Anhedonia and depression severity dissociated by dmPFC resting-state functional connectivity in adolescents

Introduction: Given the heterogeneity within depression, in this study we aim to examine how RSFC in adolescents is related to anhedonia and depression severity on a continuum in line with the RDoC approach. Methods: We examined how RSFC in the dorsal medial prefrontal cortex (dmPFC), nucleus accumbens (NAcc) and pregenual anterior cingulate cortex (pgACC) was related to anhedonia and depression severity in eighty six adolescents (13-21 yrs.). Results: We found both anhedonia and depression severity related to decreased dmPFC RSFC with the precuneus, a part of the default mode network. However we also found that increased dmPFC connectivity with the ACC/paracingulate gyrus related to anhedonia whereas increased RSFC with the frontal pole related to depression severity. Discussion: This work extends the view that the dmPFC is a potential therapeutic target for depression in two ways. 1. We report dmPFC connectivity in adolescents and 2. We show different dmPFC RSFC specific to anhedonia and depression severity, providing neural targets for intervention in young people at risk of depression

Fear responses to safety cues in anxious adolescents: preliminary evidence for atypical age-associated trajectories of functional neural circuits

Adolescent anxiety is common and impairing and often persists into adulthood. There is growing evidence that adult anxiety is characterized by abnormal fear responses to threat and safety cues, along with perturbations in fear-related neural circuits. Although some of this work has been extended to adolescents, with promising results, it is not yet clear whether changes in these circuits across developmental age varies between anxious and non-anxious adolescents. Here we used fMRI to examine how age modulates neural responses as adolescents are exposed to threat and safety cues. Participants were 15 anxious and 11 non-anxious adolescents (age 12-17) who completed a fear conditioning paradigm. The paradigm incorporated a threat cue comprising a neutral face which was paired with a fearful, screaming face, a safety cue comprising a different neutral face, and a control stimulus. Across the whole sample, neural activation to the threat cue (relative to the control cue) correlated positively with age in a number of regions, including the dorsal anterior cingulate and bilateral dorsolateral prefrontal cortex (PFC). However, neural activation to the safety cue (relative to the control cue) was modulated differently by age in the two groups: a more positive association between activation and age was observed in the control group compared to the anxious group in various regions including medial and dorsolateral PFC, anterior insula, and amygdala. These findings suggest that maturation of the neural substrates of fear responses to safety cues may be perturbed in anxious adolescents, potentially contributing to the emergence and maintenance of anxiety disorders in adulthood

Early childhood bilingualism: effects on brain structure and function [version 2; peer review: 2 approved]

Growing up in a bilingual environment is becoming increasingly common. Yet, we know little about how this enriched language environment influences the connectivity of children’s brains. Behavioural research in children and adults has shown that bilingualism experience may boost executive control (EC) skills, such as inhibitory control and attention. Moreover, increased structural and functional (resting-state) connectivity in language-related and EC-related brain networks is associated with increased executive control in bilingual adults. However, how bilingualism factors alter brain connectivity early in brain development remains poorly understood. We will combine standardised tests of attention with structural and resting-state functional magnetic resonance imaging (MRI) in bilingual children. This study will allow us to address an important field of inquiry within linguistics and developmental cognitive neuroscience by examining the following questions: Does bilingual experience modulate connectivity in language-related and EC-related networks in children? Do differences in resting-state brain connectivity correlate with differences in EC skills (specifically attention skills)? How do bilingualism-related factors, such as age of exposure to two languages, language usage and proficiency, modulate brain connectivity? We will collect structural and functional MRI, and quantitative measures of EC and language skills from two groups of English-Greek bilingual children - 20 simultaneous bilinguals (exposure to both languages from birth) and 20 successive bilinguals (exposure to English between the ages of 3 and 5 years) - and 20 English monolingual children, 8-10 years old. We will compare connectivity measures and attention skills between monolinguals and bilinguals to examine the effects of bilingual exposure. We will also examine to what extent bilingualism factors predict brain connectivity in EC and language networks. Overall, we hypothesize that connectivity and EC will be enhanced in bilingual children compared to monolingual children, and each outcome will be modulated by age of exposure to two languages and by bilingual language usage

Diffusion tensor imaging and resting state functional connectivity as advanced imaging biomarkers of outcome in infants with hypoxic-ischaemic encephalopathy treated with hypothermia

Therapeutic hypothermia confers significant benefit in term neonates with hypoxic-ischaemic encephalopathy (HIE). However, despite the treatment nearly half of the infants develop an unfavourable outcome. Intensive bench-based and early phase clinical research is focused on identifying treatments that augment hypothermic neuroprotection. Qualified biomarkers are required to test these promising therapies efficiently. This thesis aims to assess advanced magnetic resonance imaging (MRI) techniques, including diffusion tensor imaging (DTI) and resting state functional MRI (fMRI) as imaging biomarkers of outcome in infants with HIE who underwent hypothermic neuroprotection. FA values in the white matter (WM), obtained in the neonatal period and assessed by tract-based spatial statistics (TBSS), correlated with subsequent developmental quotient (DQ). However, TBSS is not suitable to study grey matter (GM), which is the primary site of injury following an acute hypoxic-ischaemic event. Therefore, a neonatal atlas-based automated tissue labelling approach was applied to segment central and cortical grey and whole brain WM. Mean diffusivity (MD) in GM structures, obtained in the neonatal period correlated with subsequent DQ. Although the central GM is the primary site of injury on conventional MRI following HIE; FA within WM tissue labels also correlated to neurodevelopmental performance scores. As DTI does not provide information on functional consequences of brain injury functional sequel of HIE was studied with resting state fMRI. Diminished functional connectivity was demonstrated in infants who suffered HIE, which associated with an unfavourable outcome. The results of this thesis suggest that MD in GM tissue labels and FA either determined within WM tissue labels or analysed with TBSS correlate to subsequent neurodevelopmental performance scores in infants who suffered HIE treated with hypothermia and may be applied as imaging biomarkers of outcome in this population. Although functional connectivity was diminished in infants with HIE, resting state fMRI needs further study to assess its utility as an imaging biomarker following a hypoxic-ischaemic brain injury.Open Acces

Task-based fMRI investigation of the newborn brain: sensorimotor development and learning

Human brain development relies upon the interaction between genetic and environmental factors, and the latter plays a critical role during the perinatal period. In this period, neuronal plasticity through experience-dependent activity is enhanced in the sensory systems, and drive the maturation of the brain. While plasticity is essential for maturation, it is also a source of vulnerability as altered early experiences may interact with the normal course of development. This is particularly evident in infants born preterm, who are prematurely exposed to a sensory-rich environment, and at risk or neurodevelopmental disorders. In keeping with the somatosensory system being at a critical period for development during late gestation, sensorimotor disorders, such as cerebral palsy, are more common in preterm compared with full-term born infants. It is therefore important to understand the normal trajectory of sensorimotor development and how this may be moulded by early sensory experiences. It is well acknowledged that the sensorimotor cortex is topographically organised so that different body parts map to a specific location within the cortex and this map is generally referred to as the ``homunculus". Although the somatotopy has been well characterised in the mature brain, it remains unknown when this organisation emerges during development. Animal studies hints that functional cortical maps might emerge across the equivalent period to the third trimester of human gestation, nevertheless there is currently no evidence. Therefore, I first investigated the topography of the preterm somatosensory cortex in a group of newborn infants. In this purpose I used fMRI and automated robotic tools and measured the functional responses to different sensory simulations (delivered to the mouth, wrists and ankles). The results provide evidence that it is possible to identify distinct areas in the somatosensory cortex devoted to different body parts even in the preterm brain supporting the presence of an immature \textit{homunculus}. Next, I wanted to investigate how activity and development in the sensorimotor system are influenced by experience. Experience-dependent plasticity is the basis of learning (e.g. adaptive behaviour), which is observed in newborn infants. Associative learning in particular has been widely investigated in infants, however, the underlining neuronal processes have previously been poorly understood. To study the neural correlates of associative learning in newborn infants, I developed and used a classical conditioning paradigm in combination with robot-assisted fMRI. The results confirm that associative learning can occur even at this early stage of life and with non-aversive stimuli. More importantly, I could observe learning-induced changes in brain activity within the primary sensory cortices, suggesting that such experience can shape cortical circuitry and is likely to influence early brain development.Open Acces

Multimodal assessment of neonatal pain

Pain assessment is critical to prevent suffering and harm in infants admitted to the neonatal care unit. As pain is a subjective experience, its assessment in nonverbal infants relies on surrogate measures. Current infant pain assessment tools that are based on behaviour and autonomic nervous system measurements lack face validity — they are unlikely to reflect pain in all its dimensions. In recent years, EEG-derived measures of pain have been developed in late preterm and term infants. Multimodal tools which include these cerebral measurements are conceptually more appropriate to measure pain. Yet, their use is still limited to specific research applications. This thesis focuses on outstanding questions that need to be addressed in order to advance the development of multimodal pain assessment tools that incorporate cerebral measurements. In the first part of this thesis, I focus on the characterisation of preterm infants’ noxious-evoked responses and their development. Across several modalities, premature infants have dampened or altered responsiveness compared to term infants, and it is uncertain if these responses can be reliably discriminated from tactile-evoked responses. In particular, a discriminative pattern of noxious-evoked EEG activity that is present in term infants, is unlikely to be present in preterm infants. In addition, it is unclear how noxious-evoked responses, especially brainderived responses, change with age. In this thesis, I use a classification model to show that infants aged 28–40 weeks postmenstrual age display discriminable multimodal responses to a noxious clinical procedure and a tactile control procedure, and I provide examples of how a such a model could be used in clinical trials of analgesics. I show that noxious-evoked responses change magnitude and morphology across this age range, and that discriminative brain activity emerges in early prematurity. In the second part of this thesis, I focus on improving the neuroscientific validity of a noxious-evoked EEG response measured at the cot-side, as the spatial neural correlates of these responses are still poorly understood. I present an EEG-fMRI pilot study to investigate the spatial neural correlates of inter-individual differences in noxious-evoked EEG responses and provide recommendations for a larger follow-up study. Overall, this thesis provides a characterisation of infants’ noxious-evoked responses and their development across multiple modalities, a crucial next step in improving multimodal neonatal pain assessment

Characterisation of the Haemodynamic Response Function (HRF) in the neonatal brain using functional MRI

Background: Preterm birth is associated with a marked increase in the risk of later neurodevelopmental impairment. With the incidence rising, novel tools are needed to provide an improved understanding of the underlying pathology and better prognostic information. Functional Magnetic Resonance Imaging (fMRI) with Blood Oxygen Level Dependent (BOLD) contrast has the potential to add greatly to the knowledge gained through traditional MRI techniques. However, it has been rarely used with neonatal subjects due to difficulties in application and inconsistent results. Central to this is uncertainity regarding the effects of early brain development on the Haemodynamic Response Function (HRF), knowledge of which is fundamental to fMRI methodology and analysis. Hypotheses: (1) Well localised and positive BOLD functional responses can be identified in the neonatal brain. (2) The morphology of the neonatal HRF differs significantly during early human development. (3) The application of an age-appropriate HRF will improve the identification of functional responses in neonatal fMRI studies. Methods: To test these hypotheses, a systematic fMRI study of neonatal subjects was carried out using a custom made somatosensory stimulus, and an adapted study design and analysis pipeline. The neonatal HRF was then characterised using an event related study design. The potential future application of the findings was then tested in a series of small experiments. Results: Well localised and positive BOLD functional responses were identified in neonatal subjects, with a maturational tendency towards an increasingly complex pattern of activation. A positive amplitude HRF was identified in neonatal subjects, with a maturational trend of a decreasing time-to-peak and increasing positive peak amplitude. Application of the empirical HRF significantly improved the precision of analysis in further fMRI studies. Conclusions: fMRI can be used to study functional activity in the neonatal brain, and may provide vital new information about both development and pathology