, thickening of the basement membrane, aberrant mitochondria, and pathological remodeling of protoplasmic astrocytes. Additionally, there were adherent red blood cells and NVU microbleeds (cortical layer III) in DBC mice, which were not observed in CKC animals. While this study represents only a “snapshot in time”, it does allow for cellular remodeling comparisons between DBC and CKC. In this paper, the first of a three-part series, we report the observational ultrastructural remodeling changes of the NVU and its protoplasmic astrocytes in relation to the surrounding neuropil. Having identified multiple abnormal cellular remodeling changes in the DBC as compared to CKC models, we will design future experiments to evaluate various treatment modalities in DBC mice.

Using diffusion anisotropy to study cerebral cortical gray matter development

Diffusion-weighted magnetic resonance imaging (diffusion MRI) is being used to characterize morphological development of cells within developing cerebral cortical gray matter. Abnormal morphology is a shared characteristic of cerebral cortical neurons for many neurodevelopmental disorders, and therefore diffusion MRI is potentially of high value for monitoring growth-related anatomical changes of relevance to brain function. Here, the theoretical framework for analyzing diffusion MRI data is summarized. An overview of quantitative methods for validating the interpretations of diffusion MRI data using light microscopy is then presented. These theoretical modeling and validation methods have been used to precisely characterize changes in water diffusion anisotropy with development in the context of several animal model systems. Further, in diffusion MRI studies of several preclinical models of neurodevelopmental disorders, the ability is demonstrated of diffusion MRI to detect abnormal morphological neural development. These animal model studies are reviewed along with recent initial efforts to translate the findings into an approach for studies of human subjects. This body of data indicates that diffusion MRI has the requisite sensitivity to detect abnormal cellular development in the context of several models of neurodevelopmental disorders, and therefore may provide a new strategy for detecting abnormalities in early stages of brain development in humans.

Neurite imaging reveals microstructural variations in human cerebral cortical gray matter

We present distinct patterns of neurite distribution in the human cerebral cortex using diffusion magnetic resonance imaging (MRI). We analyzed both high-resolution structural (T1w and T2w images) and diffusion MRI data in 505 subjects from the Human Connectome Project. Neurite distributions were evaluated using the neurite orientation dispersion and density imaging (NODDI) model, optimized for gray matter, and mapped onto the cortical surface using a method weighted towards the cortical mid-thickness to reduce partial volume effects. The estimated neurite density was high in both somatosensory and motor areas, early visual and auditory areas, and middle temporal area (MT), showing a strikingly similar distribution to myelin maps estimated from the T1w/T2w ratio. The estimated neurite orientation dispersion was particularly high in early sensory areas, which are known for dense tangential fibers and are classified as granular cortex by classical anatomists. Spatial gradients of these cortical neurite properties revealed transitions that colocalize with some areal boundaries in a recent multi-modal parcellation of the human cerebral cortex, providing mutually supportive evidence. Our findings indicate that analyzing the cortical gray matter neurite morphology using diffusion MRI and NODDI provides valuable information regarding cortical microstructure that is related to but complementary to myeloarchitecture.

Classification of brain disease in magnetic resonance images using two-stage local feature fusion.

BackgroundMany classification methods have been proposed based on magnetic resonance images. Most methods rely on measures such as volume, the cerebral cortical thickness and grey matter density. These measures are susceptible to the performance of registration and limited in representation of anatomical structure. This paper proposes a two-stage local feature fusion method, in which deformable registration is not desired and anatomical information is represented from moderate scale.MethodsKeypoints are firstly extracted from scale-space to represent anatomical structure. Then, two kinds of local features are calculated around the keypoints, one for correspondence and the other for representation. Scores are assigned for keypoints to quantify their effect in classification. The sum of scores for all effective keypoints is used to determine which group the test subject belongs to.ResultsWe apply this method to magnetic resonance images of Alzheimer's disease and Parkinson's disease. The advantage of local feature in correspondence and representation contributes to the final classification. With the help of local feature (Scale Invariant Feature Transform, SIFT) in correspondence, the performance becomes better. Local feature (Histogram of Oriented Gradient, HOG) extracted from 16×16 cell block obtains better results compared with 4×4 and 8×8 cell block.DiscussionThis paper presents a method which combines the effect of SIFT descriptor in correspondence and the representation ability of HOG descriptor in anatomical structure. This method has the potential in distinguishing patients with brain disease from controls.

HIV Distal Neuropathic Pain Is Associated with Smaller Ventral Posterior Cingulate Cortex.

. Despite modern antiretroviral therapy, HIV-associated neuropathy is one of the most prevalent, disabling and treatment-resistant complications of HIV disease. The presence and intensity of distal neuropathic pain is not fully explained by the degree of peripheral nerve damage. A better understanding of brain structure in HIV distal neuropathic pain may help explain why some patients with HIV neuropathy report pain while the majority does not. Previously, we reported that more intense distal neuropathic pain was associated with smaller total cerebral cortical gray matter volumes. The objective of this study was to determine which parts of the cortex are smaller. . HIV positive individuals with and without distal neuropathic pain enrolled in the multisite (N = 233) CNS HIV Antiretroviral Treatment Effects (CHARTER) study underwent structural brain magnetic resonance imaging. Voxel-based morphometry was used to investigate regional brain volumes in these structural brain images. . Left ventral posterior cingulate cortex was smaller for HIV positive individuals with versus without distal neuropathic pain (peak P = 0.017; peak t = 5.15; MNI coordinates x = -6, y = -54, z = 20). Regional brain volumes within cortical gray matter structures typically associated with pain processing were also smaller for HIV positive individuals having higher intensity ratings of distal neuropathic pain. . The posterior cingulate is thought to be involved in inhibiting the perception of painful stimuli. Mechanistically a smaller posterior cingulate cortex structure may be related to reduced anti-nociception contributing to increased distal neuropathic pain.