Biology subjects

McAlonan, G.

Publications and source records attributed to McAlonan, G..

At least 19 recordsLinked to original sources

bioRxiv2026

Development of Neonatal Functional Brain Network Organisation and Its Association with Childhood Neurodevelopmental Outcomes

The human brain undergoes rapid dynamic changes in the neonatal period that are essential for later cognitive and behavioural performance. Using resting-state fMRI data from 394 neonates (325 term-born, 69 preterm-born) within the first month after birth, we characterised the early development of functional network organisation, the effects of preterm birth, and the association between neonatal functional organisation and later neurodevelopmental outcomes in infancy (18 months) and childhood (4-6 years). We found increased functional integration and segregation across a wide range of functional sub-networks and increased mean functional connectivity strength (mean FCS) within the subcortical and cerebellar regions with increasing PMA at scan. Compared with term-born neonates, preterm-born neonates showed significantly lower mean FCS, functional integration and segregation globally. We further showed that whilst neonatal functional brain network organisation was not associated with neurodevelopmental outcomes measured during infancy (18 months), it was associated with later neurodevelopmental outcomes in early childhood (4-6 years). Specifically, higher functional integration and segregation at birth were linked with lower SDQ total difficulties score at 4-6 years. Our findings suggest that neonatal functional brain organisation reflects not only transient developmental processes, but also stable individual differences that provide insight into neurodevelopmental outcomes in later childhood.

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bioRxiv2026

Emergence of long- and short-range functional connectivity shapes neonatal brain gradients

The emergence of macroscale brain organisation during the perinatal period represents a critical but poorly understood process. Using resting-state fMRI in 325 term-born neonates within the first month of postnatal life, we characterised the early emergence of macroscale brain organisation with functional gradients. Neonatal functional gradients showed a distinct pattern compared with the canonical adult gradients: the principal gradient in neonates, separating the primary sensorimotor and visual networks, corresponded to the secondary gradient in adults (sensorimotor-visual axis), whereas the secondary gradient in neonates, spanning from primary visual to association networks, aligned with the principal gradient in adults (sensorimotor-association axis). We identified distance-dependent functional connectivity as a key mechanism shaping perinatal functional gradients and potentially underlying the protracted development of the sensorimotor-association hierarchy in neonates. Regions with a higher proportion of short-range functional connectivity contributed more to the sensorimotor-visual gradient in neonates, while regions with a greater proportion of middle-to long-range functional connectivity drive the sensorimotor-association hierarchy. Together, these findings highlight the critical role of short- and long-range functional connectivity in shaping neonatal macroscale functional hierarchy. Disruptions to this process during the perinatal period may alter macroscale brain organisation and contribute to the early origins of neurodevelopmental conditions. Significance statementMacroscale brain organisation, characterised by functional gradients, is a fundamental feature of the adult brain and is closely linked to neurodevelopmental conditions. Characterising its emergence in early life and the underlying mechanisms is therefore critical for understanding typical and atypical brain development. Here, we showed that macroscale brain organisation is present at birth, with neonatal functional gradients showing a reversed pattern compared to adults, highlighting the early maturation of primary visual and sensorimotor networks. We further demonstrated that the perinatal development of long- and short-range functional connectivity shapes neonatal functional gradients, identifying a potential mechanism through which early disruptions in functional connectivity may contribute to later neurodevelopmental outcomes.

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bioRxiv2025

Functional covariance modes reveal aligned fetal and neonatal brain functional connectomes.

Spatially distributed functional networks are a fundamental property of brain organisation. While these networks are already present at full-term birth, establishing whether they exist before birth remains problematic, given the challenges inherent to in utero fMRI. Here, we introduce a seed-based functional covariance modes (FCMs) approach, which leverages inter-subject variability in connectivity between distinct regions and the rest of the brain to infer whole-brain network configurations. Unlike standard group-level independent component analysis, which consistently fails to reveal spatially distributed neural networks in fetal populations, FCMs successfully delineated a range of brain-wide functional networks in utero with high spatial fidelity to neonatal network maps, including bilateral organisation - a landmark feature of many neonatal functional networks. Furthermore, we demonstrated that bilateral fetal networks preferentially clustered along the brain midline and around cortical limbic territories. In contrast, single-hemisphere dominant networks mapped into areas associated with hemispheric functional asymmetry in the mature brain, including the highly lateralised language circuits. Together, these findings provide coherent evidence that the blueprint for the functional brain architecture, including its functional specialisation, is formed before birth.

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bioRxiv2025

In vivo tractography of human neonatal white-matter pathways underlying hypothalamic and reward functions to study predispositions to neurodevelopmental conditions and obesity

White matter (WM) tracts of the reward, limbic, and autonomic systems implicate the hypothalamus, nucleus accumbens, ventral tegmental area and the amygdala and are associated with autism, ADHD, addiction and obesity. However, since most of these structures remain uncharacterised in vivo in human neonates, research on the early-life predispositions to these long-term "mind and body" conditions and the impact of common fetal exposures such as maternal obesity remains limited. Through the developing human connectome project, we acquired 3T brain diffusion and structural magnetic resonance imaging from healthy neonates born at-term to 137 normal-weight women (controls) and to 28 obese women and scanned at mean 40 weeks+6 days (+/-9 days) postmenstrual age (PMA). We first developed novel tractography protocols to reconstruct anatomical WM pathways for the neonatal medial forebrain bundle, ventral amygdalofugal pathway, amygdalo-accumbens fasciculus, stria terminalis and autonomic dorsal longitudinal fasciculus (DLF). We then quantified WM structure from the mean tract fibre bundle density (FD) and fibre cross-section (FC) and using regression path models evaluated WM change across PMA and the effects of antenatal obesity exposure and neonatal covariates. Lastly, we explored if neonatal WM FD and obesity exposure predicted child psycho-cognitive outcomes and anthropometry at 18 months. We show successful in vivo tractography of tracts with high topographical correspondence to adult histology, including in subcompartments of the hypothalamus and amygdala. The obesity exposure*PMA interaction was significant for mean FD in the bilateral amygdalo-accumbens fasciculus and right uncinate fasciculus. Males had larger FC in these same tracts bilaterally. Antenatal obesity exposure predicted lower cognitive scores and higher WHO weight and height z-scores at 18 months. Toddler reward-seeking temperament was correlated with higher weight zscore and was predicted by higher neonatal FD of the amygdalo-accumbens and uncinate fasciculi. Denser neonatal DLF predicted higher language and cognitive scores and fewer autistic traits at 18 months. In conclusion, we inform on neuroanatomical growth in vivo of discrete multisystemic regulatory networks and present evidence for early-life predispositions to psychological outcomes and obesity.

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bioRxiv2022

Neonatal brain dynamic functional connectivity: impact of preterm birth and association with early childhood neurodevelopment

Brain dynamic functional connectivity characterises transient connections between brain regions, changing over time. Features of brain dynamics have been linked to emotion and cognition in adult individuals, and atypical patterns have been associated with neurodevelopmental conditions such as autism. Although reliable functional brain networks have been consistently identified in neonates, little is known about the early development of dynamic functional connectivity. In this study we characterise dynamic functional connectivity with functional magnetic resonance imaging (fMRI) in the first few weeks of postnatal life in term-born (n = 324) and preterm-born (n = 66) individuals. We show that a dynamic landscape of brain connectivity is already established by the time of birth in the human brain, characterised by six transient states of neonatal functional connectivity with changing dynamics through the neonatal period. The pattern of dynamic connectivity is atypical in preterm-born infants, and associated with atypical social, sensory, and repetitive behaviours measured by the Quantitative Checklist for Autism in Toddlers (Q-CHAT) scores at 18 months of age.

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bioRxiv2022

Clinical, socio-demographic, and parental correlates of early autism traits

BackgroundAutism traits emerge between the ages of 1 and 2. It is not known if experiences which increase the likelihood of childhood autism are related to early trait emergence, or if other exposures are more important. Identifying factors linked to toddler autism traits in the general population may improve our understanding of the mechanisms underlying atypical neurodevelopment. MethodsClinical, socio-demographic, and parental information was collected at birth from 536 toddlers in London, UK (gestational age at birth, sex, maternal body mass index, age, parental education level, parental first language, parental history of neurodevelopmental disorders) and at 18 months (parent cohabiting status, two measures of social deprivation, three measures of maternal parenting style, and a measure of maternal postnatal depression). General neurodevelopment was assessed with the Bayley Scales of Infant and Toddler Development, 3rd Edition (BSID-III), and autism traits were assessed using the Quantitative Checklist for Autism in Toddlers (Q-CHAT). Multivariable models were used to identify associations between variables and Q-CHAT. A model including BSID-III was used to identify factors associated with Q-CHAT independent of general neurodevelopment. Models were also evaluated addressing variable collinearity with principal component analysis (PCA). ResultsA multivariable model explained 20% of Q-CHAT variance, with four individually significant variables (two measures of parenting style and two measures of socio-economic deprivation). After adding general neurodevelopment into the model 36% of Q-CHAT variance was explained, with three individually significant variables (two measures of parenting style and one measure of language development). After addressing variable collinearity with PCA, parenting style and social deprivation were positively correlated with Q-CHAT score via a single principal component, independently of general neurodevelopment. Neither sex nor family history of autism were associated with Q-CHAT score. LimitationsThe Q-CHAT is parent rated and is therefore a subjective opinion rather than a clinical assessment. We measured Q-CHAT at a single timepoint, and to date no participant has been followed up in later childhood, so we are focused purely on emerging traits rather than clinical autism diagnoses. ConclusionsAutism traits are common at age 18 months, and greater emergence is specifically related to exposure to early life adversity.

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bioRxiv2022

Development of neonatal brain functional centrality and alterations associated with preterm birth

Formation of the functional connectome in early life underpins future learning and behaviour. However, our understanding of how the functional organisation of brain regions into interconnected hubs (centrality) matures in the early postnatal period is limited, especially in response to factors associated with adverse neurodevelopmental outcomes such as preterm birth. We characterised voxel-wise functional centrality (weighted degree) in 366 neonates from the Developing Human Connectome Project. We tested the hypothesis that functional centrality matures with age at scan in term-born babies and is disrupted by preterm birth. Finally, we asked whether neonatal functional centrality predicts general neurodevelopmental outcomes at 18 months. We report an age-related increase in functional centrality predominantly within visual regions and decrease within motor and auditory regions in term-born infants. Preterm-born infants scanned at term equivalent age had higher functional centrality predominantly within visual regions and lower measures in motor regions. Functional centrality was not related to outcome at 18 months old. Thus, preterm birth appears to affect functional centrality in regions undergoing substantial development during the perinatal period. Our work raises the question of whether these alterations are adaptive or disruptive, and whether they predict neurodevelopmental characteristics that are more subtle or emerge later in life.

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bioRxiv2021

Attenuated transcriptional response to pro-inflammatory cytokines in schizophrenia hiPSC-derived neural progenitor cells

Maternal immune activation (MIA) during prenatal development is an environmental risk factor for psychiatric disorders including schizophrenia (SZ). This link is particularly well established in the case of schizophrenia. Converging lines of evidence from human and animal model studies have suggested that elevated cytokine levels in the maternal and fetal compartments are an important indication of the mechanisms driving this association. However, there is variability in susceptibility to the psychiatric risk conferred by MIA, likely influenced by genetic factors. How MIA interacts with a genetic profile susceptible to SZ is challenging to test in animal models. To address this gap, we examined whether differential gene expression responses occur in forebrain-lineage neural progenitor cells (NPCs) derived from human induced pluripotent stem cells (hiPSC) generated from three individuals with a diagnosis of schizophrenia and three healthy controls. Following acute (24 hour) treatment with either interferon-gamma (IFN{gamma}; 25 ng/l) or interleukin (IL)-1{beta} (10 ng/l), we identified, by RNA sequencing, 3380 differentially expressed genes (DEGs) in the IFN{gamma}-treated control lines (compared to untreated controls), and 1980 DEGs in IFN{gamma}-treated SZ lines (compared to untreated SZ lines). Of these, 359 genes responded differently to IFN{gamma} treatment in SZ relative to control lines, which were enriched for genes differentially expressed in adult SZ cases and in pathways related to the regulation of antigen processing, neuronal post-synaptic density, and the presynapse. There were no differentially expressed genes in the IL-1{beta}-treatment conditions after Benjamini-Hochberg correction. Gene set enrichment analysis however showed that IL-1{beta} impacts immune function and neuronal differentiation. Collectively, our data suggest that a) SZ NPCs show an attenuated transcriptional response to IFN{gamma} treatment compared to control NPCs; b) IL-1{beta} may be less relevant to NPC cultures than IFN{gamma} and c) the genes differentially regulated in schizophrenia lines are primarily mitochondrial, loss-of-function, pre- and post-synaptic genes. Our findings particularly highlight early synaptic development as a key target for future research into the mechanisms of association between maternal immune activation and schizophrenia risk. Highlights* There is a significant transcriptional response to IFN{gamma} treatment in human induced cortical neural progenitor cells (NPCs) * Differential expression implicates mitochondrial complex genes in this IFN{gamma}-dependent response, which are underexpressed in response to treatment in schizophrenia (SZ) NPCs. * SZ NPCs do not upregulate pre- and post-synaptic genes in response to IFN{gamma} as much as control NPCs * IL-1{beta} may be less relevant to NPC cultures than IFN{gamma} due to low IL1 receptor expression in NPCs.

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bioRxiv2021

Neonatal multi-modal cortical profiles predict 18-month developmental outcomes

Developmental delays in infanthood often persist, turning into life-long difficulties, and coming at great cost for the individual and community. By examining the developing brain and its relation to developmental outcomes we can start to elucidate how the emergence of brain circuits is manifested in variability of infant motor, cognitive and behavioural capacities. In this study, we examined if cortical structural covariance at birth, indexing coordinated development, is related to later infant behaviour. We included 193 healthy term-born infants from the Developing Human Connectome Project (dHCP). An individual cortical connectivity matrix derived from morphological and microstructural features was computed for each subject (morphometric similarity networks, MSNs) and was used as input for the prediction of behavioural scores at 18 months using Connectome-Based Predictive Modeling (CPM). Neonatal MSNs successfully predicted social-emotional performance. Predictive edges were distributed between and within known functional cortical divisions with a specific important role for primary and posterior cortical regions. These results reveal that multi-modal neonatal cortical profiles showing coordinated maturation are related to developmental outcomes and that network organization at birth provides an early infrastructure for future functional skills.

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bioRxiv2021

Preterm birth alters the development of cortical microstructure and morphology at term-equivalent age

IntroductionThe dynamic nature and complexity of the cellular events that take place during the last trimester of pregnancy make the developing cortex particularly vulnerable to perturbations. Abrupt interruption to normal gestation can lead to significant deviations to many of these processes, resulting in atypical trajectory of cortical maturation in preterm birth survivors. MethodsWe sought to first map typical cortical micro and macrostructure development using invivo MRI in a large sample of healthy term-born infants scanned after birth (n=270). Then we offer a comprehensive characterisation of the cortical consequences of preterm birth in 78 preterm infants scanned at term-equivalent age (37-44 weeks postmenstrual age). We describe the group-average atypicality, the heterogeneity across individual preterm infants, and relate individual deviations from normative development to age at birth and neurodevelopment at 18 months. ResultsIn the term-born neonatal brain, we observed regionally specific age-associated changes in cortical morphology and microstructure, including rapid surface expansion, cortical thickness increase, reduction in cortical anisotropy and increase in neurite orientation dispersion. By term-equivalent age, preterm infants had on average increased cortical tissue water content and reduced neurite density index in the posterior parts of the cortex, and greater cortical thickness anteriorly compared to term-born infants. While individual preterm infants were more likely to show extreme deviations (over 3.1 standard deviations) from normative cortical maturation compared to term-born infants, these extreme deviations were highly variable and showed very little spatial overlap between individuals. Measures of regional cortical development were associated with age at birth, but not with neurodevelopment at 18 months. ConclusionWe showed that preterm birth alters cortical micro and macrostructural maturation near the time of fullterm birth. Deviations from normative development were highly variable between individual preterm infants.

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bioRxiv2021

Effects of gestational age at birth on perinatal structural brain development in healthy term-born babies

Multiple studies have demonstrated less favourable childhood outcomes in infants born in early term (37-38 weeks gestation) compared to those born at full term (40-41 weeks gestation). While this could be due to higher perinatal morbidity, gestational age at birth may also have a direct effect on the brain and subsequent neurodevelopment in term-born babies. Here we characterise structural brain correlates of gestational age at birth in healthy term-born neonates and their relationship to later neurodevelopmental outcome. We used T2 and diffusion weighted Magnetic Resonance Images acquired in the neonatal period from a cohort (n=454) of healthy babies born at term age (>37 weeks gestation) and scanned between 1 and 41 days after birth. Images were analysed using tensor based morphometry (TBM) and tract based spatial statistics (TBSS). Neurodevelopment was subsequently assessed at age 18 months using the Bayley-III Scales of Infant and Toddler Development, and the effects of gestational age at birth and related neuroimaging findings on outcome were analysed with linear regression. Infants born earlier had areas of higher relative ventricular volume, and lower relative brain volume in the basal ganglia, cerebellum and brainstem. Earlier birth was also associated with lower fractional anisotropy, higher mean, axial and radial diffusivity in major white matter tracts. Gestational age at birth was positively associated with all Bayley-III subscales at age 18 months. Linear regression models predicting outcome from gestational age at birth were significantly improved by adding neuroimaging features associated with gestational age at birth. This work adds to the growing body of evidence of the impact of early term birth and highlights the importance of considering the effect of gestational age at birth in future neuroimaging studies including term-born babies.

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bioRxiv2021

The developing brain structural and functional connectome fingerprint

In the mature brain, structural and functional connectivity fingerprints can be used to identify the uniqueness of an individual. However, whether the characteristics that make a brain distinguishable from others already exist at birth remains unknown. Here, we used neuroimaging data of preterm born neonates who were scanned twice during the perinatal period to assess the developing brain fingerprint. We found that 62% of the participants could be identified based on the congruence of the later structural connectome to the initial connectivity matrix derived from the earlier timepoint. In contrast, similarity between functional connectomes only allowed to identify 12% of the participants. These suggests that structural connectivity is more stable in early life and can represent a potential connectome fingerprint. Thus, a relatively stable structural connectome appears to support a changing functional connectome at a time when neonates must rapidly acquire new skills to adapt to their new environment.

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bioRxiv2020

Individualized characterization of volumetric development in the preterm brain

The diverse cerebral consequences of preterm birth create significant challenges for understanding pathogenesis or predicting later outcome. Instead of focusing on describing effects common to the group, comparing individual infants against robust normative data offers a powerful alternative to study brain maturation. Here we used Gaussian process regression to create normative curves characterising brain volumetric development in 274 term-born infants, modelling for age at scan and sex. We then compared 89 preterm infants scanned at termequivalent age to these normative charts, relating individual deviations from typical volumetric development to perinatal risk factors and later neurocognitive scores. To test generalisability, we used a second independent dataset comprising of 253 preterm infants scanned using different acquisition parameters and scanner. We describe rapid, non-uniform brain growth during the neonatal period. In both preterm cohorts, cerebral atypicalities were widespread, often multiple, and varied highly between individuals. Deviations from normative development were associated with respiratory support, nutrition, birth weight, and later neurocognition, demonstrating their clinical relevance. Group-level understanding of the preterm brain disguise a large degree of individual differences. We provide a method and normative dataset that offer a more precise characterisation of the cerebral consequences of preterm birth by profiling the individual neonatal brain.

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bioRxiv2020

Neurometabolite Mapping Highlights Elevated Myo-inositol Profiles within the Developing Brain in Down Syndrome

The neurodevelopmental phenotype in Down Syndrome (DS), or Trisomy 21, is variable including a wide spectrum of cognitive impairment and a high risk of early-onset Alzheimers disease (AD). A key metabolite of interest within the brain in DS is Myo-inositol (Myo-ins). The NA+/Myo-ins co-transporter, is located on human chromosome 21 and is overexpressed in DS. In adults with DS, elevated brain Myo-ins has previously been associated with cognitive impairment and proposed as a risk marker for progression to AD. However, it is unknown if brain Myo-ins is increased earlier in development. The aim of this study was to assess Myo-ins and key brain metabolites [N-acetylaspartate (NAA), Choline (Cho) and Creatine(Cr)] in the developing brain in DS and aged-matched controls. To achieve this we used mass spectrometry in early (10-20 weeks post conception) ex vivo fetal brain tissue samples from DS (n=14) and control (n=30) cases; and in vivo magnetic resonance spectroscopy (MRS) in neonates with DS (n=18) and aged matched controls (n= 25) scanned just after birth (36-45 weeks postmenstrual age. We observed elevated Myo-ins in the ex vivo fetal cortical brain tissue in DS compared with controls. Relative to reference metabolites Cho and Cr, we also detected elevated ratios of Myo-ins and NAA in vivo in the basal ganglia and thalami, in neonates with DS, when compared to age-matched typically developing controls. Thus, a higher level of brain Myo-ins was evident as early as 10 weeks post conception and was measurable in vivo from 36 weeks post-menstrual age. Future work will determine if this early difference in metabolites is linked to cognitive outcomes in childhood or has utility as a potential treatment biomarker for early intervention.

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bioRxiv2020

Development of Microstructural and Morphological Cortical Profiles in the Neonatal Brain

In the perinatal brain, regional cortical architecture and connectivity lay the foundations for functional circuits and emerging behaviour. Interruptions or atypical development during or before this period may therefore have long-lasting consequences. However, to be able to investigate these deviations, we need a measure of how this architecture evolves in the typically developing brain. To this end, in a large cohort of 241 term-born infants we used Magnetic Resonance Imaging to estimate cortical profiles based on morphometry and microstructure over the perinatal period (37-44 weeks post-menstrual age, PMA). Using the covariance of these profiles as a measure of inter-areal network similarity (Morphometric Similarity Networks; MSN), we clustered these networks into distinct modules. The resulting modules were consistent and symmetric, and corresponded to known functional distinctions, including sensory-motor, limbic and association regions and were spatially mapped onto known cytoarchitectonic tissue classes. Posterior (parietal, occipital) regions became more morphometrically similar with increasing PMA, while peri-cingulate and medial temporal regions became more dissimilar. Network strength was associated with PMA: Within-network similarity increased over PMA suggesting emerging network distinction. These changes in cortical network architecture over an eight-week period are consistent with, and likely underpin, the highly dynamic behavioural and cognitive development occurring during this critical period. The resulting cortical profiles might provide normative reference to investigate atypical early brain development.

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bioRxiv2019

Antiviral signalling in human IPSC-derived neurons recapitulates neurodevelopmental disorder phenotypes

Maternal immune activation increases the risk of neurodevelopmental disorders. Elevated cytokines, such as interferon-gamma (IFN{gamma}), in offsprings brains play a central role. IFN{gamma} activates an antiviral cellular state, limiting viral entry and replication. In addition, IFN{gamma} has been implicated in brain development. Here, we hypothesise that IFN{gamma}-induced antiviral signalling contributes to molecular and cellular phenotypes associated with neurodevelopmental disorders. We find that transient IFN{gamma} treatment of neural progenitors derived from human induced pluripotent stem cells (hIPSCs) persistently increases neurite outgrowth, phenocopying hIPSC-neurons from autistic individuals. IFN{gamma} upregulates antiviral PML bodies and MHC class I (MHCI) genes, which persists through neuronal differentiation. Critically, IFN{gamma}-induced neurite outgrowth requires both PML and MHCI. We also find that IFN{gamma} disproportionately alters expression of autism and schizophrenia risk genes, suggesting convergence between these genetic and environmental risk factors. Together, these data indicate that IFN{gamma}-induced antiviral signalling may contribute to neurodevelopmental disorder aetiology.

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bioRxiv2019

Early alterations in cortical and cerebellar regional brain growth in Down Syndrome: An in-vivo fetal and neonatal MRI assessment

Down Syndrome (DS) is the most frequent genetic cause of intellectual disability with a wide spectrum of neurodevelopmental outcomes. At present, the relationship between structural brain morphology and the spectrum of cognitive phenotypes in DS, is not well understood. This study aimed to quantify development of the fetal and neonatal brain in DS using dedicated, optimised and motion-corrected in-vivo magnetic resonance imaging (MRI). We detected deviations in development and altered regional brain growth in the fetus with DS from 21 weeks gestation, when compared to age-matched controls. Reduced cerebellar volume was apparent in the second trimester with significant alteration in cortical growth becoming evident during the third trimester. Developmental abnormalities in the cortex and cerebellum are likely substrates for later neurocognitive impairment, and ongoing studies will allow us to confirm the role of antenatal MRI as an early biomarker for subsequent cognitive ability in DS. In the era of rapidly developing technologies, it is hoped that the results of this study will assist counselling for prospective parents.

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bioRxiv2019

Do direct nose-to-brain pathways underlie intranasal oxytocin-induced changes in regional cerebral blood flow in humans?

Could nose-to-brain pathways mediate the effects of peptides such as oxytocin (OT) on brain physiology when delivered intranasally? We address this question by contrasting two methods of intranasal administration (a standard nasal spray, and a nebulizer expected to improve OT deposition in nasal areas putatively involved in direct nose-to-brain transport) to intravenous administration in terms of effects on regional cerebral blood flow during two hours post-dosing. We demonstrate that OT-induced decreases in amygdala perfusion, a key hub of the OT central circuitry, are explained entirely by OT increases in systemic circulation following both intranasal and intravenous OT administration. Yet we also provide robust evidence confirming the validity of the intranasal route to target specific brain regions. Our work has important translational implications and demonstrates the need to carefully consider the method of administration in our efforts to engage specific central oxytocinergic targets for the treatment of neuropsychiatric disorders.

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