Ashok Panigrahy

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.

Hypoxic-ischemic brain injury in infants with congenital heart disease dying after cardiac surgery

Cardiac surgery for congenital heart disease is performed increasingly earlier in infancy, including in the neonatal period. With increased survival of infants, there is growing concern about the long-term neurological sequelae of hypoxic-ischemic injury due to congenital heart disease itself prior to surgery, corrective surgery with the use of low-flow cardiopulmonary bypass (CPB) and/or deep hypothermic circulatory arrest (DHCA), and/or unstable hemodynamic factors postoperatively. In analyzing the neuropathology of 38 infants dying after cardiac surgery, we tested a set of questions related to the severity and patterns of brain injury, CPB, DHCA, and age of the infants at the time of surgery. In all infants dying after cardiac surgery, irrespective of the modality, cerebral white matter damage [periventricular leukomalacia (PVL) or diffuse white matter gliosis] was the most significant lesion in terms of severity and incidence, followed by a spectrum of gray matter lesions. There was no significant association between the duration of deep hypothermic circulatory arrest and the degree of severity of overall brain injury, and the pattern of brain injury was similar irrespective of the modality of cardiac surgery. There was no significant association between the age at the time of surgery (neonatal versus postneonatal) and the severity of overall brain injury. The patterns of brain injury were not age-related in the limited time-frame analyzed, except that infants who developed acute PVL after both closed and DHCA/CPB surgery (14/38 infants, 34%) were significantly younger at death (median age 13.0xa0days) compared to unaffected infants (median age at death 42.5xa0days) (P=0.031). This observation suggests that neonatal (<30xa0postnatal days), but not postneonatal (>30xa0postnatal days), brains are at risk for acute PVL, and likely reflects the vulnerability of immature (pre-myelinating) white matter to hypoxia-ischemia.

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 = 8). 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.

Somatosensory lateralization in the newborn brain

Since the onset and early postnatal development of hemispheric lateralization in the human brain are unknown, we studied cortical activation induced by passive extension and flexion of the hand in neonates using functional magnetic resonance imaging (fMRI). In contrast to that seen in older age groups, somatosensory areas in the pre- and postcentral gyri of the neonate showed no significant hemispheric lateralization at term. Instead, our findings from independent left- and right-hand experiments suggest the presence of an emerging trend of contralateral lateralization of the somatosensory system at around term.

Neuroimaging of pediatric brain tumors: from basic to advanced magnetic resonance imaging (MRI).

In this review, the basic magnetic resonance concepts used in the imaging approach of a pediatric brain tumor are described with respect to different factors including understanding the significance of the patient’s age. Also discussed are other factors directly related to the magnetic resonance scan itself including evaluating the location of the tumor, determining if the lesion is extra-axial or intra-axial, and evaluating the contrast characteristics of the lesion. Of note, there are key imaging features of pediatric brain tumors, which can give information about the cellularity of the lesion, which can then be confirmed with advanced magnetic resonance imaging (MRI) techniques. The second part of this review will provide an overview of the major advanced MRI techniques used in pediatric imaging, particularly, magnetic resonance diffusion, magnetic resonance spectroscopy, and magnetic resonance perfusion. The last part of the review will provide more specific information about the use of advanced magnetic resonance techniques in the evaluation of pediatric brain tumors.

Metabolism of diffuse intrinsic brainstem gliomas in children

Progress in the development of effective therapies for diffuse intrinsic brainstem gliomas (DIBSGs) is compromised by the unavailability of tissue samples and the lack of noninvasive markers that can characterize disease status. The purpose of this study was to compare the metabolic profile of DIBSGs with that of astrocytomas elsewhere in the CNS and to determine whether the measurement of metabolic features can improve the assessment of disease status. Forty in vivo MR spectroscopy (MRS) studies of 16 patients with DIBSG at baseline and after radiation therapy were retrospectively reviewed. Control data for baseline studies of DIBSGs were obtained from 14 untreated regular and anaplastic astrocytomas. All spectra were acquired with single-voxel, short echo-time (35 ms), point-resolved spectroscopy. Absolute metabolite concentrations (mmol/kg) and lipid intensities (arbitrary units) were determined. At baseline, creatine and total choline (tCho) were significantly lower in DIBSGs than in astrocytomas elsewhere in the CNS (4.3 +/- 1.1 vs. 7.5 +/- 1.9 mmol/kg, p < 0.001; 1.9 +/- 0.7 vs. 4.2 +/- 2.6, p < 0.001). Serial MRS in individual subjects revealed increasing levels of tCho (p < 0.05) and lipids (p < 0.05) and reduced ratios of N-acetylaspartate, creatine, and myoinositol relative to tCho (all p < 0.01). Metabolic progression defined by increased tCho concentration in serial MRS preceded clinical deterioration by 2.4 +/- 2.7 months (p < 0.04). Low tCho of DIBSG at baseline is consistent with low proliferative tumors. Subsequent metabolic changes that have been associated with malignant degeneration preceded clinical deterioration. MRS provides early surrogate markers for disease progression.

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, α‐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. J. Comp. Neurol. 427:196–208, 2000.

Developmental changes in [3H]kainate binding in human brainstem sites vulnerable to perinatal hypoxia-ischemia

The human brainstem is especially susceptible to hypoxia-ischemia in early life. To test the hypothesis that the period of vulnerability of the developing human brainstem to hypoxia-ischemia correlates with a transient elevation in kainate receptor binding, we compared the quantitative distribution of [3H]kainate binding in brainstem nuclei between four fetuses (19-26 gestational weeks), four infants (one to nine months), and three mature individuals (one child and two adults) without neurological disease. Quantitative tissues autoradiography was used. [3H]Kainate binding decreased in all brainstem regions from early life to maturity with the most significant decreases occurring in nuclei thought to be especially vulnerable to perinatal hypoxia-ischemia (e.g. principal inferior olive, griseum pontis, inferior colliculus and reticular core). The highest binding in the fetal and infant period was found primarily in the major cerebellar-relay nuclei. In the inferior olive and arcuate nucleus, binding increased from the fetal to the infant period, and then fell 50-61% to low mature levels. In the griseum pontis, binding decreased 60% between the fetal and mature periods. In the reticular formation, binding fell 67-78% from the fetal to mature period. These data support a correlation between the period of brainstem vulnerability to hypoxia-ischemia in early life to transient elevation in kainate binding, and are particularly relevant to the topographic brainstem patterns in perinatal hypoxia-ischemia of infantile olivary gliosis, pontosubicular necrosis and reticular core damage. Striking localization of [3H]kainate binding to rhombic lip derivatives further suggests that kainate receptors may be involved in the development and function of human brainstem-cerebellar circuitry.

Apparent Diffusion and Fractional Anisotropy of Diffuse Intrinsic Brain Stem Gliomas

BACKGROUND AND PURPOSE: DIBSGs have the worst prognosis among pediatric brain tumors with no improvement of outcome for several decades. In this study, we determined whether diffusion imaging could improve patient stratification and our understanding of the impact of therapies. MATERIALS AND METHODS: Nine baseline and 24 follow-up DTI studies performed in 9 patients on a 1.5T clinical MR imaging scanner were reviewed. ADC and FA were measured for the whole lesion and at 5 anatomic levels: the rostral medulla, caudal pons, midpons, rostral pons, and caudal midbrain. Reference data were obtained from 8 controls with normal brain stem, 6 patients with medulloblastoma, and 7 patients with pilocytic astrocytoma. RESULTS: ADC was higher in untreated DIBSG than in normal brain stem and medulloblastoma (1.14 ± 0.18 [×10−3 mm2/s] versus 0.75 ± 0.06 and 0.56 ± 0.05, both P < .001). FA was lower in DIBSG than in normal brain stem (0.24 ± 0.04 versus 0.43 ± 0.02, P < .001) but was higher than that in pilocytic astrocytoma (0.17 ± 0.05, P < .05). Lower baseline ADC and higher FA correlated with a worse clinical course. Correlations were more significant at the caudal midbrain than in other regions. ADC decreased and FA increased after RT. Changes of FA after RT at the caudal midbrain correlated with event-free survival. CONCLUSIONS: Baseline ADC and FA of DIBSG revealed hypocellular tumors with extensive edema. Diffusion changes after therapy implied reduced edema but did not support a significant response to therapy. The significance of diffusion properties varied with anatomic locations, the caudal midbrain being particularly important.

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-D, 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