Chiara Nosarti

YNICL Journal 2022 Journal Article

Neonatal frontal-limbic connectivity is associated with externalizing behaviours in toddlers with Congenital Heart Disease

• Alexandra F. Bonthrone
• Andrew Chew
• Megan Ní Bhroin
• Francesca Morassutti Rech
• Christopher J. Kelly
• Daan Christiaens
• Maximilian Pietsch
• J-Donald Tournier

Children with Congenital Heart Disease (CHD) are at increased risk of neurodevelopmental impairments. The neonatal antecedents of impaired behavioural development are unknown. 43 infants with CHD underwent presurgical brain diffusion-weighted MRI [postmenstrual age at scan median (IQR) = 39.29 (38.71-39.71) weeks] and a follow-up assessment at median age of 22.1 (IQR 22.0-22.7) months in which parents reported internalizing and externalizing problem scores on the Child Behaviour Checklist. We constructed structural brain networks from diffusion-weighted MRI and calculated edge-wise structural connectivity as well as global and local brain network features. We also calculated presurgical cerebral oxygen delivery, and extracted perioperative variables, socioeconomic status at birth and a measure of cognitively stimulating parenting. Lower degree in the right inferior frontal gyrus (partial ρ = -0.687, p < 0.001) and reduced connectivity in a frontal-limbic sub-network including the right inferior frontal gyrus were associated with higher externalizing problem scores. Externalizing problem scores were unrelated to neonatal clinical course or home environment. However, higher internalizing problem scores were associated with earlier surgery in the neonatal period (partial ρ = -0.538, p = 0.014). Our results highlight the importance of frontal-limbic networks to the development of externalizing behaviours and provide new insights into early antecedents of behavioural impairments in CHD.

YNICL Journal 2022 Journal Article

White matter disruptions related to inattention and autism spectrum symptoms in tuberous sclerosis complex

• Lucy D. Vanes
• Charlotte Tye
• Jacques-Donald Tournier
• Anna J.E. Combes
• Elizabeth Shephard
• Holan Liang
• Gareth J. Barker
• Chiara Nosarti

Tuberous sclerosis complex is a rare genetic multisystem condition that is associated with a high prevalence of neurodevelopmental disorders such as autism and attention-deficit/hyperactivity disorder. The underlying neural mechanisms of the emergence of these symptom domains in tuberous sclerosis complex remain unclear. Here, we use fixel-based analysis of diffusion-weighted imaging, which allows for the differentiation between multiple fibre populations within a voxel, to compare white matter properties in 16 participants with tuberous sclerosis complex (aged 11-19) and 12 age and sex matched control participants. We further tested associations between white matter alterations and autism and inattention symptoms as well as cognitive ability in participants with tuberous sclerosis complex. Compared to controls, participants with tuberous sclerosis complex showed reduced fibre density cross-section (FDC) in the dorsal branch of right superior longitudinal fasciculus and bilateral inferior longitudinal fasciculus, reduced fibre density (FD) in bilateral tapetum, and reduced fibre cross-section (FC) in the ventral branch of right superior longitudinal fasciculus. In participants with tuberous sclerosis complex, the extent of FDC reductions in right superior longitudinal fasciculus was significantly associated with autism traits (social communication difficulties and restricted, repetitive behaviours), whereas FDC reductions in right inferior longitudinal fasciculus were associated with inattention. The observed white matter alterations were unrelated to cognitive ability. Our findings shed light on the fibre-specific biophysical properties of white matter alterations in tuberous sclerosis complex and suggest that these regional changes are selectively associated with the severity of neurodevelopmental symptoms.

YNICL Journal 2019 Journal Article

Corrigendum to “Dysconnectivity of neurocognitive networks at rest in very-preterm born adults” [NeuroImage: Clinical 4 (2014) 352–365]

• ThomasP. White
• Iona Symington
• Nazareth P. Castellanos
• Philip J. Brittain
• Seán Froudist Walsh
• Kie-Woo Nam
• João R. Sato
• Matthew P.G. Allin

YNIMG Journal 2017 Journal Article

Early development of structural networks and the impact of prematurity on brain connectivity

• Dafnis Batalle
• Emer J. Hughes
• Hui Zhang
• J.-Donald Tournier
• Nora Tusor
• Paul Aljabar
• Luqman Wali
• Daniel C. Alexander

Preterm infants are at high risk of neurodevelopmental impairment, which may be due to altered development of brain connectivity. We aimed to (i) assess structural brain development from 25 to 45 weeks gestational age (GA) using graph theoretical approaches and (ii) test the hypothesis that preterm birth results in altered white matter network topology. Sixty-five infants underwent MRI between 25+3 and 45+6 weeks GA. Structural networks were constructed using constrained spherical deconvolution tractography and were weighted by measures of white matter microstructure (fractional anisotropy, neurite density and orientation dispersion index). We observed regional differences in brain maturation, with connections to and from deep grey matter showing most rapid developmental changes during this period. Intra-frontal, frontal to cingulate, frontal to caudate and inter-hemispheric connections matured more slowly. We demonstrated a core of key connections that was not affected by GA at birth. However, local connectivity involving thalamus, cerebellum, superior frontal lobe, cingulate gyrus and short range cortico-cortical connections was related to the degree of prematurity and contributed to altered global topology of the structural brain network. The relative preservation of core connections at the expense of local connections may support more effective use of impaired white matter reserve following preterm birth.

YNIMG Journal 2017 Journal Article

Volumetric grey matter alterations in adolescents and adults born very preterm suggest accelerated brain maturation

• Vyacheslav R. Karolis
• Sean Froudist-Walsh
• Jasmin Kroll
• Philip J. Brittain
• Chieh-En Jane Tseng
• Kie-Woo Nam
• Antje A.T.S. Reinders
• Robin M. Murray

Previous research investigating structural neurodevelopmental alterations in individuals who were born very preterm demonstrated a complex pattern of grey matter changes that defy straightforward summary. Here we addressed this problem by characterising volumetric brain alterations in individuals who were born very preterm from adolescence to adulthood at three hierarchically related levels - global, modular and regional. We demarcated structural components that were either particularly resilient or vulnerable to the impact of very preterm birth. We showed that individuals who were born very preterm had smaller global grey matter volume compared to controls, with subcortical and medial temporal regions being particularly affected. Conversely, frontal and lateral parieto-temporal cortices were relatively resilient to the effects of very preterm birth, possibly indicating compensatory mechanisms. Exploratory analyses supported this hypothesis by showing a stronger association between lateral parieto-temporal volume and IQ in the very preterm group compared to controls. We then related these alterations to brain maturation processes. Very preterm individuals exhibited a higher maturation index compared to controls, indicating accelerated brain maturation and this was specifically associated with younger gestational age. We discuss how the findings of accelerated maturation might be reconciled with evidence of delayed maturation at earlier stages of development.

YNIMG Journal 2017 Journal Article

White matter alterations to cingulum and fornix following very preterm birth and their relationship with cognitive functions

• Chiara Caldinelli
• Sean Froudist-Walsh
• Vyacheslav Karolis
• Chieh-En Tseng
• Matthew P. Allin
• Muriel Walshe
• Marion Cuddy
• Robin M. Murray

Very preterm birth (VPT; <32 weeks of gestation) has been associated with impairments in memory abilities and functional neuroanatomical brain alterations in medial temporal and fronto-parietal areas. Here we investigated the relationship between structural connectivity in memory-related tracts and various aspects of memory in VPT adults (mean age 19) who sustained differing degrees of perinatal brain injury (PBI), as assessed by neonatal cerebral ultrasound. We showed that the neurodevelopmental consequences of VPT birth persist into young adulthood and are associated with neonatal cranial ultrasound classification. At a cognitive level, VPT young adults showed impairments specific to effective organization of verbal information and visuospatial memory, whereas at an anatomical level they displayed reduced volume of memory-related tracts, the cingulum and the fornix, with greater alterations in those individuals who experienced high-grade PBI. When investigating the association between these tracts and memory scores, perseveration errors were associated with the volume of the fornix and dorsal cingulum (connecting medial frontal and parietal lobes). Visuospatial memory scores were associated with the volume of the ventral cingulum (connecting medial parietal and temporal lobes). These results suggest that structural connectivity alterations could underlie memory difficulties in preterm born individuals.

YNIMG Journal 2015 Journal Article

Alterations in cortical thickness development in preterm-born individuals: Implications for high-order cognitive functions

• Kie Woo Nam
• Nazareth Castellanos
• Andrew Simmons
• Seán Froudist-Walsh
• Matthew P. Allin
• Muriel Walshe
• Robin M. Murray
• Alan Evans

Very preterm birth (gestational age <33weeks) is associated with alterations in cortical thickness and with neuropsychological/behavioural impairments. Here we studied cortical thickness in very preterm born individuals and controls in mid-adolescence (mean age 15years) and beginning of adulthood (mean age 20years), as well as longitudinal changes between the two time points. Using univariate approaches, we showed both increases and decreases in cortical thickness in very preterm born individuals compared to controls. Specifically (1) very preterm born adolescents displayed extensive areas of greater cortical thickness, especially in occipitotemporal and prefrontal cortices, differences which decreased substantially by early adulthood; (2) at both time points, very preterm-born participants showed smaller cortical thickness, especially in parahippocampal and insular regions. We then employed a multivariate approach (support vector machine) to study spatially discriminating features between the two groups, which achieved a mean accuracy of 86. 5%. The spatially distributed regions in which cortical thickness best discriminated between the groups (top 5%) included temporal, occipitotemporal, parietal and prefrontal cortices. Within these spatially distributed regions (top 1%), longitudinal changes in cortical thickness in left temporal pole, right occipitotemporal gyrus and left superior parietal lobe were significantly associated with scores on language-based tests of executive function. These results describe alterations in cortical thickness development in preterm-born individuals in their second decade of life, with implications for high-order cognitive processing.

YNICL Journal 2014 Journal Article

Dysconnectivity of neurocognitive networks at rest in very-preterm born adults

• Thomas P. White
• Iona Symington
• Nazareth P. Castellanos
• Philip J. Brittain
• Seán Froudist Walsh
• Kie-Woo Nam
• João R. Sato
• Matthew P.G. Allin

Advances in neonatal medicine have resulted in a larger proportion of preterm-born individuals reaching adulthood. Their increased liability to psychiatric illness and impairments of cognition and behaviour intimate lasting cerebral consequences; however, the central physiological disturbances remain unclear. Of fundamental importance to efficient brain function is the coordination and contextually-relevant recruitment of neural networks. Large-scale distributed networks emerge perinatally and increase in hierarchical complexity through development. Preterm-born individuals exhibit systematic reductions in correlation strength within these networks during infancy. Here, we investigate resting-state functional connectivity in functional magnetic resonance imaging data from 29 very-preterm (VPT)-born adults and 23 term-born controls. Neurocognitive networks were identified with spatial independent component analysis conducted using the Infomax algorithm and employing Icasso procedures to enhance component robustness. Network spatial focus and spectral power were not generally significantly affected by preterm birth. By contrast, Granger-causality analysis of the time courses of network activity revealed widespread reductions in between-network connectivity in the preterm group, particularly along paths including salience-network features. The potential clinical relevance of these Granger-causal measurements was suggested by linear discriminant analysis of topological representations of connection strength, which classified individuals by group with a maximal accuracy of 86%. Functional connections from the striatal salience network to the posterior default mode network informed this classification most powerfully. In the VPT-born group it was additionally found that perinatal factors significantly moderated the relationship between executive function (which was reduced in the VPT-born as compared with the term-born group) and generalised partial directed coherence. Together these findings show that resting-state functional connectivity of preterm-born individuals remains compromised in adulthood; and present consistent evidence that the striatal salience network is preferentially affected. Therapeutic practices directed at strengthening within-network cohesion and fine-tuning between-network inter-relations may have the potential to mitigate the cognitive, behavioural and psychiatric repercussions of preterm birth.

YNICL Journal 2014 Journal Article

Neural compensation in adulthood following very preterm birth demonstrated during a visual paired associates learning task

• Philip J. Brittain
• Sean Froudist Walsh
• Kie-Woo Nam
• Vincent Giampietro
• Vyacheslav Karolis
• Robin M. Murray
• Sagnik Bhattacharyya
• Anastasia Kalpakidou

Very preterm birth (VPT; < 33 weeks of gestation) is associated with an increased risk of learning disability, which contributes to more VPT-born children repeating grades and underachieving in school. Learning problems associated with VPT birth may be caused by pathophysiological alterations in neurodevelopment resulting from perinatal brain insult; however, adaptive neuroplastic processes may subsequently occur in the developing preterm brain which ameliorate, to an extent, the potential sequelae of altered neurophysiology. Here, we used functional magnetic resonance imaging (fMRI) to compare neuronal activation in 24 VPT individuals and 22 controls (CT) in young adulthood during a learning task consisting of the encoding and subsequent recognition of repeated visual paired associates. Structural MRI data were also collected and analysed in order to explore possible structure-function associations. Whilst the two groups did not differ in their learning ability, as demonstrated by their capacity to recognize previously-seen and previously-unseen visual pairs, between-group differences in linear patterns of Blood Oxygenation Level Dependant (BOLD) activity were observed across the four repeated blocks of the task for both the encoding and recognition conditions, suggesting that the way learning takes place differs between the two groups. During encoding, significant between-group differences in patterns of BOLD activity were seen in clusters centred on the cerebellum, the anterior cingulate gyrus, the midbrain/substantia nigra, medial temporal (including parahippocampal) gyrus and inferior and superior frontal gyri. During the recognition condition, significant between-group differences in patterns of BOLD activity were seen in clusters centred on the claustrum and the posterior cerebellum. Structural analysis revealed smaller grey matter volume in right middle temporal gyrus in VPT individuals compared to controls, however volume in this region was not significantly associated with functional activation. These results demonstrate that although cognitive task performance between VPT individuals and controls may be comparable on certain measures, differences in BOLD signal may also be evident, some of which could represent compensatory neural processes following VPT-related brain insult.

YNICL Journal 2014 Journal Article

Preterm birth and structural brain alterations in early adulthood

• Chiara Nosarti
• Kie Woo Nam
• Muriel Walshe
• Robin M. Murray
• Marion Cuddy
• Larry Rifkin
• Matthew P.G. Allin

Alterations in cortical development and impaired neurodevelopmental outcomes have been described following very preterm (VPT) birth in childhood and adolescence, but only a few studies to date have investigated grey matter (GM) and white matter (WM) maturation in VPT samples in early adult life. Using voxel-based morphometry (VBM) we studied regional GM and WM volumes in 68 VPT-born individuals (mean gestational age 30 weeks) and 43 term-born controls aged 19-20 years, and their association with cognitive outcomes (Hayling Sentence Completion Test, Controlled Oral Word Association Test, Visual Reproduction test of the Wechsler Memory Scale-Revised) and gestational age. Structural MRI data were obtained with a 1.5 Tesla system and analysed using the VBM8 toolbox in SPM8 with a customized study-specific template. Similarly to results obtained at adolescent assessment, VPT young adults compared to controls demonstrated reduced GM volume in temporal, frontal, insular and occipital areas, thalamus, caudate nucleus and putamen. Increases in GM volume were noted in medial/anterior frontal gyrus. Smaller subcortical WM volume in the VPT group was observed in temporal, parietal and frontal regions, and in a cluster centred on posterior corpus callosum/thalamus/fornix. Larger subcortical WM volume was found predominantly in posterior brain regions, in areas beneath the parahippocampal and occipital gyri and in cerebellum. Gestational age was associated with GM and WM volumes in areas where VPT individuals demonstrated GM and WM volumetric alterations, especially in temporal, parietal and occipital regions. VPT participants scored lower than controls on measures of IQ, executive function and non-verbal memory. When investigating GM and WM alterations and cognitive outcome scores, subcortical WM volume in an area beneath the left inferior frontal gyrus accounted for 14% of the variance of full-scale IQ (F = 12.9, p < 0.0001). WM volume in posterior corpus callosum/thalamus/fornix and GM volume in temporal gyri bilaterally, accounted for 21% of the variance of executive function (F = 9.9, p < 0.0001) and WM in the posterior corpus callosum/thalamus/fornix alone accounted for 17% of the variance of total non-verbal memory scores (F = 9.9, p < 0.0001). These results reveal that VPT birth continues to be associated with altered structural brain anatomy in early adult life, although it remains to be ascertained whether these changes reflect neurodevelopmental delays or long lasting structural alterations due to prematurity. GM and WM alterations correlate with length of gestation and mediate cognitive outcome.

YNIMG Journal 2014 Journal Article

Road work on memory lane—Functional and structural alterations to the learning and memory circuit in adults born very preterm

• Piergiorgio Salvan
• Seán Froudist Walsh
• Matthew P.G. Allin
• Muriel Walshe
• Robin M. Murray
• Sagnik Bhattacharyya
• Philip K. McGuire
• Steven C.R. Williams

Very preterm (VPT) birth is considered a risk factor not only for neurological impairment, but also for reduced function in several cognitive domains in childhood and later in life. Individuals who were born VPT are more likely to demonstrate learning and memory difficulties compared to term-born controls. These problems contribute to more VPT-born children repeating grades and underachieving in school. This, in turn, affects their prospects in adult life. Here we aimed to 1) study how the VPT-born adult brain functionally recruited specific areas during learning, i. e. encoding and recall across four repeated blocks of verbal stimuli, and to investigate how these patterns of activation differed from term-born subjects; and 2) probe the microstructural differences of white-matter tracts connecting these areas to other parts of the learning and memory network. To investigate these functional–structural relationships we analyzed functional and diffusion-weighted MRI. Functional-MRI and a verbal paired associate learning (VPAL) task were used to extract Blood Oxygenation Level Dependent (BOLD) activity in 21 VPT-born adults (<33weeks of gestation) (mean age: 19. 68 years±0. 85; IQ: 99. 86±11. 20) and 10 term-born controls (mean age: 19. 87 years±2. 04; IQ: 108. 9±13. 18). Areas in which differences in functional activation were observed between groups were used as seed regions for tractography. Fractional anisotropy (FA) of the tract-skeleton was then compared between groups on a voxel-wise basis. Results of functional MRI analysis showed a significantly different pattern of activation between groups during encoding in right anterior cingulate–caudate body, and during retrieval in left thalamus, hippocampus and parts of left posterior parahippocampal gyrus. The number of correctly recalled word pairs did not statistically differ between individuals who were born VPT and controls. The VPT-born group was found to have reduced FA in tracts passing through the thalamic/hippocampal region that was differently activated during the recall condition, with the hippocampal fornix, inferior longitudinal fasciculus and inferior fronto-occipital fasciculus particularly affected. Young adults who were born very preterm display a strikingly different pattern of activation during the process of learning in key structures of the learning and memory network, including anterior cingulate and caudate body during encoding and thalamus/parahippocampal gyrus during cued recall. Altered activation in thalamus/parahippocampal gyrus may be explained by reduced connections between these areas and the hippocampus, which may be a direct consequence of neonatal hypoxic/ischemic injury. These results could reflect the effect of adaptive plastic processes associated with high-order cognitive functions, at least when the cognitive load remains relatively low, as ex-preterm young adults displayed unimpaired performance in completing the verbal paired associate learning task.

YNIMG Journal 2011 Journal Article

COMT gene polymorphism and corpus callosum morphometry in preterm born adults

• Anirban Dutt
• Madiha Shaikh
• Taposhri Ganguly
• Chiara Nosarti
• Muriel Walshe
• Maria Arranz
• Larry Rifkin
• Colm McDonald

Introduction Preterm birth is associated with a range of neurodevelopmental deficits, including corpus callosum (CC) abnormalities, which persist into late adolescence and early adulthood. A common single-nucleotide polymorphism in the catechol-o-methyl transferase (COMT) gene (Val158Met) is associated with cognition and brain structure and may play a role in neurodevelopment. It is not known whether this polymorphism is associated with CC morphometry in individuals born preterm. Methods Structural MRI scans were acquired in 33 adults born very preterm (before 33 weeks' gestation) and 29 healthy controls. DNA was collected and COMT Val158Met polymorphism status determined using standard available assays. The mid-sagittal area of four antero-posterior subdivisions of the CC was measured. The effect of COMT Val158Met polymorphism on cross-sectional CC areas was studied using multivariate analysis and generalised linear models, adjusted for the effects of the clinical sample group (preterm vs. control), age and sex. Results The COMT Val/Val homozygous genotype was observed to be significantly associated with reduced size of the total corpus callosum, and this relationship was present for the anterior, midposterior and posterior quarters of the CC. Conclusions The COMT Val158Met polymorphism possibly influences the morphometry of the corpus callosum associated with very preterm births. Further studies with larger sample sizes are warranted to conclusively establish the effects of individual genotypes of the COMT gene on corpus callosum in preterm born adults.

YNIMG Journal 2009 Journal Article

Neural substrates of letter fluency processing in young adults who were born very preterm: Alterations in frontal and striatal regions

• Chiara Nosarti
• Sukhwinder S. Shergill
• Matthew P. Allin
• Muriel Walshe
• Larry Rifkin
• Robin M. Murray
• Philip K. McGuire

Several studies have described poorer performance in executive-type tasks in individuals who were born very preterm compared to controls. As there is evidence that high-order executive functions may be underpinned by neuronal activity in frontal–striatal circuits, we investigated with functional MRI a group of young adults who were born very preterm (n =28, gestational age <33 weeks) and controls (n =26) in order to detect possible alterations in brain activation during completion of a letter fluency task with differential cognitive loading (“easy” and “hard” letter trials). Structural MRI data were also collected to clarify whether any functional changes were associated with structural brain volume changes. Group membership, level of task difficulty and gestational age had significant effects on brain activation. In the absence of significant between-group differences in task performance, during “easy” letter trials, very preterm-born individuals showed attenuated activation in anterior cingulate gyrus, right caudate nucleus and left inferior frontal gyrus compared to controls. During “hard” letter trials, very preterm-born individuals showed both decreased and increased BOLD signal compared to controls, in left middle frontal and anterior cingulate gyrus, respectively. BOLD signal in caudate nucleus and anterior cingulate gyrus, in regions with peaks close to areas where between-group differences were observed, was linearly associated with gestational age. Analysis of structural MRI data showed altered grey matter distribution in the preterm-born group compared to controls. However, fMRI results were only partly explained by structural changes, and may reflect processes of functional plasticity for the successful completion of executive-type operations.

YNIMG Journal 2009 Journal Article

Neural substrates of visual paired associates in young adults with a history of very preterm birth: Alterations in fronto-parieto-occipital networks and caudate nucleus

• Ana Narberhaus
• Emma Lawrence
• Matthew P. Allin
• Muriel Walshe
• Philip McGuire
• Larry Rifkin
• Robin Murray
• Chiara Nosarti

This study investigated neuronal activation during visuo-perceptual learning processing in adults who were born very preterm (VPT, <33 weeks' gestation). A visual paired associates task was administered during functional magnetic resonance imaging (fMRI) and neuronal activation was compared between 21 VPT-born adults of both sexes and 22 matched controls. The task consisted of 4 conditions (encoding, recognition, same/different discrimination condition (baseline) and a low-level baseline), each containing 8 stimuli pairs. There were no group differences in terms of correctly recognized visual pairs. However, during encoding, VPT-born individuals showed increased BOLD signal response compared to controls in left caudate nucleus, right cuneus (BA 18) and left superior parietal lobule (BA 7), and decreased signal in right inferior frontal gyrus (BA 46). During recognition, VPT-born adults showed increased BOLD signal response compared to controls in right cerebellum and in anterior cingulate gyrus (BA 32) bilaterally. The fMRI data were additionally analyzed controlling for structural differences in the hippocampus bilaterally, where the VPT group showed decreased probability of the absolute amount of grey matter compared to controls. Results of our study suggest that despite good task performance, VPT-born individuals activate different neural networks during mnemonic processing of visuo-perceptual material which may indicate neural compensation for the adult consequences of perinatal brain injury following very preterm birth, as well as maturational delays.

YNIMG Journal 2001 Journal Article

Behavioural and cognitive consequences of caudate pathology in adolescents born very preterm

• Chiara Nosarti
• Matthew Allin
• Mazin Al-Asady
• Ann Stewart
• Larry Rifkin
• Robin Murray