Serafeim Loukas

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Behavioral outcome of very preterm children at 5 years of age: Prognostic utility of brain tissue volumes at term-equivalent-age, perinatal, and environmental factors

Laura Ioana Gui, Serafeim Loukas, Djalel Eddine Meskaldji

ObjectivePrematurity is associated with a high risk of long-term behavioral problems. This study aimed to assess the prognostic utility of volumetric brain data at term-equivalent-age (TEA), clinical perinatal factors, and parental social economic risk in the prediction of the behavioral outcome at 5 years in a cohort of very preterm infants (VPT,

WILEY2023

Identification of biopsychological trait markers in functional neurological disorders

Serafeim Loukas

Weber et al. provide evidence in support of a stress-diathesis model of functional neurological disorders. They identify trauma history in the form of emotional neglect as a psychological risk factor, and reduced hippocampus and amygdala volume as a predisposing biological trait marker. Stress is a well-known risk factor to develop a functional neurological disorder, a frequent neuropsychiatric medical condition in which patients experience a variety of disabling neurological symptoms. Only little is known about biological stress regulation, and how it interacts with predisposing biological and psychosocial risk factors. Dysregulation of the hypothalamic-pituitary-adrenal axis in patients with functional neurological disorders has been postulated, but its relationship to preceding psychological trauma and brain anatomical changes remains to be elucidated. We set out to study the hypothalamic-pituitary-adrenal axis analysing the cortisol awakening response and diurnal baseline cortisol in 86 patients with mixed functional neurological symptoms compared to 76 healthy controls. We then examined the association between cortisol regulation and the severity and duration of traumatic life events. Finally, we analysed volumetric brain alterations in brain regions particularly sensitive to psychosocial stress, acting on the assumption of the neurotoxic effect of prolonged cortisol exposure. Overall, patients had a significantly flatter cortisol awakening response (P < 0.001) and reported longer (P = 0.01) and more severe (P < 0.001) emotional neglect as compared to healthy controls. Moreover, volumes of the bilateral amygdala and hippocampus were found to be reduced in patients. Using a partial least squares correlation, we found that in patients, emotional neglect plays a role in the multivariate pattern between trauma history and hypothalamic-pituitary-adrenal axis dysfunction, while cortisol did not relate to reduced brain volumes. This suggests that psychological stress acts as a precipitating psychosocial risk factor, whereas a reduced brain volume rather represents a biological predisposing trait marker for the disorder. Contrarily, an inverse relationship between brain volume and cortisol was found in healthy controls, representing a potential neurotoxic effect of cortisol. These findings support the theory of reduced subcortical volumes representing a predisposing trait factor in functional neurological disorders, rather than a state effect of the illness. In summary, this study supports a stress-diathesis model for functional neurological disorders and showed an association between different attributes of trauma history and abnormalities in hypothalamus-pituitary-adrenal axis function. Moreover, we suggest that reduced hippocampal and amygdalar volumes represent a biological 'trait marker' for functional neurological disorder patients, which might contribute to a reduced resilience to stress.

OXFORD UNIV PRESS2022

Preterm birth is a major pediatric health problem that perturbs the genetically determined program of corticogenesis of the developing brain. As a consequence, prematurity has been strongly associated with adverse long-term neurodevelopmental outcome that may persist even into adulthood. Early characterization of the underlying neuronal mechanisms and early identification of infants at risk is of paramount importance since it allows better development of early therapeutic interventions aiming to prevent adverse outcomes through resilience. This dissertation aims to investigate the consequences of preterm birth on brain function and structure and their relation to adverse neurodevelopmental outcome, as well as to unveil the effect of an early music intervention on brain function. Research to date has mainly focused on the effect of early interventions on the long-term outcome but not on the effect of those interventions on brain function in preterm populations. Moreover, a clear consensus about the predictive utility of MRI volumetric data for long-term outcomes is still missing. This dissertation consists of three main parts. First, we investigate the effects of an early musical intervention in preterm infants using a task-based and resting-state fMRI paradigm. We explore brain effective connectivity changes during task and functional connectivity (FC) modulations at rest. We show that music exposure during hospitalization promotes brain auditory processing maturation. We find increased FC between the auditory cortex and regions involved in familiarity and music processing, such as the thalamus and caudate nucleus. Moreover, we report increased rs-FC in regions involved in associative memory and multisensory processing, such as the calcarine and angular gyrus with a dosage-dependent effect on this modulation. Secondly, we examine brain volumetric development and whether brain volumes are associated with cognitive and behavioural long-term outcomes. We find that perinatal risk factors, such as asphyxia and sepsis have an impact on brain tissue volume. We also find that cognitive and behavioural outcomes are strongly associated with parental SES and that brain tissue volumes at TEA have moderate predictive power. Next, inspired by studies that have characterized the progression of neurodegenerative diseases, we employ an advanced technique to unveil the sequence of biological events along the course of prematurity. Our novel findings might be of clinical use as they allow more targeted early interventions aiming to improve long-term outcomes. Finally, we propose a framework that enables the spectral graph theory analysis of the functional connectome at the voxel level. Our results indicate the presence of both functional gradients and community structure revealing fine-grained connectivity patterns. The proposed framework opens a new avenue for spectral graph theory research at the voxel level.

EPFL2021