Reversibility of Cognitive Deficits and Functional Connectivity With Transfusion in Children With Sickle Cell Disease.

BACKGROUND AND OBJECTIVES: People with sickle cell disease (SCD) are at risk of cognitive dysfunction independent of stroke. Diminished functional connectivity in select large-scale networks and white matter integrity reflect the neurologic consequences of SCD. Because chronic transfusion therapy is neuroprotective in preventing stroke and strengthening executive function abilities in people with SCD, we hypothesized that red blood cell (RBC) transfusion facilitates the acute reversal of disruptions in functional connectivity while white matter integrity remains unaffected. METHODS: Children with SCD receiving chronic transfusion therapy underwent a brain MRI measuring white matter integrity with diffusion tensor imaging and resting-state functional connectivity within 3 days before and after transfusion of RBCs. Cognitive assessments with the NIH Toolbox were acquired after transfusion and then immediately before the following transfusion cycle. RESULTS: Sixteen children with a median age of 12.5 years were included. Global assessments of functional connectivity using homotopy (p = 0.234) or modularity (p = 0.796) did not differ with transfusion. Functional connectivity within the frontoparietal network significantly strengthened after transfusion (median intranetwork Z-score 0.21 [0.17-0.30] before transfusion, 0.29 [0.20-0.36] after transfusion, p < 0.001), while there was not a significant change seen within the sensory motor, visual, auditory, default mode, dorsal attention, or cingulo-opercular networks. Corresponding to the change within the frontoparietal network, there was a significant improvement in executive function abilities after transfusion (median executive function composite score 87.7 [81.3-90.7] before transfusion, 90.3 [84.3-93.7] after transfusion, p = 0.021). Participants with stronger connectivity in the frontoparietal network before transfusion had a significantly greater improvement in the executive function composite score with transfusion (r = 0.565, 95% CI 0.020-0.851, p = 0.044). While functional connectivity and executive abilities strengthened with transfusion, there was not a significant change in white matter integrity as assessed by fractional anisotropy and mean diffusivity within 16 white matter tracts or globally with tract-based spatial statistics. DISCUSSION: Strengthening of functional connectivity with concomitant improvement in executive function abilities with transfusion suggests that functional connectivity MRI could be used as a biomarker for acutely reversible neurocognitive injury as novel therapeutics are developed for people with SCD.

Real-time motion monitoring improves functional MRI data quality in infants.

Imaging the infant brain with MRI has improved our understanding of early neurodevelopment. However, head motion during MRI acquisition is detrimental to both functional and structural MRI scan quality. Though infants are typically scanned while asleep, they commonly exhibit motion during scanning causing data loss. Our group has shown that providing MRI technicians with real-time motion estimates via Framewise Integrated Real-Time MRI Monitoring (FIRMM) software helps obtain high-quality, low motion fMRI data. By estimating head motion in real time and displaying motion metrics to the MR technician during an fMRI scan, FIRMM can improve scanning efficiency. Here, we compared average framewise displacement (FD), a proxy for head motion, and the amount of usable fMRI data (FD ≤ 0.2 mm) in infants scanned with (n = 407) and without FIRMM (n = 295). Using a mixed-effects model, we found that the addition of FIRMM to current state-of-the-art infant scanning protocols significantly increased the amount of usable fMRI data acquired per infant, demonstrating its value for research and clinical infant neuroimaging.

Cerebral oxygen metabolic stress is increased in children with sickle cell anemia compared to anemic controls.

Patients with sickle cell anemia (SCA) experience cerebral metabolic stress with an increase in oxygen extraction fraction (OEF) to compensate for reduced oxygen carrying capacity due to anemia. It remains unclear if anemia alone drives this metabolic stress. Using MRI, we collected voxel-wise OEF measurements to test our hypothesis that OEF would be elevated in anemic controls without SCA (AC) compared to healthy controls (HC), but OEF would be even higher in SCA compared to AC. Brain MRIs (N = 159) were obtained in 120 participants (34 HC, 27 AC, 59 SCA). While hemoglobin was lower in AC versus HC (p < 0.001), hemoglobin was not different between AC and SCA cohorts (p = 0.459). Whole brain OEF was higher in AC compared to HC (p < 0.001), but lower compared to SCA (p = 0.001). Whole brain OEF remained significantly higher in SCA compared to HC (p = 0.001) while there was no longer a difference between AC versus HC (p = 0.935) in a multivariate model controlling for age and hemoglobin. OEF peaked within the border zone regions of the brain in both SCA and AC cohorts, but the volume of white matter with regionally elevated OEF in AC was smaller (1.8%) than SCA (58.0%). While infarcts colocalized within regions of elevated OEF, more SCA participants had infarcts than AC (p < 0.001). We conclude that children with SCA experience elevated OEF compared to AC and HC after controlling for the impact of anemia, suggesting that there are other pathophysiologic factors besides anemia contributing to cerebral metabolic stress in children with SCA.

Functional Connectivity Decreases with Metabolic Stress in Sickle Cell Disease.

OBJECTIVE: Children with sickle cell disease (SCD) experience cognitive deficits even when unaffected by stroke. Using functional connectivity magnetic resonance imaging (MRI) as a potential biomarker of cognitive function, we tested our hypothesis that children with SCD would have decreased functional connectivity, and that children experiencing the greatest metabolic stress, indicated by elevated oxygen extraction fraction, would have the lowest connectivity. METHODS: We prospectively obtained brain MRIs and cognitive testing in healthy controls and children with SCD. RESULTS: We analyzed data from 60 participants (20 controls and 40 with sickle cell disease). There was no difference in global cognition or cognitive subdomains between cohorts. However, we found decreased functional connectivity within the sensory-motor, lateral sensory-motor, auditory, salience, and subcortical networks in participants with SCD compared with controls. Further, as white matter oxygen extraction fraction increased, connectivity within the visual (p = 0.008, parameter estimate = -0.760 [95% CI = -1.297, -0.224]), default mode (p = 0.012, parameter estimate = -0.417 [95% CI = -0.731, -0.104]), and cingulo-opercular (p = 0.009, parameter estimate = -0.883 [95% CI = -1.517, -0.250]) networks decreased. INTERPRETATION: We conclude that there is diminished functional connectivity within these anatomically contiguous networks in children with SCD compared with controls, even when differences are not seen with cognitive testing. Increased white matter oxygen extraction fraction was associated with decreased connectivity in select networks. These data suggest that elevated oxygen extraction fraction and disrupted functional connectivity are potentially presymptomatic neuroimaging biomarkers for cognitive decline in SCD. ANN NEUROL 2020;88:995-1008.

Correction of respiratory artifacts in MRI head motion estimates.

Head motion represents one of the greatest technical obstacles in magnetic resonance imaging (MRI) of the human brain. Accurate detection of artifacts induced by head motion requires precise estimation of movement. However, head motion estimates may be corrupted by artifacts due to magnetic main field fluctuations generated by body motion. In the current report, we examine head motion estimation in multiband resting state functional connectivity MRI (rs-fcMRI) data from the Adolescent Brain and Cognitive Development (ABCD) Study and comparison 'single-shot' datasets. We show that respirations contaminate movement estimates in functional MRI and that respiration generates apparent head motion not associated with functional MRI quality reductions. We have developed a novel approach using a band-stop filter that accurately removes these respiratory effects from motion estimates. Subsequently, we demonstrate that utilizing a band-stop filter improves post-processing fMRI data quality. Lastly, we demonstrate the real-time implementation of motion estimate filtering in our FIRMM (Framewise Integrated Real-Time MRI Monitoring) software package.

How to Appropriately Calculate Effective Dose for CT Using Either Size-Specific Dose Estimates or Dose-Length Product.

OBJECTIVE: The purpose of this study is to show how to calculate effective dose in CT using size-specific dose estimates and to correct the current method using dose-length product (DLP). MATERIALS AND METHODS: Data were analyzed from 352 chest and 241 abdominopelvic CT images. Size-specific dose estimate was used as a surrogate for organ dose in the chest and abdominopelvic regions. Organ doses were averaged by patient weight-based populations and were used to calculate effective dose by the International Commission on Radiological Protection (ICRP) report 103 method using tissue-weighting factors (EICRP). In addition, effective dose was calculated using population-averaged CT examination DLP for the chest and abdominopelvic region using published k-coefficients (EDLP = k × DLP). RESULTS: EDLP differed from EICRP by an average of 21% (1.4 vs 1.1) in the chest and 42% (2.4 vs 3.4) in the abdominopelvic region. The differences occurred because the published kcoefficients did not account for pitch factor other than unity, were derived using a 32-cm diameter CT dose index (CTDI) phantom for CT examinations of the pediatric body, and used ICRP 60 tissue-weighting factors. Once it was corrected for pitch factor, the appropriate size of CTDI phantom, and ICRP 103 tissue-weighting factors, EDLP improved in agreement with EICRP to better than 7% (1.4 vs 1.3) and 4% (2.4 vs 2.5) for chest and abdominopelvic regions, respectively. CONCLUSION: Current use of DLP to calculate effective dose was shown to be deficient because of the outdated means by which the k-coefficients were derived. This study shows a means to calculate EICRP using patient size-specific dose estimate and how to appropriately correct EDLP.

Size-specific dose estimate (SSDE) provides a simple method to calculate organ dose for pediatric CT examinations.

PURPOSE: To investigate the correlation of size-specific dose estimate (SSDE) with absorbed organ dose, and to develop a simple methodology for estimating patient organ dose in a pediatric population (5-55 kg). METHODS: Four physical anthropomorphic phantoms representing a range of pediatric body habitus were scanned with metal oxide semiconductor field effect transistor (MOSFET) dosimeters placed at 23 organ locations to determine absolute organ dose. Phantom absolute organ dose was divided by phantom SSDE to determine correlation between organ dose and SSDE. Organ dose correlation factors (CF(organ)(SSDE)) were then multiplied by patient-specific SSDE to estimate patient organ dose. The [CF(organ)(SSDE)) were used to retrospectively estimate individual organ doses from 352 chest and 241 abdominopelvic pediatric CT examinations, where mean patient weight was 22 kg ± 15 (range 5-55 kg), and mean patient age was 6 yrs ± 5 (range 4 months to 23 yrs). Patient organ dose estimates were compared to published pediatric Monte Carlo study results. RESULTS: Phantom effective diameters were matched with patient population effective diameters to within 4 cm; thus, showing appropriate scalability of the phantoms across the entire pediatric population in this study. Individual CF(organ)(SSDE) were determined for a total of 23 organs in the chest and abdominopelvic region across nine weight subcategories. For organs fully covered by the scan volume, correlation in the chest (average 1.1; range 0.7-1.4) and abdominopelvic region (average 0.9; range 0.7-1.3) was near unity. For organ/tissue that extended beyond the scan volume (i.e., skin, bone marrow, and bone surface), correlation was determined to be poor (average 0.3; range: 0.1-0.4) for both the chest and abdominopelvic regions, respectively. A means to estimate patient organ dose was demonstrated. Calculated patient organ dose, using patient SSDE and CF(organ)(SSDE), was compared to previously published pediatric patient doses that accounted for patient size in their dose calculation, and was found to agree in the chest to better than an average of 5% (27.6/26.2) and in the abdominopelvic region to better than 2% (73.4/75.0). CONCLUSIONS: For organs fully covered within the scan volume, the average correlation of SSDE and organ absolute dose was found to be better than ± 10%. In addition, this study provides a complete list of organ dose correlation factors (CF(organ)(SSDE)) for the chest and abdominopelvic regions, and describes a simple methodology to estimate individual pediatric patient organ dose based on patient SSDE.