Neel Madan

White matter maturation reshapes structural connectivity in the late developing human brain

From toddler to late teenager, the macroscopic pattern of axonal projections in the human brain remains largely unchanged while undergoing dramatic functional modifications that lead to network refinement. These functional modifications are mediated by increasing myelination and changes in axonal diameter and synaptic density, as well as changes in neurochemical mediators. Here we explore the contribution of white matter maturation to the development of connectivity between ages 2 and 18 y using high b-value diffusion MRI tractography and connectivity analysis. We measured changes in connection efficacy as the inverse of the average diffusivity along a fiber tract. We observed significant refinement in specific metrics of network topology, including a significant increase in node strength and efficiency along with a decrease in clustering. Major structural modules and hubs were in place by 2 y of age, and they continued to strengthen their profile during subsequent development. Recording resting-state functional MRI from a subset of subjects, we confirmed a positive correlation between structural and functional connectivity, and in addition observed that this relationship strengthened with age. Continuously increasing integration and decreasing segregation of structural connectivity with age suggests that network refinement mediated by white matter maturation promotes increased global efficiency. In addition, the strengthening of the correlation between structural and functional connectivity with age suggests that white matter connectivity in combination with other factors, such as differential modulation of axonal diameter and myelin thickness, that are partially captured by inverse average diffusivity, play an increasingly important role in creating brain-wide coherence and synchrony.

New directions in clinical imaging of cortical dysplasias

Neuroimaging is essential in the work‐up of patients with intractable epilepsy. In pediatric patients with medically refractory epilepsy, cortical dysplasias account for a large percentage of the epileptogenic substrate. Unfortunately, these are also the most subtle lesions to identify. For this reason, there has been ongoing interest in utilizing new advanced magnetic resonance imaging (MRI) techniques to improve the ability to identify, diagnose, characterize, and delineate cortical dysplasias. Technologic gains such as multichannel coils (32 phased array and beyond) and higher field strengths (3T, 7T, and greater) coupled with newer imaging sequences such as arterial spin labeling (ASL), susceptibility weighted imaging (SWI) and diffusion tensor/spectrum imaging (DTI/DSI) are likely to increase yield. Improved MRI techniques coupled with a multimodality approach including magnetoencephalography (MEG), positron emission tomography (PET), and other techniques will increase sensitivity and specificity for identifying cortical dysplasias.

MRI findings reveal three different types of tubers in patients with tuberous sclerosis complex.

Cortical tubers are very common in tuberous sclerosis complex (TSC) and widely vary in size, appearance and location. The relationship between tuber features and clinical phenotype is unclear. The aim of the study is to propose a classification of tuber types along a spectrum of severity, using magnetic resonance imaging (MRI) characteristics in 35 patients with TSC and history of epilepsy, and to investigate the relationship between tuber types and genetics, as well as clinical manifestations. Three types of tubers were identified based on the MRI signal intensity of their subcortical white matter component. (1) Tubers Type A are isointense on volumetric T1 images and subtly hyperintense on T2 weighted and fluid-attenuated inversion recovery (FLAIR); (2) Type B are hypointense on volumetric T1 images and homogeneously hyperintense on T2 weighted and FLAIR; (3) Type C are hypointense on volumetric T1 images, hyperintense on T2 weighted, and heterogeneous on FLAIR characterized by a hypointense central region surrounded by a hyperintense rim. Based on the dominant tuber type present, three distinct patient groups were also identified: Patients with Type A tuber dominance have a milder phenotype. Patients with Type C tuber dominance have more MRI abnormalities such as subependymal giant cell tumors, and were more likely to have an autism spectrum disorder, a history of infantile spasms, and a higher frequency of epileptic seizures, compared to patients who have a dominance in Type B tubers, and especially to those with a Type A dominance.

IN VIVO PROTON BEAM RANGE VERIFICATION USING SPINE MRI CHANGES

PURPOSE In proton therapy, uncertainty in the location of the distal dose edge can lead to cautious treatment plans that reduce the dosimetric advantage of protons. After radiation exposure, vertebral bone marrow undergoes fatty replacement that is visible on magnetic resonance imaging (MRI). This presents an exciting opportunity to observe radiation dose distribution in vivo. We used quantitative spine MRI changes to precisely detect the distal dose edge in proton radiation patients. METHODS AND MATERIALS We registered follow-up T1-weighted MRI images to planning computed tomography scans from 10 patients who received proton spine irradiation. A radiation dose-MRI signal intensity curve was created using the lateral beam penumbra in the sacrum. This curve was then used to measure range errors in the lumbar spine. RESULTS In the lateral penumbra, there was an increase in signal intensity with higher dose throughout the full range of 0-37.5 Gy (RBE). In the distal fall-off region, the beam sometimes appeared to penetrate farther than planned. The mean overshoot in 10 patients was 1.9 mm (95% confidence interval, 0.8-3.1 mm), on the order of the uncertainties inherent to our range verification method. CONCLUSIONS We have demonstrated in vivo proton range verification using posttreatment spine MRI changes. Our analysis suggests the presence of a systematic overshoot of a few millimeters in some proton spine treatments, but the range error does not exceed the uncertainty incorporated into the treatment planning margin. It may be possible to extend our technique to MRI sequences that show early bone marrow changes, enabling adaptive treatment modification.

A quantitative method for correlating observations of decreased apparent diffusion coefficient with elevated cerebral blood perfusion in newborns presenting cerebral ischemic insults.

In patients presenting with cerebral ischemic injury, the outcome of injured brain tissue quantified as decreased apparent diffusion coefficient (ADC) may depend on associated alterations in cerebral blood perfusion (CBP). This study proposes a non-biased method to quantify associations between ADC and CBP in newborns with global or focal cerebral ischemia. The study population consisted of nine neonates (age: 0 to 3 days) presenting with clinical and imaging evidence of ischemia (seven with global hypoxic ischemia, and two with focal arterial ischemic stroke) with decreased ADC. Six newborns without diffusion abnormalities on magnetic resonance (MR) imaging served as a comparative cohort (age: 0 days to 4 weeks). All patients underwent MR imaging including diffusion weighted imaging (DWI) to determine ADC and axial arterial spin labeling (ASL) to determine CBP. An algorithm was developed that uses the B0 volume from the DWI raw data as a reference, co-registers the ADC and ASL-CBP data to the B0, generates mask filters, and finally performs a statistical analysis to automatically select regions of interest (ROIs) with ADC or ASL-CBP values that deviate significantly from the rest of the brain. If ROIs are identified in this analysis, the algorithm then evaluates correlation based on ROI location and volume. A significant correlation was found between decreased ADC and elevated ASL-CBP with regions of elevated ASL-CBP typically larger than the corresponding ADC abnormality. The association between decreased diffusivity and increased ASL-CBP suggests that, for this cohort, cerebral ischemia is associated with hyperperfusion.

Progressive calcified tuber in a young male with tuberous sclerosis complex.

Tubers are the most common brain lesions in tuberous sclerosis complex (TSC), and typically remain stable in size and appearance. We present the case of a young male with global developmental impairment and autistic features as well as multiple and mixed daily seizures. The patient had a prominent right frontal cortical tuber characterized by a calcified component, which changed on consecutive magnetic resonance imaging between the age of 4 and 11 years, at which time the patient underwent a lesionectomy. A poor long‐term outcome is reported since the patient presents an intractable mixed seizure disorder status post‐epilepsy surgery and no significant neuropsychological improvements. Histopathology findings show typical characteristics of tubers in TSC as well as numerous calcifications within the resected nodular lesion. This case supports the notion that tubers with calcified components are not necessarily static lesions and can change with time. Investigation of the relationship between the presence of calcification in tubers and epileptogenecity in a large group of patients would provide insights into the pathogenesis of the seizures and cognitive impairment and hopefully, eventually provide better treatment options for patients with TSC.

Twists and turns of determining amyloid type and amyloid-related organ damage: discordance and clinical skepticism in the era of proteomic typing.

Abstract Systemic immunoglobulin light-chain primary amyloidosis (AL) is the most common type of systemic amyloidosis. Recent advances in AL amyloidosis include the use of definitive proteomic typing, confirming the type of amyloid in patients with two possible amyloid-forming proteins. Laser microdissection followed by mass spectrometry (LMD/MS) can correctly identify the amyloid type with over 95% sensitivity and specificity. We report the case of a 68-year-old man with a history of IgA lambda monoclonal gammopathy and peripheral neuropathy who was diagnosed with pelvic nodal and psoas amyloidosis. The amyloid was found to be AL kappa type by LMD/MS. While LMD/MS has been effective in distinguishing among AL, secondary amyloidosis and hereditary forms of amyloidosis, our case demonstrates that typing can also identify unusual instances of discordance between light chain isotypes associated with clonal processes.

Disorganized Patterns of Sulcal Position in Fetal Brains with Agenesis of Corpus Callosum

Fetuses with isolated agenesis of the corpus callosum (ACC) are associated with a broad spectrum of neurodevelopmental disability that cannot be specifically predicted in prenatal neuroimaging. We hypothesized that ACC may be associated with aberrant cortical folding. In this study, we determined altered patterning of early primary sulci development in fetuses with isolated ACC using novel quantitative sulcal pattern analysis which measures deviations of regional sulcal features (position, depth, and area) and their intersulcal relationships in 7 fetuses with isolated ACC (27.1 ± 3.8 weeks of gestation, mean ± SD) and 17 typically developing (TD) fetuses (25.7 ± 2.0 weeks) from normal templates. Fetuses with ACC showed significant alterations in absolute sulcal positions and relative intersulcal positional relationship compared to TD fetuses, which were not detected by traditional gyrification index. Our results reveal altered sulcal positional development even in isolated ACC that is present as early as the second trimester and continues throughout the fetal period. It might originate from altered white matter connections and portend functional variances in later life.

More to Atherosclerosis Than Stenosis: Symptomatic Carotid Artery With Intraplaque Hemorrhage

A 66-year-old man presented with left facial weakness on awakening. He had cerebrovascular risk factors, including HIV, hypertension, and hyperlipidemia. When the facial weakness did not resolve after a few days, he presented to a local hospital. A brain magnetic resonance imaging scan, including an axial diffusion-weighted imaging sequence, demonstrated an ischemic stroke in the face representation area of the right precentral gyrus. Transthoracic echocardiography, carotid ultrasound, and cardiac telemetry were unrevealing. He was prescribed dual antiplatelet therapy and a statin. He was referred to a vascular neurologist at our tertiary care center. After seeing the vascular neurologist, a noncontrast magnetic resonance angiogram (MRA) of the head and neck was obtained: 3-dimensional (3D) time-of-flight (TOF) imaging demonstrated ≤50% stenosis of the carotid bulbs bilaterally (40%–50% bilaterally by NASCET criteria [North American Symptomatic Carotid Endarterectomy Trial]). On these T1-weighted images and on a fat-suppressed axial T1 sequence, there were focal, crescentic, subintimal hyperintense signals at the bifurcations bilaterally (Figure 1). The findings were highly suggestive of intraplaque hemorrhage. However, given the modest degree of stenosis and an incomplete etiologic investigation, the right carotid artery was not yet considered definitively symptomatic. He then underwent 30 days of extended cardiac rhythm monitoring to investigate occult arrhythmias as a potential source of the presumed embolic stroke. The facial weakness completely resolved. Figure 1. Initial presenting magnetic resonance imaging and magnetic resonance angiogram (MRA). A , Axial diffusion-weighted imaging demonstrates a small acute infarct in the right precentral gyrus. B , Axial noncontrast MRA raw image of the neck demonstrates narrowing of the carotid bulbs with peripheral hyperintense signals (arrows, indicating intrinsic T1 hyperintensities) consistent with intraplaque hemorrhage. C , Three-dimensional MRA maximal intensity projection shows the narrowing of the carotid bulb and the adjacent intraplaque hemorrhage (arrow). D , Axial T1 fat-suppressed images corroborates the intrinsic …

OC06.01: Quantitative MRI analyses of regional brain growth and cerebral sulcal development in living fetuses with isolated ventriculomegaly and Down's syndrome

Appropriate actions were: During previous TVUS • avoiding touching the key board with a hand that had touched the patient’s vulva; • holding the probe with a gloved hand; During disinfection • hands preparation (hydro alcoholic friction (HAF), washing, or wearing gloves); • type of disinfection matching guidelines, i.e. LLD or higher in the absence of visible probe contamination and intermediate-level disinfection otherwise (immersion, H202, UV); Placing probe cover • hands preparation (HAF, washing, or wearing gloves); • probe cover matching guidelines; • coupling gel matching guidelines (sterile or bottle opened <24H, or no gel and pre-lubricated cover) Results: hrHPV DNA could not be detected on probes whereas 2 key-boards were positive. Hygiene actions are detailed on the figure. Conclusions: Following LLD, hrHPV DNA could not be detected on probes, despite suboptimal compliance with guidelines.