T1, the longitudinal relaxation time, is a time constant that represents the time required for magnetization to return to its initial state after being shifted [37]. This recovery is affected by the change in the magnetic fields of the atoms around it at the proton resonance frequency. Because of its proximity, the proton next to the water molecule is typically the main source of fluctuations. The random spinning of the water molecule, which is described by the rotational correlation time, changes the angle between the protons over time, which causes magnetic fluctuations. The T1 relaxation due to this interaction occurs most quickly when the rotational correlation time is equal to the inverse of the proton resonance frequency. Similarly, protons in lipids, especially triglycerides, are affected by protons close to them. Because the protons in lipids do not move as much, there is usually more energy at the proton resonance frequency. This shortens the T1 of the lipids. Therefore, T1 shows how mobile the molecules are (mostly water protons) and how tightly they are bound to macromolecules. T1 is mostly used to measure the macromolecular content, water binding, and water content in a number of diseases, such as inflammation and changes in the amount of myelin in the brain.

Schneider et al. [29] conducted a serial imaging investigation of preterm infants with low cerebral risk, aimed to establish reference values for T1 relaxation time, and evaluated the hypothesis that its evolution is equivalent to that of the apparent diffusion coefficient (ADC) and fractional anisotropy (FA) values, thus providing more accurate information about tissue structure. Magnetization prepared dual rapid acquisition of gradient echo, which was used in their study as a recently developed technology obtains a purely T1-weighted image and enables the generation of whole-brain T1 tissue relaxation time maps for quantitative tissue characterization [38]. The descriptive properties of T1 relaxometry are of particular interest in the preterm group because they provide structural information about tissue, such as water content and lipid and macromolecule composition, as well as predict the chronological maturation of myelin and can be regarded as one of the best markers of brain maturation. In the WM fiber tracts (PLIC, optic radiation, and corona radiata), the linear drop in ADC and T1 represented a reduction in water content, fiber packaging, and early myelination processes, particularly in the PLIC after 36 weeks. The T1 relaxation levels (milliseconds) measured in the PLIC matured rapidly compared to those in each other ROI.

In another study, Natu et al. [26] quantitatively examined T1 in 4 key sensorimotor regions. An inversion recovery-echo planar imaging (IR-EPI) sequence was used to measure the relaxation time (R1) at every voxel, an IR-EPI sequence was utilized. Spoiled gradient echo images were used in conjunction with EPI sequences to produce synthetic T1-weighted whole-brain images. R1 (R1=1/T1) was estimated for each voxel using the IR-EPI data. Contrary to the assumption that visual areas are already myelinated at birth [39], their investigation of R1 indicated that while the primary visual cortex (V1) is more mature than other visual areas at birth, it continues to develop and myelinate extensively over the first 6 months of life. Second, contrary to the belief that primary sensory-motor regions (such as V1) also myelinate the swiftest postnatally [39], an evaluation of the rate of R1 development during the first 6 months of life demonstrates that V1 does not myelinate the fastest in the human visual system. Despite having lower values at birth, R1 across several visual areas catches up to R1 in V1 by 6 months of age. The third finding was that microstructural development differed throughout the visual hierarchy. Thus, at birth, the higher visual areas of the ventral and dorsal streams had lower R1 values and were presumably less myelinated than the early retinotopic areas.In contrast, the development of R1 (and subsequently myelin) was increasingly rapid in later visual areas than in earlier areas.

Soun et al. [14] evaluated the ratio intensity values in 10 term neonates with no injury and hypothesized that the values may be sensitive to hyperintensities such as those observed in neonates with encephalopathy who experience injury. The T1/T2 ratio approach emphasizes the natural contrast of myelin [40]. The superimposition of opposing features of T1 and T2 weighting was used in this ratio method. The T1/T2 ratio has the advantage of enhancing the WM contrast-to-noise ratio without increasing scan time. Furthermore, the T1/T2 ratio may differentiate between highly and lightly myelinated cortical areas, implying that this technique can be utilized to investigate spatial variation in myelin formation in the neonatal brain. While no patient in their study population was known to have hypoxic-ischemic injury, the undiscovered subthreshold effects of hypoxia may have increased the T1 signal intensity in the PLIC and been mistaken as myelin tissue.

Owing to the rapid development of the brain during the first few months after birth, significant regional differences occur in myelin density. Their findings corroborate prior research indicating that the PLIC is highly myelinated by term birth, whereas the optic radiation is not fully myelinated [2]. According to these studies, despite variations in tissue characteristics between neonates and adults, the T1/T2 ratio indicates myelin density.

Coregistration is necessary for sequence comparison. The T1 and T2 images exhibited moderate misregistration abnormalities, particularly at the cerebrospinal-gray matter interfaces. These abnormalities may lead to incorrect contrast increases that could be mischaracterized as a myelin-related disorder. The T1/T2 ratio, if proven successful, could enhance the ability to detect myelin impairment in the developing brain. Additionally, because this approach uses routinely acquired diagnostic sequences, it does not require any extra scan time, which is critical in the neonatal population, in which movement is a major contributing factor to image quality.

Susceptibility-weighted imaging detects phase shifts and improves the visibility of iron, calcifications, veins, and blood byproducts based on paramagnetic or diamagnetic characteristics [41-43].

Relaxation time T2* is susceptible to deoxyhemoglobin, water content, and iron levels, with an even higher sensitivity than T2.It has been utilized to analyze brain function (due to changes in deoxyhemoglobin levels), myocardial oxygenation, tumor hypoxia, hemorrhage, cardiac calcification (low water content), and liver and cardiac iron [37]. Several studies [22] have found a correlation between T2* values and myelin content, which reflects nuclear interactions and field inhomogeneity due to the presence of paraor diamagnetic substances in iron and myelin. However, the neonatal brain is less likely to have high concentrations of iron and calcium because myelin is most likely the primary contributor to T2* values in the neonatal brain. The differences in susceptibility between myelin and most other water-based tissues result in signal intensity degradation in T2*-weighted imaging, which causes brain regions with higher myelin content to appear darker [41].

Although susceptibility- and T2*-based methods are primarily used to detect calcium deposition, measure iron content, and image hemorrhagic infarcts in adults [44], numerous studies have reported that myelin content is the primary contributor to T2* decay [22], particularly in neonates who are less likely to have high concentrations of iron and calcium. Considering the multifactorial nature of T2*, several studies suggested that myelin content may be the most significant contributor to this signal [22].

Olivieri et al. [5] employed T2* mapping to study brain myelination in healthy neonates and those with NE throughout the first month of life. Their findings support previous histopathological studies reporting that T2* values were significantly higher in neonates with NE who developed injury in the PLIC, thalami, and lentiform nuclei, which are actively myelinated around the time of term birth and in the month thereafter [45]. Higher T2* values indicate a lower myelin content, while lower T2* values indicate a higher myelin content.In addition, this approach has a high signal-to-noise ratio (SNR) and a short scanning period of less than 4 min, allowing it to be readily implemented in baseline procedures for imaging healthy and critically ill neonates.

Ning et al. (2014)22) used a variant of this technique called enhanced T2*-weighted angiography, which focused on R2* values (R2*=1/T2*) to analyze the myelin content in term-born healthy infants who were approximately 3 months old at the time of MRI. They found that R2* values in the gray nuclei and WM were positively associated with postmenstrual age. The phase values of the PLIC and splenium of the CC were substantially greater than those of the anterior limb of the internal capsule (ALIC) and genu of the CC in neonates. However, they mentioned that, owing to infants’ greater brain water content and significantly lower iron concentration, the boundaries of many brain regions are insufficiently distinct for automated segmentation and registration. In addition, they have more brain water than adults, which diminishes with age. Reduced water fractions may have influenced the change in R2* value with age [45].

The T2 relaxation time is susceptible to tissue composition and structure as well as iron and water content. It has been used to evaluate myelin content in the brain; inflammation, collagen composition, and structure of the cartilage and heart muscle; and edema, hemorrhage, and iron content in the heart and liver [37]. A multicomponent analysis of T1 and T2 relaxation, known as multicomponent relaxometry, may offer a more specific indicator of myelin maturation [46]. A T2 decay analysis of the brain parenchyma revealed at least 2 discrete microanatomical water domains: a rapid-relaxing water pool normally related to water bound in the lipid bilayers of the myelin sheath and a slower-relaxing water pool pertaining to water within and outside of the myelinated axon [46].

The myelin-water fraction (MWF) is a quantitative T2 measurement that enhances the pathological specificity of myelin breakdown [47]. The MWF is estimated using a multiexponential T2 fit, with a short T2 component (10–50 msec) attributed to water trapped between the myelin sheaths. Histopathology has established an association between MWF and myelin loss [48]. Myelin content can be measured indirectly by measuring the myelin-bound water signal or MWF, which correlates well with the results of histological evaluations [48].

Multicompartment T2 relaxometry has been used [30] to assess myelin by quantifying the increase in MWF in the thalamus and posterior WM (PWM) areas; the increase in the thalamus is significantly greater. In the thalamus, the overall change in T2 values was attributable to an increase in myelination, whereas in the WM, the change was associated with a decrease in free water content and an increase in tissue volume. In the PWM, the amount of myelin measured was rather insignificant, and the main change was tentatively attributed to (unmyelinated) axonal and glial proliferation confirmed by T2 relaxometry. Results from the WM PLIC and ALIC demonstrated axonal and myelin density differentiation, with high MWF values in the PLIC and significantly lower values in the ALIC.

Meanwhile, Knight et al. [28] found that T2 is longer in extremely preterm newborns than in late preterm infants across many WM regions, and these effects are particularly pronounced in WM regions that myelinate earlier and rapidly. Deoni et al. [49] further established the use of multicomponent relaxometry in the investigation of infant brain development, demonstrating qualitative agreement between MWF trends acquired from magnetic resonance (MR) and spatiotemporal myelination patterns found by histology. Deoni et al. [23] assessed myelin content in healthy infants aged 3 months to 7.5 years using a new multicomponent relaxation approach called multicomponent driven equilibrium single-pulse observation of T1 and T2. Despite its superior resolution, this method is not ideal for neonatal patients owing to the lengthier scan periods [14], making it more challenging to incorporate into the baseline MRI procedure in a critically ill neonate population. Concerns have recently been raised regarding its accuracy [50].

However, a significant disadvantage of this technique is its relatively poor SNR [15], which makes imaging more difficult because of the low myelin concentration in the neonatal brain. Until recently, obtaining MWF maps in clinical practice was challenging because acquisition was limited to a single slice and the scanning time was unduly long [37].

Specific parameters, such as the T1-relaxation constants, T2-relaxation constants, and proton density (PD) of the studied tissue, can be measured using the quantitative multidynamic multiecho (MDME) sequence which acquires all the required parameters for image postprocessing in less than 6 minutes [51]. Since the repetition time, echo time, and inversion time are all extrinsic scan parameters that can be established and adjusted postprocessing, they are not predefined in this method [52]. T1-weighted, T2-weighted, PD-weighted, and inversion recovery contrasts can all be produced from SyMRI in less than 1 min after intrinsic tissue parameters have been collected and extrinsic scan parameters have been specified [51].

Lee et al. [24] and Schmidbauer et al. [27] used a vendor-provided tool (SyMRI 8.0; SyntheticMR, Linkoping, Sweden) to construct quantification maps (T1, T2, and PD maps) simultaneously from raw data acquired by the MDME sequence. Using the MDME pulse sequence, the partial volume of myelin was calculated using R1, R2, and PD [53].

The SyMRI software generates maps relying on T1- and T2-relaxation constants and the PD, which vary among different tissues [46]. This permits the imaging of various tissue types and the quantification of myelin, resulting in a more accurate evaluation of brain development and demyelinating disorders [54]. Using quantitative maps, myelin could be better differentiated from non-myelinated gray and WM than on conventional images.

The SyMRI software automatically calculated the total estimated myelin partial volume (Msum) and the ratio of Msum to the total brain parenchyma [24]. T1 and T2 of the WM areas were extremely high at birth, with maximum values of approximately 2,600 msec and 280 msec, respectively; however, these values reduced by more than half in the first year of life.

Time is a crucial factor in clinical settings. Even using current techniques, conventional approaches for MR mapping would take 15–30 minutes [51]. Beyond the neonatal brain imaging technique, SyMRI is a quantitative imaging technique that detects myelination-related changes on an individual level. In addition, it typically reduces the examination time while offering several MR contrasts such as T1, T2, PD, and inversion recovery. Thus, SyMRI enables the generation of quantitative maps and different MR contrasts in one-third of the time required by typical quantitative mapping methods. Recent evidence indicates that SyMRI imaging data are equivalent to those of conventional T1 and T2 images [52]. In addition to standard MR contrasts, SyMRI enables the rapid generation of quantitative MR maps [51]. This suggests new avenues in diagnostic neonatal brain imaging.