Unité de recherche en neuroimagerie applicative clinique et translationnelle

Can monkeys learn simple auditory sequences and detect when a new sequence deviates from the stored pattern? Here we tested the predictive-coding hypothesis, which postulates that cortical areas encode internal models of sensory sequences at multiple hierarchical levels, and use these predictive models to detect deviant stimuli. In humans, hierarchical predictive coding has been supported by studies of auditory sequence processing, but it is unclear whether internal hierarchical models of auditory sequences are also available to nonhuman animals. Using fMRI, we evaluated the encoding of auditory regularities in awake monkeys listening to first- and second-order sequence violations. We observed distinct fMRI responses to first-order violations in auditory cortex and to second-order violations in a frontoparietal network, a distinction only demonstrated in conscious humans so far. The results indicate that the capacity to represent and predict the structure of auditory sequences is shared by humans and nonhuman primates.

In vivo evaluation of the brain white matter maturation is still a challenging task with no existing gold standards. In this article we propose an original approach to evaluate the early maturation of the white matter bundles, which is based on comparison of infant and adult groups using the Mahalanobis distance computed from four complementary MRI parameters: quantitative qT1 and qT2 relaxation times, longitudinal λ║ and transverse λ⊥ diffusivities from diffusion tensor imaging. Such multi-parametric approach is expected to better describe maturational asynchrony than conventional univariate approaches because it takes into account complementary dependencies of the parameters on different maturational processes, notably the decrease in water content and the myelination. Our approach was tested on 17 healthy infants (aged 3- to 21-week old) for 18 different bundles. It finely confirmed maturational asynchrony across the bundles: the spino-thalamic tract, the optic radiations, the cortico-spinal tract and the fornix have the most advanced maturation, while the superior longitudinal and arcuate fasciculi, the anterior limb of the internal capsule and the external capsule have the most delayed maturation. Furthermore, this approach was more reliable than univariate approaches as it revealed more maturational relationships between the bundles and did not violate a priori assumptions on the temporal order of the bundle maturation. Mahalanobis distances decreased exponentially with age in all bundles, with the only difference between them explained by different onsets of maturation. Estimation of these relative delays confirmed that the most dramatic changes occur during the first post-natal year.

Neuropathological studies showed early locus coeruleus (LC) neuronal loss associated with tauopathy in Alzheimer's Disease (AD). We used the LC signal intensity (LC-I) on 3T MRI to assess the LC integrity in AD (n = 37) and controls (n = 17). The LC-I was decreased in AD regardless of typical (amnesic) and atypical presentation (logopenic aphasia/visuo-spatial deficit), from the prodromal stage, and independently of the amyloid load measured by PiB-PET. The LC-I was correlated with memory performance of typical AD. This supports the pathophysiological model in which the LC plays a critical role in AD and may thus be a potential therapeutic target.

We present an extension of the Individual Brain Charting dataset -a high spatial-resolution, multi-task, functional Magnetic Resonance Imaging dataset, intended to support the investigation on the functional principles governing cognition in the human brain. The concomitant data acquisition from the same 12 participants, in the same environment, allows to obtain in the long run finer cognitive topographies, free from inter-subject and inter-site variability. This second release provides more data from psychological domains present in the first release, and also yields data featuring new ones. It includes tasks on e.g. mental time travel, reward, theory-of-mind, pain, numerosity, self-reference effect and speech recognition. In total, 13 tasks with 86 contrasts were added to the dataset and 63 new components were included in the cognitive description of the ensuing contrasts. As the dataset becomes larger, the collection of the corresponding topographies becomes more comprehensive, leading to better brain-atlasing frameworks. This dataset is an open-access facility; raw data and derivatives are publicly available in neuroimaging repositories.

The synaptosomal-associated protein SNAP25 is a key player in synaptic vesicle docking and fusion and has been associated with multiple psychiatric conditions, including schizophrenia, bipolar disorder, and attention-deficit/hyperactivity disorder. We recently identified a promoter variant in SNAP25 , rs6039769 , that is associated with early-onset bipolar disorder and a higher gene expression level in human prefrontal cortex. In the current study, we showed that this variant was associated both in males and females with schizophrenia in two independent cohorts. We then combined in vitro and in vivo approaches in humans to understand the functional impact of the at-risk allele. Thus, we showed in vitro that the rs6039769 C allele was sufficient to increase the SNAP25 transcription level. In a postmortem expression analysis of 33 individuals affected with schizophrenia and 30 unaffected control subjects, we showed that the SNAP25b / SNAP25a ratio was increased in schizophrenic patients carrying the rs6039769 at-risk allele. Last, using genetics imaging in a cohort of 71 subjects, we showed that male risk carriers had an increased amygdala–ventromedial prefrontal cortex functional connectivity and a larger amygdala than non-risk carriers. The latter association has been replicated in an independent cohort of 121 independent subjects. Altogether, results from these multilevel functional studies are bringing strong evidence for the functional consequences of this allelic variation of SNAP25 on modulating the development and plasticity of the prefrontal–limbic network, which therefore may increase the vulnerability to both early-onset bipolar disorder and schizophrenia. SIGNIFICANCE STATEMENT Functional characterization of disease-associated variants is a key challenge in understanding neuropsychiatric disorders and will open an avenue in the development of personalized treatments. Recent studies have accumulated evidence that the SNARE complex, and more specifically the SNAP25 protein, may be involved in psychiatric disorders. Here, our multilevel functional studies are bringing strong evidence for the functional consequences of an allelic variation of SNAP25 on modulating the development and plasticity of the prefrontal–limbic network. These results demonstrate a common genetically driven functional alteration of a synaptic mechanism both in schizophrenia and early-onset bipolar disorder and confirm the shared genetic vulnerability between these two disorders.

Mapping the chimpanzee brain connectome and comparing it to that of humans is key to our understanding of similarities and differences in primate evolution that occurred after the split from their common ancestor around 6 million years ago. In contrast to studies on macaque species' brains, fewer studies have specifically addressed the structural connectivity of the chimpanzee brain and its comparison with the human brain. Most comparative studies in the literature focus on the anatomy of the cortex and deep nuclei to evaluate how their morphology and asymmetry differ from that of the human brain, and some studies have emerged concerning the study of brain connectivity among humans, monkeys, and apes. In this work, we established a new white matter atlas of the deep and superficial white matter structural connectivity in chimpanzees. In vivo anatomical and diffusion-weighted magnetic resonance imaging (MRI) data were collected on a 3-Tesla MRI system from 39 chimpanzees. These datasets were subsequently processed using a novel fiber clustering pipeline adapted to the chimpanzee brain, enabling us to create two novel deep and superficial white matter connectivity atlases representative of the chimpanzee brain. These atlases provide the scientific community with an important and novel set of reference data for understanding the commonalities and differences in structural connectivity between the human and chimpanzee brains. We believe this study to be innovative both in its novel approach and in mapping the superficial white matter bundles in the chimpanzee brain, which will contribute to a better understanding of hominin brain evolution.

The hippocampal subfields, pivotal to episodic memory, are distinct both in terms of cyto- and myeloarchitectony. Studying the structure of hippocampal subfields in vivo is crucial to understand volumetric trajectories across the lifespan, from the emergence of episodic memory during early childhood to memory impairments found in older adults. However, segmenting hippocampal subfields on conventional MRI sequences is challenging because of their small size. Furthermore, there is to date no unified segmentation protocol for the hippocampal subfields, which limits comparisons between studies. Therefore, we introduced a novel segmentation tool called HSF short for hippocampal segmentation factory, which leverages an end-to-end deep learning pipeline. First, we validated HSF against currently used tools (ASHS, HIPS, and HippUnfold). Then, we used HSF on 3,750 subjects from the HCP development, young adults, and aging datasets to study the effect of age and sex on hippocampal subfields volumes. Firstly, we showed HSF to be closer to manual segmentation than other currently used tools ( p < 0.001), regarding the Dice Coefficient, Hausdorff Distance, and Volumetric Similarity. Then, we showed differential maturation and aging across subfields, with the dentate gyrus being the most affected by age. We also found faster growth and decay in men than in women for most hippocampal subfields. Thus, while we introduced a new, fast and robust end-to-end segmentation tool, our neuroanatomical results concerning the lifespan trajectories of the hippocampal subfields reconcile previous conflicting results.

BACKGROUND: Sedation agents affect brain hemodynamic and metabolism leading to specific modifications of the cerebral blood oxygenation level. We previously demonstrated that ultra-high field (UHF) MRI detects changes in cortical blood oxygenation following the administration of sedation drugs commonly used in animal research. Here we applied the UHF-MRI method to study clinically relevant sedation drugs for their effects on cortical and subcortical (thalamus, striatum) oxygenation levels. METHODS: We acquired T2*-weighted images of Sprague-Dawley rat brains at 17.2T in vivo. During each MRI session, rats were first anesthetized with isoflurane, then with a second sedative agent (sevoflurane, propofol, midazolam, medetomidine or ketamine-xylazine) after stopping isoflurane. We computed a T2*-oxygenation-ratio that aimed at estimating cerebral blood oxygenation level for each sedative agent in each region of interest: cortex, hippocampus, thalamus and striatum. RESULTS: The T2*-oxygenation-ratio was consistent across scan sessions. This ratio was higher with inhalational agents than with intravenous agents. Under sevoflurane and medetomidine, T2*-oxygenation-ratio was homogenous across the brain regions. Intravenous agents (except medetomidine) induced a T2*-oxygenation-ratio imbalance between cortex and subcortical regions: T2*-oxygenation-ratio was higher in the cortex than the subcortical areas under ketamine-xylazine; T2*-oxygenation-ratio was higher in subcortical regions than in the cortex under propofol or midazolam. CONCLUSION: Preclinical UHF MRI is a powerful method to monitor the changes in cerebral blood oxygenation level induced by sedative agents across brain structures. This approach also allows for a classification of sedative agents based on their differential effects on cerebral blood oxygenation level.

The hippocampus and the adjacent perirhinal, entorhinal, temporopolar and parahippocampal cortices are interconnected in a hierarchical MTL system crucial for memory processes. A probabilistic description of the anatomical location and spatial variability of MTL cortices in the child and adolescent brain would help to assess structure-function relationships. The rhinal sulcus (RS) and the collateral sulcus (CS) that border MTL cortices and influence their morphology have never been described in these populations. In this study, we identified the aforementioned structures on magnetic resonance images of 38 healthy subjects aged 7-17 years old. Relative to sulcal morphometry in the MTL, we showed RS-CS conformation is an additional factor of variability in the MTL that is not explained by other variables such as age, sex and brain volume; with an innovative method using permutation testing of the extrema of structures of interest, we showed that RS-SC conformation was not associated with differences of location of MTL sulci. Relative to probabilistic maps, we offered for the first time a systematic mapping of MTL structures in children and adolescent, mapping all the structures of the MTL system while taking sulcal morphology into account. Our results, with the probabilistic maps described here being freely available for download, will help to understand the anatomy of this region and help functional and clinical studies to accurately test structure-function hypotheses in the MTL during development.

Background: Brain magnetic resonance imaging (MRI) is a key tool for the prognostication of encephalic newborns in the context of hypoxic−ischemic events. The purpose of this study was to finely characterize brain injuries in this context. Methods: We provided a complete, descriptive analysis of the brain MRIs of infants included in the French national, multicentric cohort LyTONEPAL. Results: Among 794 eligible infants, 520 (65.5%) with MRI before 12 days of life, grade II or III encephalopathy and gestational age ≥36 weeks were included. Half of the population had a brain injury (52.4%); MRIs were acquired before 6 days of life among 247 (47.5%) newborns. The basal ganglia (BGT), white matter (WM) and cortex were the three predominant sites of injuries, affecting 33.8% (n = 171), 33.5% (n = 166) and 25.6% (n = 128) of participants, respectively. The thalamus and the periventricular WM were the predominant sublocations. The BGT, posterior limb internal capsule, brainstem and cortical injuries appeared more frequently in the early MRI group than in the late MRI group. Conclusion: This study described an overview of brain injuries in hypoxic−ischemic neonatal encephalopathy. The basal ganglia with the thalamus and the WM with periventricular sublocation injuries were predominant. Comprehensive identification of brain injuries in the context of HIE may provide insight into the mechanism and time of occurrence.

Tools are objects that are manipulated by agents with the intention to cause an effect in the world. We show that the cognitive capacity to understand tools is present in young infants, even if these tools produce arbitrary, causally opaque effects. In experiments 1-2, we used pupillometry to show that 8-mo-old infants infer an invisible causal contact to account for the-otherwise unexplained-motion of a ball. In experiments 3, we probed 8-mo-old infants' account of a state change event (flickering of a cube) that lies outside of the explanatory power of intuitive physics. Infants repeatedly watched an intentional agent launch a ball behind an occluder. After a short delay, a cube, positioned at the other end of the occluder began flickering. Rare unoccluded events served to probe infants' representation of what happened behind the occluder. Infants exhibited larger pupil dilation, signaling more surprise, when the ball stopped before touching the cube, than when it contacted the cube, suggesting that infants inferred that the cause of the state change was contact between the ball and the cube. This effect was canceled in experiment 4, when an inanimate sphere replaced the intentional agent. Altogether, results suggest that, in the infants' eyes, a ball (an inanimate object) has the power to cause an arbitrary state change, but only if it inherits this power from an intentional agent. Eight-month-olds are thus capable of representing complex event structures, involving an intentional agent causing a change with a tool.

The aim of this study was to investigate the impact of breath-hold diving strategies regarding loss of consciousness (LOC). Three international competitions were examined through video in constant weight diving with (CWT) or without (CNF) fins. We analysed three breath-hold parameters (time, speed, and movements count) for the following phases: active descent, passive descent, turning, and ascent. Divers who had LOC during CNF were slower in the active descent phase, faster in the passive descent phase with a longer turn, and slower in the ascent phase than divers who did not have LOC. They also had lower amplitude and higher frequency. Men were deeper (72.9 m vs. 56.3 m) for a longer dive time (181.1 s vs. 154.6 s), faster, with a greater amplitude than women. In CWT, divers with an LOC had longer dive times (197 s vs. 167 s) with a faster active descent phase. Men had lower amplitude and greater frequency than women. This is the first study showing that breath-hold divers undergoing an LOC event shown differences in efficiency during CWT and CNF regarding velocities, amplitudes, and frequencies. In conclusion, our results suggest that the speed parameter during active descent phase influence the LOC.

BACKGROUND: Magnetic resonance imaging (MRI) is currently considered a safe imaging technique because, unlike computed tomography, MRI does not expose patients to ionising radiation. However, conflicting literature reports possible genotoxic effects of MRI. We herein examine the chromosomal effects of repeated MRI scans by performing a longitudinal follow-up of chromosomal integrity in volunteers. METHODS: This ethically approved study was performed on 13 healthy volunteers (mean age 33 years) exposed to up to 26 3-T MRI sessions. The characterisation of chromosome damage in peripheral blood lymphocytes was performed using the gold-standard biodosimetry technique augmented with telomere and centromere staining. RESULTS: Cytogenetic analysis showed no detectable effect after a single MRI scan. However, repeated MRI sessions (from 10 to 20 scans) were associated with a small but significant increase in chromosomal breaks with the accumulation of cells with chromosomal terminal deletions with a coefficient of 9.5% (95% confidence interval 6.5-12.5%) per MRI (p < 0.001). Additional exposure did not result in any further increase. This plateauing of damage suggests lymphocyte turnover. Additionally, there was no significant induction of dicentric chromosomes, in contrast to what is observed following exposure to ionising radiation. CONCLUSIONS: Our study showed that MRI can affect chromosomal integrity. However, the amount of damage per cell might be so low that no chromosomal rearrangement by fusion of two deoxyribonucleic breaks is induced, unlike that seen after exposure to computed tomography. This study confirms that MRI is a safe imaging technique.

7 Effectiveness of synchronous action observation and mental practice on upper extremity motor recovery after strokeKrystal Robinson-Berta, Nancy WoodsaaMessiah University, Mechanicsburg, USAABSTRA...

Cerebellum plays a role in the regulation of cognitive processes. Cerebellar alterations could explain cognitive impairments in schizophrenia. We describe the case of a 50 years old patient with schizophrenia whom underwent cerebellar transcranial direct current stimulation (tDCS). In order to study the effect of cerebellar stimulation on cognitive functions, the patient underwent a neuropsychological assessment and an eyeblink conditioning (EBC) protocol. Although the effect of brain stimulation cannot be only assessed in a single-case study, our results suggest that cerebellar stimulation may have an effect on a broad range of cognitive functions typically impaired in patients with schizophrenia, including verbal episodic, short term, and working memory. In addition to neuropsychological tests, we evaluated the cerebellar function by performing EBC before and after tDCS. Our data suggest that tDCS can improve EBC. Further clinical trials are required for better understanding of how cerebellar stimulation can modulate cognitive processes in patients with schizophrenia and healthy controls.

INTRODUCTION: Neonatal arterial ischemic stroke (NAIS) is a common model to study the impact of a unilateral early brain insult on developmental brain plasticity and the appearance of long-term outcomes. Motor difficulties that may arise are typically related to poor function of the affected (contra-lesioned) hand, but surprisingly also of the ipsilesional hand. Although many longitudinal studies after NAIS have shown that predicting the occurrence of gross motor difficulties is easier, accurately predicting hand motor function (for both hands) from morphometric MRI remains complicated. The hypothesis of an association between the structural organization of the basal ganglia (BG) and thalamus with hand motor function seems intuitive given their key role in sensorimotor function. Neuroimaging studies have frequently investigated these structures to evaluate the correlation between their volumes and motor function following early brain injury. However, the results have been controversial. We hypothesize the involvement of other structural parameters. METHOD: The study involves 35 children (mean age 7.3 years, SD 0.4) with middle cerebral artery NAIS who underwent a structural T1-weighted 3D MRI and clinical examination to assess manual dexterity using the Box and Blocks Test (BBT). Graphs are used to represent high-level structural information of the BG and thalami (volumes, elongations, distances) measured from the MRI. A graph neural network (GNN) is proposed to predict children's hand motor function through a graph regression. To reduce the impact of external factors on motor function (such as behavior and cognition), we calculate a BBT score ratio for each child and hand. RESULTS: The results indicate a significant correlation between the score ratios predicted by our method and the actual score ratios of both hands (p < 0.05), together with a relatively high accuracy of prediction (mean L1 distance < 0.03). The structural information seems to have a different influence on each hand's motor function. The affected hand's motor function is more correlated with the volume, while the 'unaffected' hand function is more correlated with the elongation of the structures. Experiments emphasize the importance of considering the whole macrostructural organization of the basal ganglia and thalami networks, rather than the volume alone, to predict hand motor function. CONCLUSION: There is a significant correlation between the structural characteristics of the basal ganglia/thalami and motor function in both hands. These results support the use of MRI macrostructural features of the basal ganglia and thalamus as an early biomarker for predicting motor function in both hands after early brain injury.

Importance: Baseline cerebral microbleeds (CMBs) and APOE ε4 allele copy number are important risk factors for amyloid-related imaging abnormalities in patients with Alzheimer disease (AD) receiving therapies to lower amyloid-β plaque levels. Objective: To provide prevalence estimates of any, no more than 4, or fewer than 2 CMBs in association with amyloid status, APOE ε4 copy number, and age. Design, Setting, and Participants: This cross-sectional study used data included in the Amyloid Biomarker Study data pooling initiative (January 1, 2012, to the present [data collection is ongoing]). Data from 15 research and memory clinic studies were pooled and harmonized. Participants included individuals for whom data on age, cognitive status, amyloid status, and presence of CMBs were available. Data were analyzed from October 22, 2023, to April 26, 2024. Main Outcomes and Measures: The main outcomes were age, cognitive status, amyloid status and presence, location, and number of CMBs. Presence of amyloid pathology was determined based on 42 amino acid-long form of amyloid-β peptide (Aβ42) levels in cerebrospinal fluid or on amyloid-positron emission tomography. Presence and, in a subset, location (lobar vs deep) and number of CMBs were determined on magnetic resonance imaging (locally with visual rating). Results: Among 4080 participants included in the analysis, the mean (SD) age was 66.5 (8.9) years, and 2241 (54.9%) were female. A total of 2973 participants had no cognitive impairment (cognitive unimpairment [CU]), and 1107 had mild cognitive impairment (MCI) or AD dementia (ADD). One thousand five hundred and thirteen participants (37.1%) had amyloid pathology, 1368 of 3599 (38.0%) with data available were APOE ε4 carriers, and 648 (15.9%) had CMBs. In the CU group, amyloid pathology and APOE ε4 copy number were not associated with presence of any, no more than 4, or fewer than 2 CMBs but were associated with increased odds of lobar CMBs (odds ratio [OR] for amyloid, 1.42 [95% CI, 1.20-1.69], P < .001; OR for 2 vs 0 alleles, 1.81 [95% CI, 1.19-2.74], P = .006; OR for 1 vs 0 alleles, 1.10 [95% CI, 0.83-1.46], P = .49; and OR for 2 vs 1 allele, 1.64 [95% CI, 0.90-2.97], P = .11; overall P = .02). In the MCI-ADD group, amyloid pathology was associated with presence of any CMBs (OR, 1.51 [95% CI, 1.17-1.96], P = .002), no more than 4 CMBs (OR, 1.44 [95% CI, 1.18-1.82], P = .002), and fewer than 2 CMBs (OR 1.34 [95% CI, 1.03-1.74], P = .03) but not lobar CMBs. APOE ε4 copy number was associated with presence of any (OR for 2 vs 0 alleles, 1.72 [95% CI, 0.88-3.35], P = .11; OR for 1 vs 0 alleles, 0.78 [95% CI, 0.59-1.04], P = .09; and OR for 2 vs 1 allele, 2.20 [95% CI, 1.32-3.67], P = .002; overall P < .001) and no more than 4 CMBs (OR for 2 vs 0 alleles, 1.31 [95% CI, 0.64-2.68], P = .45; OR for 1 vs 0 alleles, 0.75 [95% CI, 0.54-1.04], P = .08; and OR for 2 vs 1 allele, 1.76 [95% CI, 0.97-3.19], P = .06; overall P = .03) but not with fewer than 2 or lobar CMBs. Prevalence estimates of CMBs ranged from 6% at 50 years of age in a non-APOE ε4 allele carrier with no amyloid pathology and no cognitive impairment to 52% at 90 years of age in an APOE ε4 homozygote carrier with amyloid pathology and cognitive impairment. Conclusions and Relevance: In this cross-sectional study of 4080 participants, prevalence estimates of CMBs were associated with amyloid status, APOE ε4 copy number, and age. CMB prevalence estimates may help inform safety evaluations for antiamyloid clinical trials.

Abstract We present the first release of p-HCP (Prenatal Human Connectome Patterns), an imaging dataset of human fetal brain development covering the second half of gestation. This dataset was acquired ex vivo using magnetic resonance imaging (MRI) at ultra high field (11.7 teslas), and includes whole-hemisphere T 2 -weighted images at 100 µm isotropic resolution, quantitative relaxometry (T 1 , T 2 , and ), and high angular resolution diffusion-weighted images for multiple b-values at 200 µm. Brains larger than the workspace of the small-bore scanner were sectioned into blocks, acquired blockwise, and digitally reconstructed using a dedicated semi-automatic method. This initial data release includes three gestational ages (18, 27, and 31 post-conceptional weeks) with a complete set of anatomical images, relaxometry maps, and diffusion-based microstructure measurements. This dataset offers new opportunities to investigate neurodevelopmental processes that have not yet been explored with full three-dimensional coverage at this resolution by MRI, and may serve as a multimodal mesoscopic reference template for the fetal brain.

In the spirit of the historic Millennium Prize Problems that heralded a new era for mathematics, the newly formed International Society for Tractography (IST) has launched the Millennium Pathways for Tractography, a community-driven roadmap designed to shape the future of the field. Conceived during the inaugural Tract-Anat Retreat, this initiative reflects a collective vision for advancing tractography over the coming decade and beyond. The roadmap consists of 40 grand challenges, developed by international experts and organized into seven categories spanning three overarching themes: neuroanatomy, tractography methods, and clinical applications. By defining shared short-, medium-, and long-term goals, these pathways provide a structured framework to confront fundamental limitations, promote rigorous validation, and accelerate the translation of tractography into a robust tool for neuroscience and medicine. Ultimately, the Millennium Pathways aim to guide and inspire future research and collaboration, ensuring the continued scientific and clinical relevance of tractography well into the future.

Brain folding patterns have been reported to carry clinically relevant information. The brain folds mainly during the last trimester of pregnancy, and the process might be durably disturbed by preterm birth. Yet little is known about preterm-specific patterns. In this work, we train a self-supervised model (SimCLR) on the UKBioBank cohort (21070 adults) to represent the right superior temporal sulcus (STS) region and apply it to sulci images of 374 babies from the dHCP database, containing preterms and full-terms, and acquired at 40 weeks post-menstrual age. We find a lower variability in the preterm embeddings, supported by the identification of a knob pattern, missing in the extremely preterm population.