Non-invasive in-utero quantification of vascular reactivity in human placenta.

OBJECTIVE: Placental vascular reactivity (PlVR) indicates the ability of the placental vasculature to match blood supply to fetal demand. Many pregnancy disorders alter the characteristics of PlVR, resulting in suboptimal oxygen delivery, although current understanding is limited by the lack of non-invasive, repeatable methods to measure PlVR in utero. Our objective was to quantify PlVR by measuring the placental response to transient changes in maternal carbon dioxide (CO2) using blood-oxygen-level-dependent (BOLD) magnetic resonance imaging (MRI). We hypothesized that PlVR will increase with gestational age to meet the changing demands of a growing fetus, and that PlVR will be driven by a maternal response to changes in CO2 concentration. METHODS: This was a cross-sectional study of 35 women with a healthy singleton pregnancy, of whom 31 were included in the analysis. The median gestational age was 32.6 (range, 22.6-38.4) weeks. Pregnant women were instructed to follow audiovisual breathing cues during a MRI scan. Maternal end-tidal CO2 (EtCO2) was measured concurrently with resting placental BOLD MRI for a total of 7-8 min. Preprocessing of magnetic resonance images consisted of manual delineation of placental anatomy and motion correction. In each placental voxel, vascular reactivity was computed using a coherence-weighted general linear model between MRI signal and EtCO2 stimulus. Global PlVR was computed as the mean of voxel-wise PlVR values across the placenta. RESULTS: PlVR, quantified by the placental response to induced, transient changes in maternal CO2, was consistently measured in utero using BOLD MRI. PlVR increased non-linearly with advancing gestational age (P < 0.001) and was higher on the fetal side of the placenta. PlVR was associated positively with fetal brain volume after accounting for gestational age. PlVR did not show any significant associations with maternal characteristics. CONCLUSIONS: We present, for the first time, a non-invasive paradigm to quantify PlVR in ongoing human pregnancies without the use of exogenous gases or contrast agents. Our findings suggest that PlVR is driven by a fetal response to changes in maternal CO2. Ease of translation to the clinical setting makes PlVR a promising biomarker for the identification and management of high-risk pregnancies. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Regional brain injury on conventional and diffusion weighted MRI is associated with outcome after pediatric cardiac arrest.

BACKGROUND: To assess regional brain injury on magnetic resonance imaging (MRI) after pediatric cardiac arrest (CA) and to associate regional injury with patient outcome and effects of hypothermia therapy for neuroprotection. METHODS: We performed a retrospective chart review with prospective imaging analysis. Children between 1 week and 17 years of age who had a brain MRI in the first 2 weeks after CA without other acute brain injury between 2002 and 2008 were included. Brain MRI (1.5 T General Electric, Milwaukee, WI, USA) images were analyzed by 2 blinded neuroradiologists with adjudication; images were visually graded. Brain lobes, basal ganglia, thalamus, brain stem, and cerebellum were analyzed using T1, T2, and diffusion-weighted images (DWI). RESULTS: We examined 28 subjects with median age 1.9 years (IQR 0.4-13.0) and 19 (68 %) males. Increased intensity on T2 in the basal ganglia and restricted diffusion in the brain lobes were associated with unfavorable outcome (all P < 0.05). Therapeutic hypothermia had no effect on regional brain injury. Repeat brain MRI was infrequently performed but demonstrated evolution of lesions. CONCLUSION: Children with lesions in the basal ganglia on conventional MRI and brain lobes on DWI within the first 2 weeks after CA represent a group with increased risk of poor outcome. These findings may be important for developing neuroprotective strategies based on regional brain injury and for evaluating response to therapy in interventional clinical trials.

ADC Histogram Analysis of Pediatric Low-Grade Glioma Treated with Selumetinib: A Report from the Pediatric Brain Tumor Consortium.

BACKGROUND AND PURPOSE: Selumetinib is a promising MAP (mitogen-activated protein) kinase (MEK) 1/2 inhibitor treatment for pediatric low-grade gliomas. We hypothesized that MR imaging-derived ADC histogram metrics would be associated with survival and response to treatment with selumetinib. MATERIALS AND METHODS: Children with recurrent, refractory, or progressive pediatric low-grade gliomas who had World Health Organization grade I pilocytic astrocytoma with KIAA1549-BRAF fusion or the BRAF V600E mutation (stratum 1), neurofibromatosis type 1-associated pediatric low-grade gliomas (stratum 3), or sporadic non-neurofibromatosis type 1 optic pathway and hypothalamic glioma (OPHG) (stratum 4) were treated with selumetinib for up to 2 years. Quantitative ADC histogram metrics were analyzed for total and enhancing tumor volumes at baseline and during treatment. RESULTS: Each stratum comprised 25 patients. Stratum 1 responders showed lower values of SD of baseline ADC_total as well as a larger decrease with time on treatment in ADC_total mean, mode, and median compared with nonresponders. Stratum 3 responders showed a greater longitudinal decrease in ADC_total. In stratum 4, higher baseline ADC_total skewness and kurtosis were associated with shorter progression-free survival. When all 3 strata were combined, responders showed a greater decrease with time in ADC_total mode and median. Compared with sporadic OPHG, neurofibromatosis type 1-associated OPHG had lower values of ADC_total mean, mode, and median as well as ADC_enhancement mean and median and higher values of ADC_total skewness and kurtosis at baseline. The longitudinal decrease in ADC_total median during treatment was significantly greater in sporadic OPHG compared with neurofibromatosis type 1-associated OPHG. CONCLUSIONS: ADC histogram metrics are associated with progression-free survival and response to treatment with selumetinib in pediatric low-grade gliomas.

Ventricular and total brain volumes in infants with congenital heart disease: a longitudinal study.

BACKGROUND: Quantitative MRI techniques help recognize delayed brain development in fetuses with congenital heart disease (CHD). Ventriculomegaly became an early marker of brain dysmaturity. OBJECTIVE: Evaluate longitudinally the cerebral ventricular and total brain volumes (TBV) in infants with CHD compared to normal neonates: testing the fetal brain dysmaturity and following its progression post operatively. STUDY DESIGN: Fetal and post-operative MRIs were obtained on fetuses/neonates with CHD requiring invasive intervention within the first month after birth. Volumetric measurement was done with ITK-SNAP and analyzed post-hoc. RESULTS: Ten cases were evaluated with a significant decrease in ventricular volumes from the fetal to the post-operative neonatal timepoint (p = 0.0297). Infants with HLHS had a significant increase postoperatively in their TBV (p = 0.0396). CONCLUSIONS: TBV increased post operatively inversely mirrored by the decrement of the ventricular volumes. This could be explained by the establishment an increase of brain blood flow after surgery.

Fetal microphthalmia diagnosed by magnetic resonance imaging.

We report a case of fetal microphthalmia diagnosed midtrimester by ultrasound and fetal MRI. Included is a comparison of MRI measurements of normal fetuses at similar gestational age and a review of the literature.

Ventricular shape and relative position abnormalities in preterm neonates.

Recent neuroimaging findings have highlighted the impact of premature birth on subcortical development and morphological changes in the deep grey nuclei and ventricular system. To help characterize subcortical microstructural changes in preterm neonates, we recently implemented a multivariate tensor-based method (mTBM). This method allows to precisely measure local surface deformation of brain structures in infants. Here, we investigated ventricular abnormalities and their spatial relationships with surrounding subcortical structures in preterm neonates. We performed regional group comparisons on the surface morphometry and relative position of the lateral ventricles between 19 full-term and 17 preterm born neonates at term-equivalent age. Furthermore, a relative pose analysis was used to detect individual differences in translation, rotation, and scale of a given brain structure with respect to an average. Our mTBM results revealed broad areas of alterations on the frontal horn and body of the left ventricle, and narrower areas of differences on the temporal horn of the right ventricle. A significant shift in the rotation of the left ventricle was also found in preterm neonates. Furthermore, we located significant correlations between morphology and pose parameters of the lateral ventricles and that of the putamen and thalamus. These results show that regional abnormalities on the surface and pose of the ventricles are also associated with alterations on the putamen and thalamus. The complementarity of the information provided by the surface and pose analysis may help to identify abnormal white and grey matter growth, hinting toward a pattern of neural and cellular dysmaturation.

Synchronous Aberrant Cerebellar and Opercular Development in Fetuses and Neonates with Congenital Heart Disease: Correlation with Early Communicative Neurodevelopmental Outcomes, Initial Experience.

Patients with congenital heart disease (CHD) demonstrate multidomain cognitive delays. Cingulo-opercular and cerebellar brain networks are critical to language functions. This is a description of our initial experience aiming to identify an anatomic correlate for CHD patients with expressive language delays. Fetal CHD patients, prospectively enrolled, underwent serial fetal (1.5T), postnatal pre- and postoperative (3T) MRI. Non-CHD patients were enrolled retrospectively from the same epoch. Comparable fetal and neonatal T2 contrast was used for manual linear cross-sectional measurement. Multivariable analysis was used for adjustments and curve fitting. Neurodevelopment was assessed with Battelle Developmental Inventory, 2nd ed. between 9 and 36 months of age. This interim analysis included patients from our longitudinal CHD study who had fetal, postnatal imaging and neurodevelopmental data-yielding a total of 62 mothers (11 CHD fetuses and 51 non-CHD fetuses). Altered brain trajectories were seen in selected cerebellar and opercular measurements in CHD patients compared with the non-CHD group. Smaller inferior cerebellar vermis measurements were associated with multiple communication-related abnormalities. Altered early structural development of the cerebellum and operculum is present in patients with CHD, which correlates with specific neurodevelopmental abnormalities.

Quantitative short echo time 1H-MR spectroscopy of untreated pediatric brain tumors: preoperative diagnosis and characterization.

PURPOSE: Our aims were to evaluate the metabolic profiles of pediatric brain tumors with short echo time (TE) MR spectroscopy and absolute quantitation of metabolite concentrations (in mmol/kg of tissue) and to describe metabolic features that distinguish individual tumor types and that may help to improve preoperative diagnosis of specific tumors. METHODS: MR imaging examinations of 60 patients with untreated brain tumors (14 medulloblastomas, 5 anaplastic astrocytomas, 3 low-grade astrocytomas, 17 pilocytic astrocytomas, 4 anaplastic ependymomas, 5 ependymomas, 3 choroid plexus papillomas, 3 choroid plexus carcinomas, and 6 pineal germinomas) were reviewed. Single-voxel proton MR spectroscopy with a TE of 35 ms was performed and absolute metabolite concentrations were determined by using fully automated quantitation. RESULTS: Taurine (Tau) was significantly elevated in medulloblastomas (P < .00001) compared with all other tumors pooled (All Other). Tau was also observed consistently, at lower concentration, in pineal germinomas. Creatine (Cr) was significantly reduced in pilocytic astrocytomas, distinguishing them from All Other (P < .000001). The MR spectra of choroid plexus papillomas exhibited low Cr (P < .01) concentrations; however, myoinositol was elevated (P < .01) and total choline (tCho) (P < .0001) was reduced relative to All Other. Choroid plexus carcinomas had low Cr (P < .01 versus All Other) and the lowest Cr/tCho ratio (P < .0001 versus All Other) among all tumors studied. Guanidinoacetate was reduced in low-grade astrocytomas and anaplastic astrocytomas (P < .00001) versus All Other, whereas ependymoma and anaplastic ependymomas exhibited particularly low N-acetylaspartate (P < .00001 versus All Other). CONCLUSION: Quantitative proton MR spectroscopy reveals features of pediatric brain tumors that are likely to improve preoperative diagnoses.

Corrigendum to "Developmental synergy between thalamic structure and interhemispheric connectivity in the visual system of preterm infants" [NeuroImage: Clinical 8 (2015) 462-472].

[This corrects the article DOI: 10.1016/j.nicl.2015.05.014.].

Regional differences in fiber tractography predict neurodevelopmental outcomes in neonates with infantile Krabbe disease.

BACKGROUND: Krabbe disease is a fatal neurodegenerative disease caused by rapid demyelination of the central and peripheral nervous systems. The only available treatment, unrelated umbilical cord blood transplantation, is effective only if performed before clinical symptoms appear. Phenotypic expressions of disease-causing mutations vary widely, but genotype-phenotype relationships are unclear. Therefore, we evaluated diffusion tensor imaging (DTI) tractography with volumetric analysis as a biomarker of early white matter changes and functional disability in presymptomatic infants. METHODS: We obtained DTI and structural scans of newborns with early-infantile Krabbe disease (n = 9) diagnosed by family history or newborn screening. We compared white matter fiber tract properties to those of normal controls (n = 336) and assessed the ability of tract-based properties to predict longitudinal development in four functional domains (cognitive, fine motor, gross motor, adaptive behavior) after treatment with unrelated umbilical cord blood transplantation. We also assessed the relationship between the standard evaluation (modified Loes score) and DTI results, and the volumetric differences between the Krabbe subjects and normal controls. FINDINGS: Reductions in fractional anisotropy were significant in the corticospinal tract in the Krabbe patients compared to controls, which strongly correlated with motor and cognitive outcomes after transplantation. Significant regional differences were observed in the splenium and uncinate fasciculus in Krabbe patients and these differences correlated only with cognitive outcomes. Regional brain volumes of Krabbe patients were slightly larger than controls. Loes scores did not correlate with DTI results. INTERPRETATION: Neonatal microstructural abnormalities correlate with neurodevelopmental treatment outcomes in patients treated for infantile Krabbe disease. DTI with quantitative tractography is an excellent biomarker for evaluating infants with Krabbe disease identified through newborn screening.

Parametric Response Mapping of Apparent Diffusion Coefficient as an Imaging Biomarker to Distinguish Pseudoprogression from True Tumor Progression in Peptide-Based Vaccine Therapy for Pediatric Diffuse Intrinsic Pontine Glioma.

BACKGROUND AND PURPOSE: Immune response to cancer therapy may result in pseudoprogression, which can only be identified retrospectively and may disrupt an effective therapy. This study assesses whether serial parametric response mapping (a voxel-by-voxel method of image analysis also known as functional diffusion mapping) analysis of ADC measurements following peptide-based vaccination may help prospectively distinguish progression from pseudoprogression in pediatric patients with diffuse intrinsic pontine gliomas. MATERIALS AND METHODS: From 2009 to 2012, 21 children, 4-18 years of age, with diffuse intrinsic pontine gliomas were enrolled in a serial peptide-based vaccination protocol following radiation therapy. DWI was acquired before immunotherapy and at 6-week intervals during vaccine treatment. Pseudoprogression was identified retrospectively on the basis of clinical and radiographic findings, excluding DWI. Parametric response mapping was used to analyze 96 scans, comparing ADC measures at multiple time points (from the first vaccine to up to 12 weeks after the vaccine was halted) with prevaccine baseline values. Log-transformed fractional increased ADC, fractional decreased ADC, and parametric response mapping ratio (fractional increased ADC/fractional decreased ADC) were compared between patients with and without pseudoprogression, by using generalized estimating equations with inverse weighting by cluster size. RESULTS: Median survival was 13.1 months from diagnosis (range, 6.4-24.9 months). Four of 21 children (19%) were assessed as experiencing pseudoprogression. Patients with pseudoprogression had higher fitted average log-transformed parametric response mapping ratios (P = .01) and fractional decreased ADCs (P = .0004), compared with patients without pseudoprogression. CONCLUSIONS: Serial parametric response mapping of ADC, performed at multiple time points of therapy, may distinguish pseudoprogression from true progression in patients with diffuse intrinsic pontine gliomas treated with peptide-based vaccination.

Developmental changes in neurotransmitter receptor binding in the human periaqueductal gray.

The periaqueductal gray (PAG) plays a central role in the integration of defense responses to threatening or stressful stimuli. Little is known about the neurochemical development of the human PAG around the time of birth, when the fetus makes the transition to extrauterine life and independent defense responses are needed. We analyzed receptor binding to selected neurotransmitters implicated in PAG function in 7 fetuses (19 to 26 gestational weeks), 9 infants (38 to 74 postconceptional weeks), 1 child (4 years), and 3 adults (20 to 68 years). Tissue autoradiography was used with radioligands for opioid, nicotinic, muscarinic, kainate, and serotoninergic receptors. By midgestation, binding to nicotinic, muscarinic, serotoninergic, opioid, and kainate receptors is already localized to the human PAG. The subsequent developmental profiles are unique for each radioligand. Binding to nicotinic and serotoninergic receptors decreases significantly from the fetal to mature periods, but at different tempos. In contrast, there is no significant change from midgestation to infancy for muscarinic, kainate, and opioid binding: between infancy and the mature period there is a downward trend in binding for muscarinic and kainate receptors and an upward trend for opioid receptors. This study provides baseline information about the neurochemical development of the human PAG in early life. This information is of value in considering the neurochemical substrate of the maturation of defense responses in human infancy, and in evaluating potential neurochemical disorders of the developing human PAG.

Developmental changes in [3H]lysergic acid diethylamide ([3H]LSD) binding to serotonin receptors in the human brainstem.

The ontogeny of serotonin receptors in the human brainstem is largely unknown, despite the putative roles of serotonin in neural development, synaptic transmission, brainstem modulation of vegetative functions, and clinical disorders of serotonergic function. This study provides baseline information about the quantitative distribution of [3H]LSD binding to serotonergic receptors (5-HT1A-1D, 5-HT2) in the human brainstem, from midgestation through maturity, with a focus upon early infancy. Brainstems were analyzed from 5 fetuses (19-25.5 weeks postconception), 5 infants (42-55.5 weeks postconception), and 3 mature individuals (4, 20, and 52 years). Tissue autoradiography was used with [3H]LSD for total serotonergic receptor binding and [3H]LSD and serotonin for nonspecific binding; computer-based quantitation was applied. The highest levels of [3H]LSD binding occurred prenatally throughout the brainstem. At all ages, the highest relative binding localized to the rostral raphe. A marked decline in [3H]LSD binding occurred between the midgestation and infancy in brainstem regions involved in control of cardiovascular function, respiration, and pain. The fetal peak in [3H]LSD binding to 5-HT receptors is consistent with a trophic role of serotonin in immature human brainstem, and a decrease, between midgestation and infancy, in serotonergic modulation of vegetative functions controlled by the brainstem.

Decreased kainate receptor binding in the arcuate nucleus of the sudden infant death syndrome.

The human arcuate nucleus is postulated to be homologous to ventral medullary surface cells in animals that participate in ventilatory and blood pressure responses to hypercarbia and asphyxia. Recently, we reported a significant decrease in muscarinic cholinergic receptor binding in the arcuate nucleus in victims of the sudden infant death syndrome compared with control patients that died of acute causes. To test the specificity of the deficit to muscarinic cholinergic binding, we examined kainate binding in the arcuate nucleus in the same database. We assessed 3H-kainate binding to kainate receptors with tissue receptor autoradiography in 17 brainstem nuclei. Analysis of covariance was used to examine differences in binding by diagnosis, adjusted for postconceptional age (the covariate). Cases were classified as SIDS, 47; acute control, 15; and chronic group with oxygenation disorder, 17. (Acute controls are infants who died suddenly and unexpectedly and in whom a complete autopsy established a cause of death). The arcuate nucleus was the only region in which there was a significant difference in the age-adjusted mean kainate binding between the SIDS group (37+/-2 fmol/mg tissue) and both the acute controls (77+/-4 fmol/mg tissue) (p < 0.0001) and the chronic group (69+/-4 fmol/mg tissue) (p < 0.0001). There was a positive correlation between the density of muscarinic cholinergic and kainate binding in the SIDS cases only (R = 0.460; p = 0.003). The neurotransmitter deficit in the arcuate nucleus in SIDS victims involves more than one receptor type relevant to carbon dioxide and blood pressure responses at the ventral medullary surface.

Brainstem 3H-nicotine receptor binding in the sudden infant death syndrome.

Maternal cigarette smoking during pregnancy has been shown to be a major risk factor for the sudden infant death syndrome (SIDS). We hypothesized that SIDS is associated with altered 3H-nicotine binding to nicotinic receptors in brainstem nuclei related to cardiorespiratory control and/or arousal. We analyzed 3H-nicotine binding in 14 regions in SIDS and control brainstems using quantitative tissue receptor autoradiography. Three groups were analyzed: SIDS (n = 42), acute controls (n = 15), and a chronic group with oxygenation disorders (n = 18). The arcuate nucleus, postulated to be important in cardiorespiratory control and abnormal in at least some SIDS victims, contained binding below the assay detection limits in all (SIDS and control) cases. We found no significant differences among the 3 groups in mean 3H-nicotine binding in the 14 brainstem sites analyzed. When a subset of the cases were stratified by the history of the presence or absence of maternal cigarette smoking during pregnancy, however, we found that there was no expected increase (upregulation) of nicotinic receptor binding in SIDS cases exposed to cigarette smoke in utero in 3 nuclei related to arousal or cardiorespiratory control. This finding raises the possibility that altered development of nicotinic receptors in brainstem cardiorespiratory and/or arousal circuits put at least some infants, i.e. those exposed to cigarette smoke in utero, at risk for SIDS, and underscores the need for further research into brainstem nicotinic receptors in SIDS in which detailed correlations with smoking history can be made.

Alpha2 receptor binding in the medulla oblongata in the sudden infant death syndrome.

The sudden infant death syndrome (SIDS) is the leading cause of postnatal infant mortality in the United States. Its etiology remains unknown. We propose that SIDS, or a subset of SIDS, is due to a failure of autoresuscitation, a protective brainstem response to asphyxia or hypoxia, in a vulnerable infant during a critical developmental period. Gasping is an important component of autoresuscitation that is thought to be mediated by the "gasping center" in the lateral tegmentum of the medulla, a region homologous in its cytoarchitecture and chemical anatomy to the intermediate reticular zone (IRZ) in the human. Since we found that [3H]para-aminoclonidine ([3H]PAC) binding to alpha2-adrenergic receptors localizes to this region in human infants and, thereby provides a neurochemical marker for it, we tested the hypothesis that [3H]PAC binding to alpha2-adrenergic receptors is decreased in the IRZ in SIDS victims. Using quantitative tissue autoradiography with [3H]PAC as the radioligand and phentolamine as the displacer, we analyzed alpha2-receptor binding density in the IRZ, as well as in 7 additional sites for comparison, in 10 SIDS and 10 control medullae. There were no significant differences in alpha2 receptor binding in the IRZ, vagal nuclei, or other medullary sites examined between SIDS and control cases. These results suggest that the putative gasping defect in the IRZ in SIDS victims is not related to [3H]PAC binding to alpha2-adrenergic receptors.

Decreased serotonergic receptor binding in rhombic lip-derived regions of the medulla oblongata in the sudden infant death syndrome.

The sudden infant death syndrome (SIDS) is postulated to result from a failure of homeostatic responses to life-threatening challenges (e.g. asphyxia, hypercapnia) during sleep. The ventral medulla participates in sleep-related homeostatic responses, including chemoreception, arousal, airway reflex control, thermoregulation, respiratory drive, and blood pressure regulation, in part via serotonin and its receptors. The ventral medulla in humans contains the arcuate nucleus, in which we have shown isolated defects in muscarinic and kainate receptor binding in SIDS victims. We also have demonstrated that the arcuate nucleus is anatomically linked to the nucleus raphé obscurus, a medullary region with serotonergic neurons. We tested the hypothesis that serotonergic receptor binding is decreased in both the arcuate nucleus and nucleus raphé obscurus in SIDS victims. Using quantitative autoradiography, 3H-lysergic acid diethylamide (3H-LSD binding) to serotonergic receptors (5-HT1A-D and 5-HT2 subtypes) was measured blinded in 19 brainstem nuclei. Cases were classified as SIDS (n = 52), acute controls (infants who died suddenly and in whom a complete autopsy established a cause of death) (n = 15), or chronic cases with oxygenation disorders (n = 17). Serotonergic binding was significantly lowered in the SIDS victims compared with controls in the arcuate nucleus (SIDS, 6 +/- 1 fmol/mg tissue; acutes, 19 +/- 1; and chronics, 16 +/- 1; p = 0.0001) and n. raphé obscurus (SIDS, 28 +/- 3 fmol/mg tissue; acutes, 66 +/- 6; and chronics, 59 +/- 1; p = 0.0001). Binding, however, was also significantly lower (p < 0.05) in 4 other regions that are integral parts of the medullary raphé/serotonergic system, and/or are derived, like the arcuate nucleus and nucleus raphé obscurus, from the same embryonic anlage (rhombic lip). These data suggest that a larger neuronal network than the arcuate nucleus alone is involved in the pathogenesis of SIDS, that is, a network composed of inter-related serotonergic nuclei of the ventral medulla that are involved in homeostatic mechanisms, and/or are derived from a common embryonic anlage.

Three-dimensional distribution of [3H]quinuclidinyl benzilate binding to muscarinic cholinergic receptors in the developing human brainstem.

Acetylcholine has been implicated in brainstem mechanisms of cardiac and ventilatory control, arousal, rapid eye movement (REM) sleep, and cranial nerve motor activity. Virtually nothing is known about the developmental profiles of cholinergic perikarya, fibers, terminals, and/or receptors in the brainstems of human fetuses and infants. This study provides baseline information about the quantitative distribution of muscarinic cholinergic receptors in fetal and infant brainstems. Brainstem sections were analyzed from 6 fetuses (median age: 21.5 postconceptional weeks), 4 premature infants (median age: 26 postconceptional weeks), and 11 infants (median age: 53 postconceptional weeks). One child and three adult brainstems were examined as indices of maturity for comparison. The postmortem interval in all cases was less than or equal to 24 hours (median: 10 hours). Muscarinic receptors were localized by autoradiographic methods with the radiolabeled antagonist [3H]quinuclidinyl benzilate ([3H]QNB). Computer-based methods permitted quantitation of [3H]QNB binding in specific nuclei and three-dimensional reconstructions of binding patterns. By midgestation, muscarinic cholinergic receptor binding is already present and regionally distributed, with the highest binding levels in the interpeduncular nucleus, inferior colliculus, griseum pontis, nucleus of the solitary tract, motor cranial nerve nuclei, and reticular formation. During the last half of gestation, [3H]QNB binding decreases in most, but not all of the nuclei sampled. The most substantial decline occurs in the reticular formation of the medulla and pons, a change that is not fully explained by progressive myelination and lipid quenching. Binding levels remain essentially constant in the inferior olive and griseum pontis. Around the time of birth or shortly thereafter, the relative distribution of binding becomes similar to that in the adult, with the highest levels in the interpeduncular nucleus and griseum pontis, although binding levels are higher overall in the infant. In the rostral pontine reticular formation, paramedian bands of high muscarinic binding are present which do not correspond to a cytoarchitectonically defined nucleus. By analogy to animal studies, these bands may comprise a major cholinoreceptive region of the human rostral pontine reticular formation involved in REM sleep. In the human interpeduncular nucleus in all age periods examined, muscarinic binding localizes to the lateral portions bilaterally, indicative of a heterogeneous chemoarchitecture. Muscarinic binding is high in the arcuate nucleus, a component of the putative respiratory chemosensitive fields along the ventral surface of the infant medulla. This observation is consistent with the known effects of muscarinic agents on chemosensitivity and ventilatory responses applied to the ventral medullary surface in animal models. The nonuniform distribution of muscarinic binding in the caudorostral plane in individual brainstem nuclei, as illustrated by three-dimensional reconstructions, underscores the need for rigorous sampling at precisely matched levels in quantitative studies. This study provides basic information toward understanding the neurochemical basis of brainstem disorders involving dysfunction of autonomic and ventilatory control, arousal, and REM sleep in preterm and full-term newborns and infants and for developing cholinergic drugs for such disorders in the pediatric population.

Differential expression of glutamate receptor subtypes in human brainstem sites involved in perinatal hypoxia-ischemia.

This study delineates the development of N-methyl-D-aspartate (NMDA) and non-NMDA receptor binding in the human brainstem, particularly as it relates to issues of the trophic effects of glutamate, the glutamate-mediated ventilatory response to hypoxia, and regional excitotoxic vulnerability to perinatal hypoxia-ischemia. We used tissue autoradiography to map the development of binding to NMDA, alpha-amino-3-hydroxy-5-methyl-4-isoxazole-proprionate (AMPA), and kainate receptors in brainstem sites involved in the glutamate ventilatory response to hypoxia, as well as recognized sites vulnerable to perinatal hypoxia-ischemia. NMDA receptor/channel binding was virtually undetectable in all regions of the human fetal brainstem at midgestation, an unexpected finding given the trophic role for NMDA receptors in early central nervous system maturation in experimental animals. In contrast, non-NMDA (AMPA and kainate) receptor binding was markedly elevated in multiple nuclei at midgestation. Although NMDA binding increased between midgestation and early infancy to moderately high adult levels, AMPA binding dramatically fell over the same time period to low adult levels. High levels of kainate binding did not change significantly between midgestation and infancy, except for an elevation in the infant compared with fetal inferior olive; after infancy, kainate binding decreased to negligible adult levels. Our data further suggest a differential development of components of the NMDA receptor/channel complex. This baseline information is critical in considering glutaminergic mechanisms in human brainstem development, physiology, and pathology.

Developmental changes in heterogeneous patterns of neurotransmitter receptor binding in the human interpeduncular nucleus.

The interpeduncular nucleus (IPN) exhibits many complex features, including multiple subnuclei, widespread projections with the forebrain and brainstem, and neurotransmitter heterogeneity. Despite the putative importance of this nucleus, very little is known about its neurochemical development in the human. The human IPN is cytoarchitectonically simple, unlike the rat IPN, which displays considerable heterogeneity. In the following study, we hypothesized that the developing human IPN is neurochemically heterogeneous despite its cytological simplicity. The chemoarchitecture in this study was defined by neurotransmitter receptor binding patterns by using quantitative tissue autoradiography for the muscarinic, nicotinic, serotoninergic, opioid, and kainate receptors. We examined neurotransmitter receptor binding in the developing human IPN in a total of 15 cases. The midbrains of five midgestational fetuses (19-26 gestational weeks) and six infants (38-74 postconceptional weeks) were examined. The midbrain of one child (4 years) and three adults (20-68 years) were analyzed as indices of maturity. At all ages examined, high muscarinic binding was localized to the lateral subdivision of the IPN, high serotoninergic binding was localized to the dorsal IPN, and high opioid receptor binding was localized to the medial IPN. The developmental profile was unique for each radioligand. We report a heterogenous distribution of neurotransmitter receptor binding in the developing human IPN, which supports a complex role for it in human brain function.