Regional Brain Tissue Research Articles

Effects of acetazolamide on intracranial pressure and brain tissue oxygenation on patients with acute brain injury: A pilot physiological study.

The effect of acetazolamide on regional brain tissue oxygenation in patients with acute brain injury (ABI) is unknown. We studied adult patients with ABI who received acetazolamide as per the treating physician's decision and had ICP and brain oxygen pressure (PbtO2) monitoring. Baseline measurements of ICP, cerebral perfusion pressure (CPP), and PbtO2 were taken before administering acetazolamide; subsequent measurements were recorded every 5 min for a total of 20 min. Mean cerebral blood velocities (FVm) and pulsatility index (PI) were measured using transcranial color-coded duplex (TCCD) sonography at baseline and after 20 min. Fourteen patients with subarachnoid hemorrhage (n = 6), traumatic brain injury (n = 7), and intracranial hemorrhage (n = 1) were included. Following administration of acetazolamide, ICP showed a significant increase within 20 min (p < 0.001), with no significant change in CPP (p = 0.08). PbtO2 demonstrated a significant increase (p < 0.001), with a noticeable change observed at 10 min after acetazolamide administration (15 [14-17] vs. 28 [26-30] mmHg). Additionally, FVm exhibited a significant increase (p < 0.001), and PI showed a reduction (p < 0.001). Administration of acetazolamide in ABI patients resulted in a significant increase in brain oxygenation, associated with a rise in ICP and FVm, suggesting increased cerebral volume and vasodilation.

Effects of Early Enteral to Parenteral Protein Ratios on Brain Volume and Somatic Growth in Very Low Birth Weight Infants

To evaluate whether a higher proportion of enteral vs parenteral protein ratio (E:P ratio) in the first 28days after birth is associated with increased brain volume and somatic growth in very low birth weight (VLBW; birth weight <1500 g) infants. This was a retrospective analysis of a subcohort of VLBW infants (n=256, gestational age mean 28.07 [SD 2.17] weeks, birth weight 1038.80 [SD 262.95] grams) from the Cincinnati Infant Neurodevelopment Early Prediction Study, a regional prospective study of infants born at ≤32weeks' gestation. Brain magnetic resonance imaging was obtained at term-equivalent age. Macronutrient intake and growth metrics for the first 28days were collected retrospectively. The primary outcome was total brain tissue volume. The relationships between E:P ratio, total and regional brain tissue volumes, and somatic growth were analyzed by multivariable linear regression models; composite variables were used to adjust for potential confounders including pregnancy risk factors and initial severity of illness. Higher E:P ratio was associated with increased total brain tissue volume but was not associated with change in head circumference z score. In secondary analyses, higher E:P ratio was associated with increased weight velocity. There were no significant associations between E:P ratio and change in weight or length z scores or regional brain volumes. Higher E:P ratio in the first 28days was positively associated with total brain volume and weight gain. Promoting the provision of enteral over parenteral protein may improve brain and somatic growth in VLBW infants.

Inflammation subsequent to mild iron excess differentially alters regional brain iron metabolism, oxidation and neuroinflammation status in mice.

Iron dyshomeostasis and neuroinflammation, characteristic features of the aged brain, and exacerbated in neurodegenerative disease, may induce oxidative stress-mediated neurodegeneration. In this study, the effects of potential priming with mild systemic iron injections on subsequent lipopolysaccharide (LPS)-induced inflammation in adult C57Bl/6J mice were examined. After cognitive testing, regional brain tissues were dissected for iron (metal) measurements by total reflection X-ray fluorescence and synchrotron radiation X-Ray fluorescence-based elemental mapping; and iron regulatory, ferroptosis-related, and glia-specific protein analysis, and lipid peroxidation by western blotting. Microglial morphology and astrogliosis were assessed by immunohistochemistry. Iron only treatment enhanced cognitive performance on the novel object location task compared with iron priming and subsequent LPS-induced inflammation. LPS-induced inflammation, with or without iron treatment, attenuated hippocampal heme oxygenase-1 and augmented 4-hydroxynonenal levels. Conversely, in the cortex, elevated ferritin light chain and xCT (light chain of System Xc-) were observed in response to LPS-induced inflammation, without and with iron-priming. Increased microglial branch/process lengths and astrocyte immunoreactivity were also increased by combined iron and LPS in both the hippocampus and cortex. Here, we demonstrate iron priming and subsequent LPS-induced inflammation led to iron dyshomeostasis, compromised antioxidant function, increased lipid peroxidation and altered neuroinflammatory state in a brain region-dependent manner.

Examining the relationship between anxiety and regional brain volumes in the National Alzheimer's Coordinating Center uniform, imaging, and biomarker datasets

Anxiety has been associated with a greater risk of Alzheimer's disease (AD). Existing research has identified structural differences in regional brain tissue in participants with anxiety, but results have been inconsistent. We sought to determine the association between anxiety and regional brain volumes, and the moderation effect of APOE ε4. Using data from participants in the National Alzheimer's Coordinating Center (NACC) Uniform Data Set, with complete imaging (MRI) and biomarker data (n = 1533), multiple linear regression estimated the adjusted effect of anxiety on 30 structural MRI regions. The moderation effect of APOE ε4 on the relation between structural MRI regions and anxiety was assessed as was the moderation effect of cognitive status. False discovery rate was used to adjust for multiple comparisons. After controlling for intracranial volume, age, sex, years of education, race, Hispanic ethnicity, and cognitive status, seven MRI regions demonstrated lower volumes among participants with anxiety: total cerebrum gray matter volume, right hippocampus volume, hippocampal volume (total), right and left frontal lobe cortical gray matter volume, and right and total temporal lobe cortical gray matter volume. Findings suggest that anxiety is associated with significant atrophy in multiple brain regions, with corresponding ventricular enlargement. Future research should investigate if anxiety-related changes to brain morphology contribute to greater AD risk.

Versatile MRI acquisition and processing protocol for population‐based neuroimaging

AbstractBackgroundNeuroimaging plays an essential role in epidemiological studies and a special focus is directed towards the employment of versatile MRI acquisition and processing. The proposed multi‐purpose MRI protocol was designed for large‐scale and long‐term population neuroimaging and includes structural, diffusion‐weighted, and functional MRI modalities. It directly links the acquisition of an extensive set of MRI contrasts with fully automated data processing pipelines and quality assurance of the MRI data and image‐derived phenotypes.MethodThe MRI acquisition protocol is largely based on in‐house developed MR sequences. With a total scan time below one hour per participant, it allows to acquire multiple MR contrasts at 3T with whole‐brain coverage and high isotropic image resolution, while keeping potential subject discomfort and motion artifacts at manageable levels. Designed to be kept constant, but also adaptive, the scan protocol separates into a core imaging protocol with MR contrasts of high relevance acquired for all study participants, and a free protocol to accommodate alternative promising MRI techniques in smaller sub‐populations. The analysis protocol handles large‐scale imaging data by means of fast and fully automated processing pipelines that incorporate state‐of‐the‐art image analysis tools and innovative machine learning methods, particularly using deep learning. Dedicated quality assessment (QA) includes visual rating and inspection for incidental findings on structural MRI and QA workflows tailored for each postprocessing pipeline to automatically identify problematic data based on the distribution of subject‐specific QA metrics with respect to the population average.ResultThe MRI protocol has been successfully applied in the Rhineland Study, a prospective cohort study in Bonn, Germany, with currently over 10,000 participants. Image‐derived phenotypes include: global and regional brain tissue volume, thickness and surface measures from multi‐modal structural MRI, global and regional microstructural measures based on diffusion‐weighted MRI, brain functional connectivity using resting‐state functional MRI, and volumes of subcutaneous and visceral adipose tissue based on a single‐breathhold abdominal MRI (Figure 1).ConclusionWe present a versatile MRI protocol with acquisition and analysis methods that are generally applicable and not geared towards a specific disease or research question. Thus, this protocol may be of specific interest for many neuroimaging applications including population imaging studies.

Versatile MRI acquisition and processing protocol for population‐based neuroimaging

AbstractBackgroundNeuroimaging plays an essential role in epidemiological studies and a special focus is directed towards the employment of versatile MRI acquisition and processing. The proposed multi‐purpose MRI protocol was designed for large‐scale and long‐term population neuroimaging and includes structural, diffusion‐weighted, and functional MRI modalities. It directly links the acquisition of an extensive set of MRI contrasts with fully automated data processing pipelines and quality assurance of the MRI data and image‐derived phenotypes.MethodThe MRI acquisition protocol is largely based on in‐house developed MR sequences. With a total scan time below one hour per participant, it allows to acquire multiple MR contrasts at 3T with whole‐brain coverage and high isotropic image resolution, while keeping potential subject discomfort and motion artifacts at manageable levels. Designed to be kept constant, but also adaptive, the scan protocol separates into a core imaging protocol with MR contrasts of high relevance acquired for all study participants, and a free protocol to accommodate alternative promising MRI techniques in smaller sub‐populations. The analysis protocol handles large‐scale imaging data by means of fast and fully automated processing pipelines that incorporate state‐of‐the‐art image analysis tools and innovative machine learning methods, particularly using deep learning. Dedicated quality assessment (QA) includes visual rating and inspection for incidental findings on structural MRI and QA workflows tailored for each postprocessing pipeline to automatically identify problematic data based on the distribution of subject‐specific QA metrics with respect to the population average.ResultThe MRI protocol has been successfully applied in the Rhineland Study, a prospective cohort study in Bonn, Germany, with currently over 10,000 participants. Image‐derived phenotypes include: global and regional brain tissue volume, thickness and surface measures from multi‐modal structural MRI, global and regional microstructural measures based on diffusion‐weighted MRI, brain functional connectivity using resting‐state functional MRI, and volumes of subcutaneous and visceral adipose tissue based on a single‐breathhold abdominal MRI (Figure 1).ConclusionWe present a versatile MRI protocol with acquisition and analysis methods that are generally applicable and not geared towards a specific disease or research question. Thus, this protocol may be of specific interest for many neuroimaging applications including population imaging studies.

Temporal Statistical Relationship between Regional Cerebral Oxygen Saturation (rSO2) and Brain Tissue Oxygen Tension (PbtO2) in Moderate-to-Severe Traumatic Brain Injury: A Canadian High Resolution-TBI (CAHR-TBI) Cohort Study.

Brain tissue oxygen tension (PbtO2) has emerged as a cerebral monitoring modality following traumatic brain injury (TBI). Near-infrared spectroscopy (NIRS)-based regional cerebral oxygen saturation (rSO2) can non-invasively examine cerebral oxygen content and has the potential for high spatial resolution. Past studies examining the relationship between PbtO2 and NIRS-based parameters have had conflicting results with varying degrees of correlation. Understanding this relationship will help guide multimodal monitoring practices and impact patient care. The aim of this study is to examine the relationship between PbtO2 and rSO2 in a cohort of TBI patients by leveraging contemporary statistical methods. A multi-institutional retrospective cohort study of prospectively collected data was performed. Moderate-to-severe adult TBI patients were included with concurrent rSO2 and PbtO2 monitoring during their stay in the intensive care unit (ICU). The high-resolution data were analyzed utilizing time series techniques to examine signal stationarity as well as the cross-correlation relationship between the change in PbtO2 and the change in rSO2 signals. Finally, modeling of the change in PbtO2 by the change in rSO2 was attempted utilizing linear methods that account for the autocorrelative nature of the data signals. A total of 20 subjects were included in the study. Cross-correlative analysis found that changes in PbtO2 were most significantly correlated with changes in rSO2 one minute earlier. Through mixed-effects and time series modeling of parameters, changes in rSO2 were found to often have a statistically significant linear relationship with changes in PbtO2 that occurred a minute later. However, changes in rSO2 were inadequate to predict changes in PbtO2. In this study, changes in PbtO2 were found to correlate most with changes in rSO2 approximately one minute earlier. While changes in rSO2 were found to contain information about future changes in PbtO2, they were not found to adequately model them. This strengthens the body of literature indicating that NIRS-based rSO2 is not an adequate substitute for PbtO2 in the management of TBI.

Investigating genetically stratified subgroups to better understand the etiology of alcohol misuse.

Alcohol misuse (AM) is highly prevalent and harmful, with theorized subgroups differing on internalizing and externalizing dimensions. Despite known heterogeneity, genome-wide association studies (GWAS) are usually conducted on unidimensional phenotypes. These approaches have identified important genes related to AM but fail to capture a large part of the heritability, even with recent increases in sample sizes. This study aimed to address phenotypic heterogeneity in GWAS to aid gene finding and to uncover the etiology of different types of AM. Genetic and phenotypic data from 410,414 unrelated individuals of multiple ancestry groups (primarily European) in the UK Biobank were obtained. Mixture modeling was applied to measures of alcohol misuse and internalizing/externalizing psychopathology to uncover phenotypically homogenous subclasses, which were carried forward to GWAS and functional annotation. A four-class model emerged with "low risk", "internalizing-light/non-drinkers", "heavy alcohol use-low impairment", and "broad high risk" classes. SNP heritability ranged from 3 to 18% and both known AM signals and novel signals were captured by genomic risk loci. Class comparisons showed distinct patterns of regional brain tissue enrichment and genetic correlations with internalizing and externalizing phenotypes. Despite some limitations, this study demonstrated the utility of genetic research on homogenous subclasses. Not only were novel genetic signals identified that might be used for follow-up studies, but addressing phenotypic heterogeneity allows for the discovery and investigation of differential genetic vulnerabilities in the development of AM, which is an important step towards the goal of personalized medicine.

Comprehensive volumetric phenotyping of the neonatal brain in Down syndrome.

Down syndrome (DS) is the most common genetic cause of intellectual disability with a wide range of neurodevelopmental outcomes. To date, there have been very few in vivo neuroimaging studies of the neonatal brain in DS. In this study we used a cross-sectional sample of 493 preterm- to term-born control neonates from the developing Human Connectome Project to perform normative modeling of regional brain tissue volumes from 32 to 46weeks postmenstrual age, accounting for sex and age variables. Deviation from the normative mean was quantified in 25 neonates with DS with postnatally confirmed karyotypes from the Early Brain Imaging in DS study. Here, we provide the first comprehensive volumetric phenotyping of the neonatal brain in DS, which is characterized by significantly reduced whole brain, cerebral white matter, and cerebellar volumes; reduced relative frontal and occipital lobar volumes, in contrast with enlarged relative temporal and parietal lobar volumes; enlarged relative deep gray matter volume (particularly the lentiform nuclei); and enlargement of the lateral ventricles, amongst other features. In future, the ability to assess phenotypic severity at the neonatal stage may help guide early interventions and, ultimately, help improve neurodevelopmental outcomes in children with DS.

Association of blood pressure with brain perfusion and structure: A population-based prospective study

PurposeTo explore the association of blood pressure (BP) measurements with cerebral blood flow (CBF) and brain structure in general population. MethodThis prospective study included 902 participants from Kailuan community. All participants underwent brain MRI and BP measurements. The association of BP indicators with CBF, brain tissue volume and white matter hyperintensity (WMH) volume were investigated. In addition, mediation analysis was used to determine whether significantly changed brain tissue volume explained associations between BP and CBF. ResultsElevated diastolic BP (DBP), but not systolic BP (SBP), was associated with lower CBF in the total brain (β [95 % CI]: −0.62 [−1.14, −0.10]), total gray matter (β [95 % CI]: −0.71 [−1.27, −0.14]), hippocampus (β [95 % CI]: −0.59 [−1.13, −0.05]), frontal (β [95 % CI]: −0.72 [−1.31, −0.13]), parietal (β [95 % CI]: −0.92 [−1.54, −0.3]), temporal (β [95 % CI]: −0.63 [−1.18, −0.08]), and occipital lobe (β [95 % CI]: −0.69 [−1.37, −0.01]). Higher SBP and DBP were associated with reduced total and regional brain tissue volume (all p < 0.05). Increased SBP and PP were associated with higher total and periventricular WMH volume (all p < 0.05). In addition, mediation analysis identified that significantly decreased brain volume did not mediate the associations of BP measurements and lower CBF in corresponding region (all p > 0.05). ConclusionsElevated BP level was associated with decreased total and regional CBF and brain tissue volume and increased WMH burden.

A single mild juvenile TBI in male mice leads to regional brain tissue abnormalities at 12 months of age that correlate with cognitive impairment at the middle age

Traumatic brain injury (TBI) has the highest incidence amongst the pediatric population and its mild severity represents the most frequent cases. Moderate and severe injuries as well as repetitive mild TBI result in lasting morbidity. However, whether a single mild TBI sustained during childhood can produce long-lasting modifications within the brain is still debated. We aimed to assess the consequences of a single juvenile mild TBI (jmTBI) at 12 months post-injury in a mouse model. Non-invasive diffusion tensor imaging (DTI) revealed significant microstructural alterations in the hippocampus and the in the substantia innominata/nucleus basalis (SI/NB), structures known to be involved in spatial learning and memory. DTI changes paralled neuronal loss, increased astrocytic AQP4 and microglial activation in the hippocampus. In contrast, decreased astrocytic AQP4 expression and microglia activation were observed in SI/NB. Spatial learning and memory were impaired and correlated with alterations in DTI-derived derived fractional ansiotropy (FA) and axial diffusivity (AD). This study found that a single juvenile mild TBI leads to significant region-specific DTI microstructural alterations, distant from the site of impact, that correlated with cognitive discriminative novel object testing and spatial memory impairments at 12 months after a single concussive injury. Our findings suggest that exposure to jmTBI leads to a chronic abnormality, which confirms the need for continued monitoring of symptoms and the development of long-term treatment strategies to intervene in children with concussions.

Abstract 10514: Compromised Cerebral Artery Integrity is Associated With Brain Tissue Injury and Cognition Deficits in Adolescents With Complex Congenital Heart Disease

Introduction: Adolescents with complex congenital heart disease (CCHD) show brain tissue injury in regions associated with cognitive deficits. Alteration in cerebral artery integrity (CAI), as measured by arterial transit time (ATT), may lead to perfusion deficits, and be a potential cause of brain injury in CCHD. To date, there are no reports of CAI in CCHD or associations between CAI, brain tissue integrity, and cognition in CCHD. Methods: 70 subjects (37 CCHD / 33 controls), 14-18 years of age, undergone surgical palliation (CCHD), and no contraindications for a magnetic resonance imaging (MRI) and healthy controls (age- and sex-matched) participated. Participants completed cognitive testing (Montreal Assessment of Cognition [MoCA] and the Wide Range Assessment of Memory and Learning [General Memory Index, GMI]) and brain MRI using 3.0 Tesla scanner. ATT values (via diffusion-weighted pseudo-continuous arterial spin labeling [pCASL] procedures), and regional brain mean diffusivity [MD] (measure of tissue integrity) were computed in whole brain. Descriptive, partial correlations, and ANCOVA analyses used (covariates, age and sex). Results: Mean MoCA [23.1 ± 4.1 vs. 28.1 ± 2.3; p &lt;.001] and GMI scores [86.8 ± 15.4 vs. 110.3 ± 14.5; p&lt;.001] show significant cognitive deficits in CCHD compared to controls. ATT was significantly increased in CCHD vs controls (mean ± SD, sec, 1.3±0.13 vs 1.22±0.13, p=0.02), respectively, indicating compromised CAI. Partial correlations between ATT, MD values, and cognition (covariates, age and sex, p&lt; 0.005) showed significant associations in various areas including the hippocampus, prefrontal cortices, cerebellum, frontal white matter, anterior and posterior cingulate, frontal cortex, temporal cortices, and midbrain. Conclusion: Adolescents with CCHD have prolonged ATTs compared to controls indicative of compromised CAI and altered cerebral perfusion. CAI is significantly associated with alterations in regional brain tissue integrity and cognitive impairment. Further evaluation is needed to test interventions to increase cerebral perfusion and to protect neural tissue.

High Incidence of Intracerebral Hemorrhaging Associated with the Application of Low-Intensity Focused Ultrasound Following Acute Cerebrovascular Injury by Intracortical Injection.

Low-intensity transcranial focused ultrasound (FUS) has gained momentum as a non-/minimally-invasive modality that facilitates the delivery of various pharmaceutical agents to the brain. With the additional ability to modulate regional brain tissue excitability, FUS is anticipated to confer potential neurotherapeutic applications whereby a deeper insight of its safety is warranted. We investigated the effects of FUS applied to the rat brain (Sprague-Dawley) shortly after an intracortical injection of fluorescent interstitial solutes, a widely used convection-enhanced delivery technique that directly (i.e., bypassing the blood–brain-barrier (BBB)) introduces drugs or interstitial tracers to the brain parenchyma. Texas Red ovalbumin (OA) and fluorescein isothiocyanate-dextran (FITC-d) were used as the interstitial tracers. Rats that did not receive sonication showed an expected interstitial distribution of OA and FITC-d around the injection site, with a wider volume distribution of OA (21.8 ± 4.0 µL) compared to that of FITC-d (7.8 ± 2.7 µL). Remarkably, nearly half of the rats exposed to the FUS developed intracerebral hemorrhaging (ICH), with a significantly higher volume of bleeding compared to a minor red blood cell extravasation from the animals that were not exposed to sonication. This finding suggests that the local cerebrovascular injury inflicted by the micro-injection was further exacerbated by the application of sonication, particularly during the acute stage of injury. Smaller tracer volume distributions and weaker fluorescent intensities, compared to the unsonicated animals, were observed for the sonicated rats that did not manifest hemorrhaging, which may indicate an enhanced degree of clearance of the injected tracers. Our results call for careful safety precautions when ultrasound sonication is desired among groups under elevated risks associated with a weakened or damaged vascular integrity.

Optimal bispectral index level of sedation and cerebral oximetry in traumatic brain injury: a non-invasive individualized approach in critical care?

BackgroundImpaired cerebral autoregulation has been linked with worse outcomes, with literature suggesting that current therapy guidelines fail to significantly impact cerebrovascular reactivity. The cerebral oximetry index (COx_a) is a surrogate measure of cerebrovascular reactivity which can in theory be obtained non-invasively using regional brain tissue oxygen saturation and arterial blood pressure. The goal of this study was to assess the relationship between objectively measured depth of sedation through BIS and autoregulatory capacity measured through COx_a.MethodsIn a prospectively maintained observational study, we collected continuous regional brain tissue oxygen saturation, intracranial pressure, arterial blood pressure and BIS in traumatic brain injury patients. COx_a was obtained using the Pearson’s correlation between regional brain tissue oxygen saturation and arterial blood pressure and ranges from − 1 to 1 with higher values indicating impairment of cerebrovascular reactivity. Using BIS values and COx_a, a curve-fitting method was applied to determine the minimum value for the COx_a. The associated BIS value with the minimum COx_a is called BISopt. This BISopt was both visually and algorithmically determined, which were compared and assessed over the whole dataset.ResultsOf the 42 patients, we observed that most had a parabolic relationship between BIS and COx_a. This suggests a potential “optimal” depth of sedation where COx_a is the most intact. Furthermore, when comparing the BISopt algorithm with visual inspection of BISopt, we obtained similar results. Finally, BISopt % yield (determined algorithmically) appeared to be independent from any individual sedative or vasopressor agent, and there was agreement between BISopt found with COx_a and the pressure reactivity index (another surrogate for cerebrovascular reactivity).ConclusionsThis study suggests that COx_a is capable of detecting disruption in cerebrovascular reactivity which occurs with over-/under-sedation, utilizing a non-invasive measure of determination and assessment. This technique may carry implications for tailoring sedation in patients, focusing on individualized neuroprotection.

AUTOMATIC SEGMENTATION OF INFANT BRAIN MRI USING SOFT COMPUTING TECHNIQUES

This article is concerned with exploration and diagnostic implementation of an effective neo-anatomical brain MRI classification method to classify primal cognitive development and investigate neuro-anatomical intellectual disability correlations. A crucial stage in the research as well as appraisal of the newborn brain growth is neonatal brain tissue classification. Owing to the major variations in anatomy and tissues among neonate and mature brains, the largest proportion of developing technology for the classification and segmentation of the adult brain really aren''''t sufficient for newborns brain. The existing brain tissue classification strategies for MRIs rely either on manual interactions or involve the use of atlases or models, which ultimately skew the findings from the population used to extract atlas. This article, focuses on atlas free soft computing approach to classify the neonatal brain tissue. Classification of brain tissue is the main process in which regional brain tissue examination is conducted. This helps the regional brain development to be characterized and the correspondence with therapeutic conditions to be studied. The modified BM3D approach is utilized for image enhancement along with 32 Gabor filter bank based feature extraction. The innovative aspect of this research is the multistage classification methodology, which produces higher dice coefficients and lower MHD values when compared to existing approaches.

Default-Mode Network Connectivity Changes Correlate with Attention Deficits in ALL Long-Term Survivors Treated with Radio- and/or Chemotherapy.

Simple SummaryBoth chemotherapy and radiotherapy play a role in the neurocognitive impairment of long-term survivors from acute lymphoblastic leukemia, but it is unknown if similar mechanisms are involved. We assessed neurocognitive alterations, brain tissue volumes, and functional connectivity of the main hubs of the default-mode network, in 13 patients treated with chemotherapy and radiotherapy (Group A) and in 13 treated with chemotherapy only (Group B). Correlations with neuropsychological scores, independent of group, were assessed for regions that showed significant differences between the two groups at neuroimaging. Compared to Group B, Group A performed significantly worse at the digit span and digit symbol tests and showed increased functional connectivity between the medial prefrontal cortex and the rolandic operculi, along with the absence of differences in regional brain tissue volumes. Functional connectivity in these regions correlated inversely with speed of processing in both groups, suggesting that similar mechanisms may be involved in the neurocognitive deficits in both groups.Whether chemotherapy (ChT) and radiotherapy (RT) determine neurocognitive impairment in acute lymphoblastic leukemia long-term survivors (ALL LTSs) through similar mechanisms affecting the same brain regions is still unknown. We compared neurocognitive alterations, regional brain tissue volumes (by voxel-based morphometry), and functional connectivity of the main default-mode network hubs (by seed-based analysis of resting state functional MRI data), in 13 ALL LTSs treated with RT and ChT (Group A) and 13 treated with ChT only (Group B). Group A performed significantly worse than Group B at the digit span and digit symbol tests (p = 0.023 and 0.013, respectively). Increased connectivity between the medial prefrontal cortex (the main anterior hub of the default-mode network) and the rolandic operculi was present in Group A compared to Group B, along with the absence of significant differences in regional brain tissue volumes. In these regions, the functional connectivity correlated inversely with the speed of processing scores, independent of treatment group. These results suggest that similar mechanisms may be involved in the neurocognitive deficits in ALL LTS patients, regardless of the treatment group. Further studies are needed to clarify whether these changes represent a direct expression of the mechanisms underlying the cognitive deficits or ineffective compensatory phenomena.

Consideration of Time From Planning to Treatment for Frameless Fractionated Stereotactic Radiosurgery in Patients With Intact Large Brain Metastases

Patients with large brain metastases may receive fractionated stereotactic radiosurgery (FSRS) if they are not surgical candidates yet still pursuing cancer-directed therapy. FSRS with limited margins can allow for optimal sparing of uninvolved regional brain tissue. However, due to required treatment planning process, there is often elapsed time between MRI brain and treatment start which may contribute to marginal misses. Growth rates of large brain metastases and implications for optimal margin to account for growth rate and time interval between planning MRI and FSRS are incompletely characterized.Patients treated at a single institution from 2018-2020 who received frameless FSRS on a Cobalt-60 treatment unit for large (> 2cm diameter) brain metastases were identified. Patients with a prior diagnostic brain MRI scan with technically similar parameters to a second MRI obtained for treatment planning were included. Resection cavities and lesions undergoing re-treatment after prior SRS were excluded. Brain metastasis volumes were obtained by contouring on both diagnostic and planning MRIs. Patient characteristics and treatment details were also collected. Analysis was conducted using paired Student's t test and Pearson's R and growth rate was determined using a linear model.Thirty-six patients with 54 brain metastases met inclusion criteria. The most common primary cancer sites were lung (36%), colorectal (14%), and skin (14%), and most common histologies were adenocarcinoma (53%) and melanoma (17%). Nearly half (47%) of patients were on systemic therapy at the time of FSRS and the majority (85%) received steroids prior to starting FSRS. Treatment dose ranged from 24-32.5 Gy in 3-5 fractions, with median of 30 Gy in 5 fractions with zero margin. Median time from diagnostic to planning MRI was 15 days (IQR: 11-21) and planning MRI to FSRS was 1 day (IQR 1-3). The median size of included brain metastases on planning MRI was 7.38cc (IQR: 5.09-11.55) compared to 6.03cc (IQR: 3.87-8.95) on prior diagnostic MRI (P < 0.001). Eight metastases (15%) decreased in size in the context of concurrent central nervous system-penetrant systemic therapy or steroids. Median calculated daily growth was 0.10cc (2.37%) per day (IQR: 0.02-0.21cc, 0.41-3.78%). There was no significant association between lesion growth rate and histology, intracranial location, steroid use, and baseline tumor size. A 1.0 mm, 1.5 mm, 2.0 mm, and 2.5 mm margin would have covered anticipated growth in > 90% of lesions over 3, 7, 10, and 14 days between planning and treatment, respectively.In the absence of expedited planning, FSRT for intact large brain metastases with limited margins may result in geometric under treatment. An adaptive margin strategy based upon initial tumor size, and time between planning imaging and treatment delivery may be afforded to maintain ideal conformity, properly targeting a growing target lesion while maximally sparing uninvolved regional brain.J. Chew: None. S. Sinha: None. S.J. Liu: None. S.E. Fogh: Independent Contractor; Accuray. L. Boreta: None. D. Raleigh: None. L. Ma: Patent/License Fees/Copyright; University of California Regents. S.E. Braunstein: Advisory Board; Radiation Oncology Questions, LLC.

Regional brain tissue changes in patients with cystic fibrosis

BackgroundCystic fibrosis (CF) patients present with a variety of symptoms, including mood and cognition deficits, in addition to classical respiratory, and autonomic issues. This suggests that brain injury, which can be examined with non-invasive magnetic resonance imaging (MRI), is a manifestation of this condition. However, brain tissue integrity in sites that regulate cognitive, autonomic, respiratory, and mood functions in CF patients is unclear. Our aim was to assess regional brain changes using high-resolution T1-weighted images based gray matter (GM) density and T2-relaxometry procedures in CF over control subjects.MethodsWe acquired high-resolution T1-weighted images and proton-density (PD) and T2-weighted images from 5 CF and 15 control subjects using a 3.0-Tesla MRI. High-resolution T1-weighted images were partitioned to GM-tissue type, normalized to a common space, and smoothed. Using PD- and T2-weighted images, whole-brain T2-relaxation maps were calculated, normalized, and smoothed. The smoothed GM-density and T2-relaxation maps were compared voxel-by-voxel between groups using analysis of covariance (covariates, age and sex; SPM12, p < 0.001).ResultsSignificantly increased GM-density, indicating tissues injury, emerged in multiple brain regions, including the cerebellum, hippocampus, amygdala, basal forebrain, insula, and frontal and prefrontal cortices. Various brain areas showed significantly reduced T2-relaxation values in CF subjects, indicating predominant acute tissue changes, in the cerebellum, cerebellar tonsil, prefrontal and frontal cortices, insula, and corpus callosum.ConclusionsCystic fibrosis subjects show predominant acute tissue changes in areas that control mood, cognition, respiratory, and autonomic functions and suggests that tissue changes may contribute to symptoms resulting from ongoing hypoxia accompanying the condition.

Transcranial focused ultrasound modulates cortical and thalamic motor activity in awake sheep

Transcranial application of pulsed low-intensity focused ultrasound (FUS) modulates the excitability of region-specific brain areas, and anesthetic confounders on brain activity warrant the evaluation of the technique in awake animals. We examined the neuromodulatory effects of FUS in unanesthetized sheep by developing a custom-fit headgear capable of reproducibly placing an acoustic focus on the unilateral motor cortex (M1) and corresponding thalamic area. The efferent responses to sonication, based on the acoustic parameters previously identified in anesthetized sheep, were measured using electromyography (EMG) from both hind limbs across three experimental conditions: on-target sonication, off-target sonication, and without sonication. Excitatory sonication yielded greater amplitude of EMG signals obtained from the hind limb contralateral to sonication than that from the ipsilateral limb. Spurious appearance of motion-related EMG signals limited the amount of analyzed data (~ 10% selection of acquired data) during excitatory sonication, and the averaged EMG response rates elicited by the M1 and thalamic stimulations were 7.5 ± 1.4% and 6.7 ± 1.5%, respectively. Suppressive sonication, while sheep walked on the treadmill, temporarily reduced the EMG amplitude from the limb contralateral to sonication. No significant change was found in the EMG amplitudes during the off-target sonication. Behavioral observation throughout the study and histological analysis showed no sign of brain tissue damage caused by the acoustic stimulation. Marginal response rates observed during excitatory sonication call for technical refinement to reduce motion artifacts during EMG acquisitions as well as acoustic aberration correction schemes to improve spatial accuracy of sonication. Yet, our results indicate that low-intensity FUS modulated the excitability of regional brain tissues reversibly and safely in awake sheep, supporting its potential in theragnostic applications.

Regional Brain Tissue Displacement and Strain is Elevated in Subjects with Chiari Malformation Type I Compared to Healthy Controls: A Study Using DENSE MRI.

While the degree of cerebellar tonsillar descent is considered the primary radiologic marker of Chiari malformation type I (CMI), biomechanical forces acting on the brain tissue in CMI subjects are less studied and poorly understood. In this study, regional brain tissue displacement and principal strains in 43 CMI subjects and 25 controls were quantified using a magnetic resonance imaging (MRI) methodology known as displacement encoding with stimulated echoes (DENSE). Measurements from MRI were obtained for seven different brain regions-the brainstem, cerebellum, cingulate gyrus, corpus callosum, frontal lobe, occipital lobe, and parietal lobe. Mean displacements in the cerebellum and brainstem were found to be 106 and 64% higher, respectively, for CMI subjects than controls (p < .001). Mean compression and extension strains in the cerebellum were 52 and 50% higher, respectively, in CMI subjects (p < .001). Brainstem mean extension strain was 41% higher in CMI subjects (p < .001), but no significant difference in compression strain was observed. The other brain structures revealed no significant differences between CMI and controls. These findings demonstrate that brain tissue displacement and strain in the cerebellum and brainstem might represent two new biomarkers to distinguish between CMI subjects and controls.