pydesigner-v10-pythonic-implementation-designer-pipeline-for

PyDesigner v1.0: A Pythonic Implementation of the DESIGNER Pipeline for Diffusion Magnetic Resonance Imaging

PyDesigner is a Python-based software package based on the original Diffusion parameter EStImation with Gibbs and NoisE Removal (DESIGNER) pipeline (Dv1) ...

Medical University of South Carolina

Persistent oxidative stress depletes reduced glutathione (GSH), an intracellular antioxidant and an important determinant of CNS injury after hypoxia ischemia. We used standard, short echo time Stimulated Echo Acquisition Mode (STEAM) to detect GSH by magnetic resonance spectroscopy (MRS) in 24 term neonates with hypoxic-ischemic encephalopathy (HIE), on day of life 5-6, after rewarming from therapeutic hypothermia. MRS demonstrated reliable, consistent GSH of 1·64 ± 0·20 mM in the basal ganglia immediately before intravenous infusion of N-acetylcysteine. N-acetylcysteine resulted in a rapid and significant GSH increase to 1·93 ± 0.23 mM within 12-30 min after completion of infusion ( n = 21, p < 0.0001, paired t-test), compared with those who did not receive N-acetylcysteine ( n = 3, GSH = 1.66 ± 0.06 mM and 1.64 ± 0.09 mM). In one perinatal stroke patient, GSH in the diffusion-restricted stroke area was 1.0 mM, indicating significant compromise of intracellular redox potential, which also improved after N-acetylcysteine. For comparison, GSH in healthy term neonates has been reported at 2.5 ± 0.9 mM in the thalamus. This is the first report to show persistent oxidative stress reflected in GSH during the subacute phase in neonates with HIE and rapid response to N-acetylcysteine, using a short echo MRS sequence that is available on all clinical scanners without spectral editing.

N-Acetylcysteine rapidly replenishes central nervous system glutathione measured via magnetic resonance spectroscopy in human neonates with hypoxic-ischemic encephalopathy.

Little attention has been paid to relating MRS outputs of vendor-supplied platforms to those from research software. This comparison is crucial to advance MRS as a clinical prognostic tool for disease or injury, recovery, and outcome. The work presented here investigates the agreement between metabolic ratios reported from vendor-provided and LCModel fitting algorithms using MRS data obtained on Siemens 3 T TIM Trio and 3 T Skyra MRI scanners in a total of 55 premature infants and term neonates with hypoxic ischemic encephalopathy (HIE). We compared peak area ratios in single voxels placed in basal ganglia (BG) and frontal white matter (WM) using standard PRESS (TE = 30 ms and 270 ms) and STEAM (TE = 20 ms) MRS sequences at multiple times after birth from 5 to 60 days. A total of 74 scans met quality standards for inclusion, reflecting a spectrum of neonatal disease and several months of early infant development. For the long TE PRESS sequence, N-acetylaspartate (NAA) and Choline (Cho) ratios to Creatine (Cr) correlated strongly between LCModel and vendor-supplied software in the BG. For shorter TEs, the ratios of NAA/Cr and Cho/Cr were more closely related using STEAM at TE = 20 ms in BG and WM, which was significantly better than using PRESS at TE = 30 ms in the BG of HIE infants. At short TEs, however, it is still unclear which MRS sequence, STEAM or PRESS, is superior and thus more work is required in this regard for translating research-generated MRS ratios to clinical diagnosis and prognostication, and unlocking the potential of MRS for in vivo metabolomics. MRS at both long and short TEs is desirable for standard metabolites such as NAA, Cho and Cr, along with important lower concentration metabolites such as myo-inositol and glutathione.

Identifying the translational complexity of magnetic resonance spectroscopy in neonates and infants.

The inverse Funk transform of high angular resolution diffusion imaging (HARDI) data provides an estimate for the fiber orientation density function (fODF) in white matter (WM). Since the inverse Funk transform is a straightforward linear transformation, this technique, referred to as fiber ball imaging (FBI), offers a practical means of calculating the fODF that avoids the need for a response function or nonlinear numerical fitting. Nevertheless, the accuracy of FBI depends on both the choice of b-value and the number of diffusion-encoding directions used to acquire the HARDI data. To inform the design of optimal scan protocols for its implementation, FBI predictions are investigated here with in vivo data from healthy adult volunteers acquired at 3 T for b-values spanning 1000 to 10,000 s/mm, for diffusion-encoding directions varying in number from 30 to 256 and for TE ranging from 90 to 120 ms. Our results suggest b-values above 4000 s/mm with at least 64 diffusion-encoding directions are adequate to achieve reasonable accuracy with FBI for calculating axon-specific diffusion measures and for performing WM fiber tractography (WMFT).

Optimization of data acquisition and analysis for fiber ball imaging.

To demonstrate how triple diffusion encoding (TDE) MRI can be applied to separately estimate the intra-axonal and extra-axonal diffusion tensors in white matter (WM).

Triple diffusion encoding MRI predicts intra-axonal and extra-axonal diffusion tensors in white matter.

Neonatal abstinence syndrome (NAS) is a significant problem. Opioid withdrawal induces oxidative stress and disrupts glutamate and glutathione homeostasis. We hypothesized that N-acetylcysteine (NAC) administered during acute opioid withdrawal in neonatal rats would decrease withdrawal behaviors and normalize CNS glutathione and glutamate.

N-acetylcysteine mitigates acute opioid withdrawal behaviors and CNS oxidative stress in neonatal rats.

To demonstrate an optimized rectification strategy for fiber orientation density functions (fODFs).

Optimized rectification of fiber orientation density function.

Therapeutic hypothermia does not improve outcomes in neonatal hypoxia ischemia (HI) complicated by perinatal infection, due to well-described, pre-existing oxidative stress and neuroinflammation that shorten the therapeutic window. For effective neuroprotection post-injury, we must first define and then target CNS metabolomic changes immediately after endotoxin-sensitized HI (LPS-HI). We hypothesized that LPS-HI would acutely deplete reduced glutathione (GSH), indicating overwhelming oxidative stress in spite of hypothermia treatment in neonatal rats. Post-natal day 7 rats were randomized to sham ligation, or severe LPS-HI (0.5 mg/kg 4 h before right carotid artery ligation, 90 min 8% O), followed by hypothermia alone or with -acetylcysteine (25 mg/kg) and vitamin D (1,25(OH)D, 0.05 μg/kg) (NVD). We quantified in vivo CNS metabolites by serial 7T MR Spectroscopy before, immediately after LPS-HI, and after treatment, along with terminal plasma drug concentrations. GSH was significantly decreased in all LPS-HI rats compared with baseline and sham controls. Two hours of hypothermia alone did not improve GSH and allowed glutamate + glutamine (GLX) to increase. Within 1 h of administration, NVD increased GSH close to baseline and suppressed GLX. The combination of NVD with hypothermia rapidly improved cellular redox status after LPS-HI, potentially inhibiting important secondary injury cascades and allowing more time for hypothermic neuroprotection.

NAC and Vitamin D Restore CNS Glutathione in Endotoxin-Sensitized Neonatal Hypoxic-Ischemic Rats.

The fiber orientation density function (fODF) in white matter is a primary physical quantity that can be estimated with diffusion MRI. It has often been employed for fiber tracking and microstructural modeling. Requirements for the construction of high fidelity fODFs, in the sense of having good angular resolution, adequate data to avoid sampling errors, and minimal noise artifacts, are described for fODFs calculated with fiber ball imaging. A criterion is formulated for the number of diffusion encoding directions needed to achieve a given angular resolution. The advantages of using large b-values (≥6000 s/mm ) are also discussed. For the direct comparison of different fODFs, a method is developed for defining a local frame of reference tied to each voxel's individual axonal structure. The Matusita anisotropy axonal is proposed as a scalar fODF measure for quantifying angular variability. Experimental results, obtained at 3 T from human volunteers, are used as illustrations.

High fidelity fiber orientation density functions from fiber ball imaging.

N-acetylcysteine (NAC) and vitamin D provide effective neuroprotection in animal models of severe or inflammation-sensitized hypoxic ischemic encephalopathy (HIE). To translate these FDA-approved drugs to HIE neonates, we conducted an early phase, open-label trial of 10 days of NAC (25, 40 mg/kg q12h) + 1,25(OH)D (calcitriol 0.05 mg/kg q12h, 0.03 mg/kg q24h), (NVD), for pharmacokinetic (PK) estimates during therapeutic hypothermia and normothermia. We paired PK samples with pharmacodynamic (PD) targets of plasma isoprostanoids, CNS glutathione (GSH) and total creatine (tCr) by serial MRS in basal ganglia (BG) before and after NVD infusion at five days. Infants had moderate ( = 14) or severe HIE ( = 16), funisitis (32%), and vitamin D deficiency (75%). NVD resulted in rapid, dose-responsive increases in CNS GSH and tCr that correlated positively with plasma [NAC], inversely with plasma isofurans, and was greater in infants with lower baseline [GSH] and [tCr], suggesting increases in these PD markers were titrated by neural demand. Hypothermia and normothermia altered NAC PK estimates. NVD was well tolerated. Excluding genetic syndromes (2), prolonged ECMO (2), lost-to-follow-up (1) and SIDS death (1), 24 NVD treated HIE infants have no evidence of cerebral palsy, autism or cognitive delay at 24-48 months. These data confirm that low, safe doses of NVD in HIE neonates decreased oxidative stress in plasma and CNS, improved CNS energetics, and are associated with favorable developmental outcomes at two to four years.

NAC and Vitamin D Improve CNS and Plasma Oxidative Stress in Neonatal HIE and Are Associated with Favorable Long-Term Outcomes.

Preterm infants are at risk for overt and silent CNS injury, with developmental consequences that are difficult to predict. The novel Specific Test of Early Infant Motor Performance, administered in preterm infants at term age, is indicative of later developmental gross motor and cognitive scores at 12 months. Here, we assessed whether functional performance on this early assessment correlates with CNS integrity via MR spectroscopy or diffusional kurtosis imaging and whether these quantitative neuroimaging methods improve predictions for future 12-month developmental scores.

Quantitative Diffusion and Spectroscopic Neuroimaging Combined with a Novel Early-Developmental Assessment Improves Models for 1-Year Developmental Outcomes.

Transcutaneous auricular vagus nerve stimulation (taVNS) is a non-invasive neuromodulation technique that may improve oromotor skills when paired with feeding in at-risk infants, but effects on other motor function and how motor function relates to white matter (WM) microstructure are unknown.

Transcutaneous auricular vagus nerve stimulation (taVNS) given for poor feeding in at-risk infants also improves their motor abilities.

Age-related white matter degeneration is characterized by myelin breakdown and neuronal fiber loss that preferentially occur in regions that myelinate later in development. Conventional diffusion MRI (dMRI) has demonstrated age-related increases in diffusivity but provide limited information regarding the tissue-specific changes driving these effects. A recently developed dMRI biophysical modeling technique, Fiber Ball White Matter (FBWM) modeling, offers enhanced biological interpretability by estimating microstructural properties specific to the intra-axonal and extra-axonal spaces. We used FBWM to illustrate the biological mechanisms underlying changes throughout white matter in healthy aging using data from 63 cognitively unimpaired adults ages 45-85 with no radiological evidence of neurodegeneration or incipient Alzheimer's disease. Conventional dMRI and FBWM metrics were computed for two late-myelinating (genu of the corpus callosum and association tracts) and two early-myelinating regions (splenium of the corpus callosum and projection tracts). We examined the associations between age and these metrics in each region and tested whether age was differentially associated with these metrics in late- vs. early-myelinating regions. We found that conventional metrics replicated patterns of age-related increases in diffusivity in late-myelinating regions. FBWM additionally revealed specific intra- and extra-axonal changes suggestive of myelin breakdown and preferential loss of smaller-diameter axons, yielding  corroboration of findings from histopathological studies of aged brains. These results demonstrate that advanced biophysical modeling approaches, such as FBWM, offer novel information about the microstructure-specific alterations contributing to white matter changes in healthy aging. These tools hold promise as sensitive indicators of early pathological changes related to neurodegenerative disease.

Fiber Ball White Matter Modeling Reveals Microstructural Alterations in Healthy Brain Aging.

To describe an optimized fiber orientation density function (fODF) rectification procedure that removes negative values and absorbs all features below a specified threshold into a constant background.

Optimized rectification of fiber orientation density function with background threshold.

To determine whether transcutaneous auricular vagus nerve stimulation (taVNS) paired with twice daily bottle feeding increases the volume of oral feeds and white matter neuroplasticity in term-age-equivalent infants failing oral feeds and determined to need a gastrostomy tube.

Higher Dose Noninvasive Transcutaneous Auricular Vagus Nerve Stimulation Increases Feeding Volumes and White Matter Microstructural Complexity in Open-Label Study of Infants Slated for Gastrostomy Tube.

Article	Year
N-Acetylcysteine rapidly replenishes central nervous system glutathione measured via magnetic resonance spectroscopy in human neonates with hypoxic-ischemic encephalopathy. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism\| PubMed ID: 29561203	2018
Identifying the translational complexity of magnetic resonance spectroscopy in neonates and infants. NMR in biomedicine\| PubMed ID: 30924565	2019
Optimization of data acquisition and analysis for fiber ball imaging. NeuroImage\| PubMed ID: 31284026	2019
Triple diffusion encoding MRI predicts intra-axonal and extra-axonal diffusion tensors in white matter. Magnetic resonance in medicine\| PubMed ID: 31763730	2020
N-acetylcysteine mitigates acute opioid withdrawal behaviors and CNS oxidative stress in neonatal rats. Pediatric research\| PubMed ID: 31935745	2020
Optimized rectification of fiber orientation density function. Magnetic resonance in medicine\| PubMed ID: 32710476	2021
NAC and Vitamin D Restore CNS Glutathione in Endotoxin-Sensitized Neonatal Hypoxic-Ischemic Rats. Antioxidants (Basel, Switzerland)\| PubMed ID: 33804757	2021
High fidelity fiber orientation density functions from fiber ball imaging. NMR in biomedicine\| PubMed ID: 34510596	2022
NAC and Vitamin D Improve CNS and Plasma Oxidative Stress in Neonatal HIE and Are Associated with Favorable Long-Term Outcomes. Antioxidants (Basel, Switzerland)\| PubMed ID: 34572976	2021
Quantitative Diffusion and Spectroscopic Neuroimaging Combined with a Novel Early-Developmental Assessment Improves Models for 1-Year Developmental Outcomes. AJNR. American journal of neuroradiology\| PubMed ID: 34949592	2022
Transcutaneous auricular vagus nerve stimulation (taVNS) given for poor feeding in at-risk infants also improves their motor abilities. Journal of pediatric rehabilitation medicine\| PubMed ID: 36093716	2022
Fiber Ball White Matter Modeling Reveals Microstructural Alterations in Healthy Brain Aging. Aging brain\| PubMed ID: 36324695	2022
Optimized rectification of fiber orientation density function with background threshold. Magnetic resonance imaging\| PubMed ID: 36368495	2023
Higher Dose Noninvasive Transcutaneous Auricular Vagus Nerve Stimulation Increases Feeding Volumes and White Matter Microstructural Complexity in Open-Label Study of Infants Slated for Gastr... The Journal of pediatrics\| PubMed ID: 37329979	2023

Hunter G. Moss

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