Several conditions can lead to an abrupt impairment of placental perfusion or oxygen delivery in the umbilical cord, resulting in acute profound asphyxia. These conditions include among others placental abruption, umbilical cord prolapse, shoulder dystocia and uterine rupture. As there is insufficient time to redirect blood flow through autoregulation, these sentinel events will especially affect the brain areas with the highest metabolic demand. These include the basal ganglia and thalami (BGT), mainly the ventrolateral thalami and posterior putamina, and the perirolandic cortex (Figure 1) [21]. This pattern of injury is associated with impaired motor neurodevelopment, including cerebral palsy (CP) [22,23]. A strong association between the severity of BGT abnormalities and the severity of motor impairment has been demonstrated, with a predictive accuracy of severe BGT lesions being 0.89 (95% CI 0.83–0.96) for severe motor impairment [22].

Mild to moderate asphyxia, also known as partial prolonged asphyxia, allows time for cerebral autoregulation to redirect blood flow to the brain areas with the highest metabolic demand, at the cost of the watershed areas of the anterior, middle, and posterior cerebral arteries [20]. This results in a watershed predominant pattern of injury (Figure 2). As injury follows a parasagittal distribution along these vascular border zones, this pattern is also known as the “parasagittal pattern of injury” [24]. In the more severely affected infants, injury can also be seen in the parasagittal cortex and the subcortical white matter. Physiological and neurological manifestations in infants with WM/WS predominant pattern of injury are often not severe and only present for a short time after birth, in contrast to infants with BGT pattern of injury who in general have lower Apgar scores, need more intensive resuscitation at birth, and present with more severe encephalopathy [25]. Nevertheless, clinical and neurological abnormalities may progress over time, highlighting the importance of careful observation of infants with perinatal asphyxia [26]. Severe motor impairment is rare in infants with mild to moderate WM/WS pattern of injury [25,27]. At early follow-up around 12–18 months after birth, they are often considered to have a normal outcome [28]. However, these infants are likely to grow into their deficits and develop cognitive problems over the years. Long-term follow-up to detect disabilities early in life and ensure an early start of interventions is therefore important [25,27,29,30].

Some infants with HIE show abnormalities restricted to the periventricular white matter, including punctate white matter lesions (PWMLs), small focal patches of increased signal intensity on T1-weighted imaging, and decreased intensity on T2-weighted imaging [31,32]. Hayman et al. studied 44 (near-)term infants with PWMLs, of whom 45% were associated with perinatal asphyxia [31]. None of these infants had evidence of BGT injury or another more extensive pattern of injury. The majority of infants in this study had normal early outcomes or mild neurologic deficits. Most of those who experienced severe neurological sequelae had an underlying genetic disorder.

Near total injury, which is also referred to as “global injury”, is characterized by diffuse injury in both the BGT and white matter. This pattern is seen in newborns affected by very severe and prolonged asphyxia. It is less often reported compared to BGT or WM/WS patterns of injury, as infants with near total injury may be too ill to be scanned after birth and pass away before MRI can be performed [25] (Figure 3). The cerebellum may look relatively normal on DWI in contrast to a completely white cerebrum, which is why this pattern is also being referred to as the “white cerebrum” [33]. Nevertheless, it has been demonstrated that cerebellar abnormalities may be underestimated on DWI, and that only in cases of very severe cytotoxic edema abnormalities are found [34]. There is growing evidence for a superior role of advanced MRI modalities, such as quantitative diffusion tensor imaging (DTI) analysis, to adequately detect cerebellar injury [35].

Vascular abnormalities, including perinatal arterial ischemic stroke, perinatal hemorrhagic stroke, and sinovenous thrombosis,  have also been demonstrated in infants with encephalopathy due to perinatal asphyxia [36,37]. Previous studies have demonstrated perinatal stroke in 4–5% of newborns with HIE [37,38] (Figure 4). Whether there is a causal relationship between perinatal asphyxia and neonatal stroke is controversial. Asphyxia has been proposed to be involved in the development of neonatal stroke in experimental and clinical studies [39,40]. Findings from a study by Harbert and colleagues have suggested that therapeutic hypothermia could potentially reduce seizures after perinatal stroke [41]. However, the exact etiology of this disease remains to be further elucidated.

Some infants with HIE show brain injury in the limbic system, particularly in the hippocampal region, which can lead to long-term memory impairment at school age [42,43]. Additionally, a recent study has demonstrated that the mammillary bodies (MB), which are also part of the limbic circuit and play an important role in episodic memory, are often injured in infants with HIE [44] (Figure 5). Molavi and colleagues showed that 13% of full-term infants with HIE had abnormal signal intensity on T2-weighted imaging. In all but one of the infants with follow-up MRI, these initial signal abnormalities resulted in MB atrophy [44]. In another study across multiple centers, it was demonstrated that approximately 40% of infants with HIE who had received hypothermia had signal abnormalities in the MBs [45]. Annink et al. reported that MB atrophy was significantly associated with lower intelligence quotients, verbal long-term memory scores, and visual-spatial long-term memory scores at 10 years of age [46].

MRI has been performed in infants with HIE since the late 1980s, and initially included T1- and T2-weighted imaging [47]. The introduction of DWI has greatly improved the assessment of brain lesions in newborns with asphyxia. T1-weighted imaging aids in the assessment of myelination, the depiction of ischemia, and the detection of subacute hemorrhage in regions with important prognostic implications, such as the BGT and the brainstem [48]. T2-weighted sequences are useful to identify white matter abnormalities and to assess the gray-white matter differentiation at the cortex [48]. Abnormalities in this delineation can reveal cortical injury, also referred to as “loss of the cortical ribbon” (Figure 2). During the first days after birth, the abnormalities on T1- and T2-weighted imaging are often subtle, but they become gradually more apparent by the second half of the first week [49]. It has been demonstrated that the absence of normal high-signal intensity of the posterior limb of the internal capsule (PLIC) on T1- and T2-weighted imaging is highly predictive of severe adverse motor outcomes [22,50]. However, these results derived from studies performing MRI in both the first and second week after birth, and one should be aware that signal abnormalities of the PLIC may take up to 4 days to become visible when only T1- and T2-weighted imaging are being used (Figure 1) [22].

DWI is an imaging modality based upon the measurement of the random motion of water molecules within a voxel of brain tissue, providing information on the functional state of the brain tissue. The apparent diffusion coefficient (ADC) is an indicator of the magnitude of movement of water protons within the tissue. As the ADC indicates the overall diffusion restriction, low ADC values will cause a high-signal intensity on isotropic DWI [51]. A variety of studies have demonstrated restricted water diffusion due to hypoxic-ischemic injury, which can be visible at an early stage when conventional T1 and T2 sequences are still inconspicuous [52,53]. In general, abnormalities seen on DWI peak at 3–5 days after the insult and subsequently normalize at approximately 11–12 days for infants treated with therapeutic hypothermia and 6–8 days in non-cooled infants. One must keep in mind that DWI obtained within the first day after birth and near the time of pseudo-normalization may lead to an underestimation of the extent of brain injury [54].

Susceptibility weighted imaging (SWI) is a three-dimensional MRI modality with high spatial resolution and flow compensation that accentuates the magnetic properties of blood, iron, blood products, and calcifications [55]. It is exquisitely useful to detect vascular abnormalities, such as hemorrhages and cerebral vascular malformations (Figure 6). As this sequence is very sensitive to the detection of blood oxygenation changes within the veins, due to the increased magnetic susceptibility of deoxygenated blood, it can also play an important role in the early detection of HIE and prognostication [56,57]. The compensatory increase in the oxygen extraction fraction following hypoxia-ischemia results in an increased level of deoxygenated hemoglobin in the cerebral vessels draining the injured areas. This may be depicted in SWI as prominent hypo-intense veins. It has been demonstrated that SWI may reveal vascular brain abnormalities even before cytotoxic edema is visible on DWI [58].

In contrast to DWI, DTI also accounts for the effects of the diffusion directionality of water. This is expressed as the functional anisotropy (FA). DTI is a powerful tool to assess microstructural abnormalities of the brain. However, while abnormalities on DWI can be interpreted visually, the acquisition and analysis of DTI data are significantly more complex and, in general, require a reliable quantitative analysis method to draw meaningful conclusions [59]. One of these methods is the region of interest analysis, in which diffusion measures are obtained from a specific brain region, defined by manual delineation or automated parcellation or segmentation. In a systematic review on DTI, Dibble et al. identified three key regions of interest showing altered diffusion in infants with HIE: the PLIC, and the genu and splenium of the corpus callosum [14]. Lower FA values in these areas were associated with worse neurodevelopmental outcomes. Another method for quantitative analysis is tract-based spatial statistics (TBSS). This is an automated objective observer-independent whole-brain approach that analyzes aligned FA images from multi-subject diffusion data, allowing powerful comparisons of DTI without requiring a subjective prespecification of regions of interest [59]. Using TBSS, Porter et al. demonstrated widespread microstructural abnormalities in white matter tracts in term infants with HIE, which were reduced after therapeutic hypothermia, showing that TBSS is suitable to compare white matter tissue integrity among infants and a promising biomarker for early phase trials of new neuroprotective strategies [60]. In another study including 43 infants with HIE, Tusor and colleagues demonstrated that DTI analyzed by TBSS could predict 2-year outcomes of these infants, with those having an adverse outcome showing significantly lower FA values in the corpus callosum, the centrum semiovale, anterior and posterior limb of the internal capsule, cerebral peduncles, external capsule, optic radiation, fornix, cingulum and inferior longitudinal fasciculus [18].

Arterial spin labelin (ASL) is a noninvasive technique to measure brain perfusion, by using magnetically labeled water protons as a tracer [61]. Following the acute phase of injury after the hypoxic-ischemic event, impaired autoregulation often results in cerebral hyperperfusion, which can lead to delayed brain injury and correlates with an adverse neurodevelopmental outcome [62].

Perfusion abnormalities visualized with ASL have been shown to aid in early diagnosis and prognostication of infants with HIE [16,63,64]. Wintermark et al. assessed brain perfusion using ASL in the first week after birth in 18 infants with perinatal asphyxia, of whom 11 were treated with hypothermia and 4 were control patients, and demonstrated that abnormal cerebral blood flow values can precede injury seen on later MRI [63]. Cooled infants who developed evidence of hypoxic-ischemic brain injury on MRI showed more markedly decreased perfusion on the first day after birth in the brain areas subsequently exhibiting injury, in comparison to the control group and the cooled infants who did not develop brain injury. On the second day after birth, all but one of these infants demonstrated hyperperfusion in these injured brain areas, suggesting that an initial hypoperfusion phase followed by a hyperperfusion phase in specific brain regions correlates with the development of injury in those regions. Newborns with perinatal asphyxia who did not receive hypothermia therapy and developed brain injury showed hyperperfusion on days 1–6 after birth in the brain areas showing injury on MRI. Another study evaluated the predictive value of ASL in 28 infants with HIE and reported that perfusion in the BGT was higher in those with an adverse outcome at 9–18 months of age than in the neonates with a favorable outcome [16]. When comparing the predictive value of ASL with other MRI predictive markers, the combination of ASL with Lactate/N-acetylaspartate (NAA) measured by ¹H-MRS, was demonstrated to be the best outcome predictor. ASL seems most relevant when performed in the first days after the hypoxic-ischemic insult. Based on a study on newborns with HIE who underwent MRI around 4 days and 11 days after birth, Proisy et al. demonstrated that cerebral blood flow levels measured in the BGT around day 4 were significantly higher in infants with ischemic lesions on MRI compared to infants with normal MRI [65]. No significant difference in cerebral blood flow levels measured in the BGT around 11 days after birth was demonstrated between these groups. However, this could also be due to the small sample size of this study.