RESUMO
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.
Assuntos
Neoplasias Encefálicas , Glioma , Neurofibromatose 1 , Benzimidazóis , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Criança , Imagem de Difusão por Ressonância Magnética , Glioma/diagnóstico por imagem , Glioma/tratamento farmacológico , Glioma/genética , Humanos , Neurofibromatose 1/diagnóstico por imagem , Neurofibromatose 1/tratamento farmacológico , Proteínas Proto-Oncogênicas B-rafRESUMO
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.
Assuntos
Encéfalo , Cardiopatias Congênitas , Encéfalo/diagnóstico por imagem , Feto , Cardiopatias Congênitas/diagnóstico por imagem , Cardiopatias Congênitas/cirurgia , Humanos , Lactente , Recém-Nascido , Estudos Longitudinais , Imageamento por Ressonância MagnéticaRESUMO
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.
Assuntos
Neoplasias do Tronco Encefálico/patologia , Vacinas Anticâncer/uso terapêutico , Imagem de Difusão por Ressonância Magnética/métodos , Glioma/patologia , Adolescente , Neoplasias do Tronco Encefálico/terapia , Criança , Pré-Escolar , Progressão da Doença , Feminino , Glioma/terapia , Humanos , Interpretação de Imagem Assistida por Computador/métodos , Imunização/métodos , Masculino , Estudos RetrospectivosRESUMO
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.
Assuntos
Encéfalo/patologia , Desenvolvimento Infantil , Interpretação de Imagem Assistida por Computador/métodos , Leucodistrofia de Células Globoides/patologia , Vias Neurais/patologia , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Imagem de Tensor de Difusão , Feminino , Humanos , Recém-Nascido , Leucodistrofia de Células Globoides/terapia , Imageamento por Ressonância Magnética , Masculino , Resultado do Tratamento , Substância Branca/patologiaRESUMO
BACKGROUND AND PURPOSE: Patients with transfusional iron overload develop iron deposits in the pituitary gland, which are associated with volume loss and HH. The purpose of this study was to characterize R2 and volumetric data in a healthy population for diagnostic use in patients with transfusional iron overload. MATERIALS AND METHODS: One hundred healthy controls without iron overload between the ages of 2 and 48 were recruited to have MR imaging of the brain to assess their pituitary R2 and volume. Pituitary R2 was assessed with a 8-echo spin-echo sequence, and pituitary volumes, by a 3D spoiled gradient-echo sequence with 1-mm(3) resolution. A 2-component continuous piecewise linear approximation was used for creating volumetric and R2 nomograms. Equations were generated from regression relationships for convenient z-score calculation. RESULTS: Pituitary R2 rose weakly with age (r(2) = 0.19, P < .0001). Anterior and total pituitary volumes increased steadily up to 18 years of age, after which volume slightly decreased. Females had larger pituitary glands, most likely representing their larger lactotroph population. CONCLUSIONS: From these data, a clinician can calculate the z scores for R2 and pituitary volume in patients with iron overload. Normal ranges are well-differentiated from values previously associated with endocrine disease in transfusional siderosis; this finding suggests that preclinical iron overload can be recognized and appropriately treated.
Assuntos
Ferro/metabolismo , Imageamento por Ressonância Magnética , Hipófise/anatomia & histologia , Hipófise/metabolismo , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Ferro/análise , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão , Hipófise/química , Valores de Referência , Adulto JovemRESUMO
BACKGROUND AND PURPOSE: The neuroanatomic substrate of cognitive deficits in long-term survivors of prematurity with PVL is poorly understood. The thalamus is critically involved in cognition via extensive interconnections with the cerebral cortex. We hypothesized that the thalamus is atrophic (reduced in volume) in childhood survivors of prematurity with neuroimaging evidence of PVL and that the atrophy is associated with selective microstructural abnormalities within its subdivisions. MATERIALS AND METHODS: We performed quantitative volumetric and DTI measurements of the thalamus in 17 children with neuroimaging evidence of PVL (mean postconceptional age, 5.6 ± 4.0 years) who were born prematurely and compared these with 74 term control children (5.7 ± 3.4 years). RESULTS: The major findings were the following: 1) a significant reduction in the overall volume of the thalamus in patients with PVL compared with controls (P < .0001), which also correlated with the severity of PVL (P = .001); 2) significantly decreased FA (P = .003) and increased λ(â¥) (P = .02) in the thalamus overall and increased axial, radial, and mean diffusivities in the pulvinar (P < .03), suggesting injury to afferent and efferent myelinated axons; and 3) a positive correlation of pulvinar abnormalities with those of the parieto-occipital white matter in periventricular leukomalacia, suggesting that the pulvinar abnormalities reflect secondary effects of damaged interconnections between the pulvinar and parieto-occipital cortices in the cognitive visual network. CONCLUSIONS: There are volumetric and microstructural abnormalities of the thalamus in preterm children with PVL, very likely reflecting neuronal loss and myelinated axonal injury. The selective microstructural damage in the pulvinar very likely contributes to abnormal cognitive visual processing known to occur in such survivors.
Assuntos
Imagem de Difusão por Ressonância Magnética/métodos , Leucomalácia Periventricular/patologia , Fibras Nervosas Mielinizadas/patologia , Nascimento Prematuro/patologia , Tálamo/patologia , Atrofia , Criança , Feminino , Humanos , Recém-Nascido , Masculino , SobreviventesRESUMO
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⻳ 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.
Assuntos
Astrocitoma/patologia , Neoplasias do Tronco Encefálico/patologia , Imagem de Difusão por Ressonância Magnética/métodos , Meduloblastoma/patologia , Anisotropia , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Bulbo/patologia , Mesencéfalo/patologia , Ponte/patologia , Valor Preditivo dos Testes , PrognósticoRESUMO
BACKGROUND AND PURPOSE: In a subset of in vivo MR spectra acquired from pediatric brain tumors, we have observed an unassigned peak. The goal of this study was to determine the molecule of origin, and the prevalence and concentration of this chemical in various pediatric brain tumors. MATERIALS AND METHODS: Single-voxel point-resolved spectroscopy (PRESS) spectra from 85 patients with brain tumors and 469 control subjects were analyzed. Citrate seemed to be a likely candidate, and model spectra of citrate were added to the basis set of metabolites for automated processing with use of LCModel software. Absolute "apparent" concentrations of citrate and the Cramer-Rao lower bounds (CRLB), indicators for the reliability of detection, were determined. RESULTS: "Apparent" citrate was detected in 26 of 85 patients with CRLB of less than 25%. Diffuse intrinsic brain stem glioma (DIBSG) had the highest mean concentration (4.0 +/- 1.1 mmol/kg in all subjects), and 8 of 12 patients had CRLB less than 25%. A significant reduction of citrate (P < .01) was observed in 6 DIBSGs that had follow-up MR spectroscopy studies after radiation therapy. "Apparent" citrate with CRLB less than 25% was detected in 5 of 22 medulloblastomas (mean citrate, 2.9 +/- 2.2 mmol/kg), in 5 of 14 ependymomas (2.6 +/- 1.8 mmol/kg), 5 of 14 astrocytomas (1.9 +/- 1.2 mmol/kg), and 3 of 23 pilocytic astrocytomas (1.4 +/- 1.1 mmol/kg). In control subjects older than 6 months, CRLB less than 25% was not observed, whereas CRLB less than 25% was observed in 39 of 194 subjects younger than 6 months,. CONCLUSION: MR signal consistent with citrate was observed in pediatric brain tumors and in the developing brain of infants younger than 6 months.
Assuntos
Neoplasias Encefálicas/metabolismo , Encéfalo/metabolismo , Ácido Cítrico/metabolismo , Espectroscopia de Ressonância Magnética/métodos , Adolescente , Adulto , Biomarcadores/metabolismo , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , MasculinoRESUMO
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.
Assuntos
Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/metabolismo , Espectroscopia de Ressonância Magnética , Adolescente , Criança , Pré-Escolar , Humanos , Lactente , Espectroscopia de Ressonância Magnética/métodos , Cuidados Pré-OperatóriosRESUMO
OBJECTIVE: The purpose of this study was to compare both the volumes of the lateral ventricles and the cerebral white matter with gestational age at birth of children with periventricular white matter (PVWM) T2-signal hyperintensities on MR images. The spectrum of neuromotor abnormalities associated with these hyperintensities was also determined. MATERIALS AND METHODS: We retrospectively reviewed the MR images of 70 patients who were between the ages of 1 and 5 years and whose images showed PVWM T2-signal hyperintensities. The patients were divided into premature (n = 35 children) and term (n = 35) groups depending on their gestational age at birth. Volumetric analysis was performed on four standardized axial sections using T2-weighted images. Volumes of interest were digitized on the basis of gray-scale densities of signal intensities to define the hemispheric cerebral white matter and lateral ventricles. Age-adjusted comparisons of volumetric measurements between the premature and term groups were performed using analysis of covariance. RESULTS: The volume of the cerebral white matter was smaller in the premature group (54 +/- 2 cm(3)) than in the term group (79 +/- 3 cm(3), p < 0.0001). The volume of the lateral ventricles was greater among the patients in the premature group (30 +/- 2 cm(3)) than among those in the term group (13 +/- 1 cm(3), p < 0.0001). Fifty percent of all the premature children had spastic diplegia or quadriplegia. Thirty-two percent of all the term children had hypotonia. There were patients in both groups whose PVWM T2-signal hyperintensities did not correlate with any neuromotor abnormalities but were associated with seizures or developmental delays. CONCLUSION: The differences in volumetric measurements of cerebral white matter and lateral ventricles in children with PVWM T2-signal hyperintensities are related to their gestational age at birth. Several neurologic motor abnormalities are found in children with such hyperintensities.
Assuntos
Ventrículos Cerebrais/patologia , Doenças do Prematuro/diagnóstico , Leucomalácia Periventricular/diagnóstico , Imageamento por Ressonância Magnética , Peso ao Nascer , Encéfalo/patologia , Dano Encefálico Crônico/diagnóstico , Cefalometria , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Masculino , Prognóstico , Fatores de RiscoRESUMO
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.
Assuntos
Tronco Encefálico/metabolismo , Receptores Nicotínicos/metabolismo , Morte Súbita do Lactente , Núcleo Arqueado do Hipotálamo/metabolismo , Nível de Alerta/fisiologia , Autorradiografia , Tronco Encefálico/fisiologia , Pré-Escolar , Feminino , Sistema de Condução Cardíaco/fisiologia , Humanos , Processamento de Imagem Assistida por Computador , Lactente , Mães , Gravidez , Sistema Respiratório/inervação , Fumar , TrítioRESUMO
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.
Assuntos
Mesencéfalo/metabolismo , Receptores de Neurotransmissores/metabolismo , Adulto , Animais , Pré-Escolar , Desenvolvimento Embrionário e Fetal/fisiologia , Humanos , Recém-Nascido , Ácido Caínico/metabolismo , Dietilamida do Ácido Lisérgico/metabolismo , Mesencéfalo/embriologia , Mesencéfalo/crescimento & desenvolvimento , Antagonistas Muscarínicos/metabolismo , Naloxona/metabolismo , Nicotina/metabolismo , Quinuclidinil Benzilato/metabolismo , Ensaio Radioligante , Ratos , Receptores Muscarínicos/metabolismo , Receptores Nicotínicos/metabolismo , Receptores de Serotonina/metabolismo , Especificidade da EspécieRESUMO
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.