Identification of biopsychological trait markers in functional neurological disorders.

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.

Musical memories in newborns: A resting-state functional connectivity study.

Music is known to induce emotions and activate associated memories, including musical memories. In adults, it is well known that music activates both working memory and limbic networks. We have recently discovered that as early as during the newborn period, familiar music is processed differently from unfamiliar music. The present study evaluates music listening effects at the brain level in newborns, by exploring the impact of familiar or first-time music listening on the subsequent resting-state functional connectivity in the brain. Using a connectome-based framework, we describe resting-state functional connectivity (RS-FC) modulation after music listening in three groups of newborn infants, in preterm infants exposed to music during their neonatal-intensive-care-unit (NICU) stay, in control preterm, and full-term infants. We observed modulation of the RS-FC between brain regions known to be implicated in music and emotions processing, immediately following music listening in all newborn infants. In the music exposed group, we found increased RS-FC between brain regions known to be implicated in familiar and emotionally arousing music and multisensory processing, and therefore implying memory retrieval and associative memory. We demonstrate a positive correlation between the occurrence of the prior music exposure and increased RS-FC in brain regions implicated in multisensory and emotional processing, indicating strong engagement of musical memories; and a negative correlation with the Default Mode Network, indicating disengagement due to the aforementioned cognitive processing. Our results describe the modulatory effect of music listening on brain RS-FC that can be linked to brain correlates of musical memory engrams in preterm infants.

Preterm birth leads to impaired rich-club organization and fronto-paralimbic/limbic structural connectivity in newborns.

Prematurity disrupts brain development during a critical period of brain growth and organization and is known to be associated with an increased risk of neurodevelopmental impairments. Investigating whole-brain structural connectivity alterations accompanying preterm birth may provide a better comprehension of the neurobiological mechanisms related to the later neurocognitive deficits observed in this population. Using a connectome approach, we aimed to study the impact of prematurity on neonatal whole-brain structural network organization at term-equivalent age. In this cohort study, twenty-four very preterm infants at term-equivalent age (VPT-TEA) and fourteen full-term (FT) newborns underwent a brain MRI exam at term age, comprising T2-weighted imaging and diffusion MRI, used to reconstruct brain connectomes by applying probabilistic constrained spherical deconvolution whole-brain tractography. The topological properties of brain networks were quantified through a graph-theoretical approach. Furthermore, edge-wise connectivity strength was compared between groups. Overall, VPT-TEA infants' brain networks evidenced increased segregation and decreased integration capacity, revealed by an increased clustering coefficient, increased modularity, increased characteristic path length, decreased global efficiency and diminished rich-club coefficient. Furthermore, in comparison to FT, VPT-TEA infants had decreased connectivity strength in various cortico-cortical, cortico-subcortical and intra-subcortical networks, the majority of them being intra-hemispheric fronto-paralimbic and fronto-limbic. Inter-hemispheric connectivity was also decreased in VPT-TEA infants, namely through connections linking to the left precuneus or left dorsal cingulate gyrus - two regions that were found to be hubs in FT but not in VPT-TEA infants. Moreover, posterior regions from Default-Mode-Network (DMN), namely precuneus and posterior cingulate gyrus, had decreased structural connectivity in VPT-TEA group. Our finding that VPT-TEA infants' brain networks displayed increased modularity, weakened rich-club connectivity and diminished global efficiency compared to FT infants suggests a delayed transition from a local architecture, focused on short-range connections, to a more distributed architecture with efficient long-range connections in those infants. The disruption of connectivity in fronto-paralimbic/limbic and posterior DMN regions might underlie the behavioral and social cognition difficulties previously reported in the preterm population.

Music processing in preterm and full-term newborns: A psychophysiological interaction (PPI) approach in neonatal fMRI.

Neonatal Intensive Care Units (NICU) provide special equipment designed to give life support for the increasing number of prematurely born infants and assure their survival. More recently NICU's strive to include developmentally oriented care and modulate sensory input for preterm infants. Music, among other sensory stimuli, has been introduced into NICUs, but without knowledge on the basic music processing in the brain of preterm infants. In this study, we explored the cortico-subcortical music processing of different types of conditions (Original music, Tempo modification, Key transposition) in newborns shortly after birth to assess the effective connectivity of the primary auditory cortex with the entire newborn brain. Additionally, we investigated if early exposure during NICU stay modulates brain processing of music in preterm infants at term equivalent age. We approached these two questions using Psychophysiological Interaction (PPI) analyses. A group of preterm infants listened to music (Original music) starting from 33 weeks postconceptional age until term equivalent age and were compared to two additional groups without music intervention; preterm infants and full-term newborns. Auditory cortex functional connectivity with cerebral regions known to be implicated in tempo and familiarity processing were identified only for preterm infants with music training in the NICU. Increased connectivity between auditory cortices and thalamus and dorsal striatum may not only reflect their sensitivity to the known music and the processing of its tempo as familiar, but these results are also compatible with the hypothesis that the previously listened music induces a more arousing and pleasant state. Our results suggest that music exposure in NICU's environment can induce brain functional connectivity changes that are associated with music processing.

BOLD signal variability as potential new biomarker of functional neurological disorders.

BACKGROUND: Functional neurological disorder (FND) is a common neuropsychiatric condition with established diagnostic criteria and effective treatments but for which the underlying neuropathophysiological mechanisms remain incompletely understood. Recent neuroimaging studies have revealed FND as a multi-network brain disorder, unveiling alterations across limbic, self-agency, attentional/salience, and sensorimotor networks. However, the relationship between identified brain alterations and disease progression or improvement is less explored. METHODS: This study included resting-state functional magnetic resonance imaging (fMRI) data from 79 patients with FND and 74 age and sex-matched healthy controls (HC). First, voxel-wise BOLD signal variability was computed for each participant and the group-wise difference was calculated. Second, we investigated the potential of BOLD signal variability to serve as a prognostic biomarker for clinical outcome in 47 patients who attended a follow-up measurement after eight months. RESULTS: The results demonstrated higher BOLD signal variability in key networks, including the somatomotor, salience, limbic, and dorsal attention networks, in patients compared to controls. Longitudinal analysis revealed an increase in BOLD signal variability in the supplementary motor area (SMA) in FND patients who had an improved clinical outcome, suggesting SMA variability as a potential state biomarker. Additionally, higher BOLD signal variability in the left insula at baseline predicted a worse clinical outcome. CONCLUSION: This study contributes to the understanding of FND pathophysiology, emphasizing the dynamic nature of neural activity and highlighting the potential of BOLD signal variability as a valuable research tool. The insula and SMA emerge as promising regions for further investigation as prognostic and state markers.

Non-invasive neuromodulation of the right temporoparietal junction using theta-burst stimulation in functional neurological disorder.

Background: Disrupted sense of agency (SoA)-the sense of being the agent of one's own actions-has been demonstrated in patients with functional neurological disorder (FND), and a key area of the corresponding neuronal network is the right temporoparietal junction (rTPJ). Several functional MRI (fMRI) studies have found hypoactivation as well as hyperactivation of the rTPJ in FND. In a proof-of-concept study, we tested whether repetitive transcranial magnetic stimulation (rTMS) over the rTPJ could restore this aberrant activity. Methods: In a randomised, crossover, single-blinded, sham-controlled study design, theta-burst stimulation (tb-rTMS) was applied over the rTPJ in 23 patients with FND and 19 healthy controls (HC), with each participant undergoing three stimulatory visits (inhibitory continuous TBS (cTBS), excitatory intermittent TBS (iTBS) and sham). During fMRI, participants played a visuomotor task artificially reducing their SoA (manipulated agency, MA), repeated after each neurostimulation. We compared brain activity and behavioural SoA as primary outcomes before and after tb-rTMS and investigated the feasibility of tb-rTMS over the rTPJ in FND as secondary outcome. Results: At baseline, patients showed decreased accuracy in detecting reduced agency compared with controls (p<0.001), paralleled by lower brain activation in the rTPJ during MA (p=0.037, volume of interest). A region of interest analysis on the rTPJ showed no effect of the sham condition in FND or HC (p=0.917; p=0.375) but revealed a significant effect of stimulation protocol (cTBS/iTBS, p=0.037) in patients with FND, with the excitatory protocol increasing the blood-oxygen-level-dependent (BOLD) signal, whereas this effect was not found in HC. In neither group, a behavioural effect of tb-rTMS was observed. Conclusion: Aberrant processing of agency in FND was confirmed at baseline, reflected in behavioural outcome and reduced activity in the rTPJ. Tb-rTMS over this key region elicited neuronal changes in patients, paving ways for future studies exploring TMS as neurobiologically informed intervention to restore SoA in FND. We critically discuss methodological intricacies and outline further steps in this research line.

Transient resting-state salience-limbic co-activation patterns in functional neurological disorders.

BACKGROUND: Functional neurological disorders were historically regarded as the manifestation of a dynamic brain lesion which might be linked to trauma or stress, although this association has not yet been directly tested yet. Analysing large-scale brain network dynamics at rest in relation to stress biomarkers assessed by salivary cortisol and amylase could provide new insights into the pathophysiology of functional neurological symptoms. METHODS: Case-control resting-state functional magnetic resonance imaging study of 79 patients with mixed functional neurological disorders (i.e., functional movement disorders, functional seizures, persistent perceptual-postural dizziness) and 74 age- and sex-matched healthy controls. Using a two-step hierarchical data-driven neuroimaging approach, static functional connectivity was first computed between 17 resting-state networks. Second, dynamic alterations in these networks were examined using co-activation pattern analysis. Using a partial least squares correlation analysis, the multivariate pattern of correlation between altered temporal characteristics and stress biomarkers as well as clinical scores were evaluated. RESULTS: Compared to healthy controls, patients presented with functional aberrancies of the salience-limbic network connectivity. Thus, the insula and amygdala were selected as seed-regions for the subsequent analyses. Insular co-(de)activation patterns related to the salience network, the somatomotor network and the default mode network were detected, which patients entered more frequently than controls. Moreover, an insular co-(de)activation pattern with subcortical regions together with a wide-spread co-(de)activation with diverse cortical networks was detected, which patients entered less frequently than controls. In patients, dynamic alterations conjointly correlated with amylase measures and duration of symptoms. CONCLUSION: The relationship between alterations in insular co-activation patterns, stress biomarkers and clinical data proposes inter-related mechanisms involved in stress regulation and functional (network) integration. In summary, altered functional brain network dynamics were identified in patients with functional neurological disorder supporting previously raised concepts of impaired attentional and interoceptive processing.

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.

OBJECTIVE: Prematurity 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, <32 gestational weeks). METHODS: T2-weighted magnetic resonance brain images of 80 VPT children were acquired at TEA and automatically segmented into cortical gray matter, deep subcortical gray matter, white matter (WM), cerebellum (CB), and cerebrospinal fluid. The gray matter structure of the amygdala was manually segmented. Children were examined at 5 years of age with a behavioral assessment, using the strengths and difficulties questionnaire (SDQ). The utility of brain volumes at TEA, perinatal factors, and social economic risk for the prediction of behavioral outcome was investigated using support vector machine classifiers and permutation feature importance. RESULTS: The predictive modeling of the volumetric data showed that WM, amygdala, and CB volumes were the best predictors of the SDQ emotional symptoms score. Among the perinatal factors, sex, sepsis, and bronchopulmonary dysplasia were the best predictors of the hyperactivity/inattention score. When combining the social economic risk with volumetric and perinatal factors, we were able to accurately predict the emotional symptoms score. Finally, social economic risk was positively correlated with the scores of conduct problems and peer problems. CONCLUSIONS: This study provides information on the relation between brain structure at TEA and clinical perinatal factors with behavioral outcome at age 5 years in VPT children. Nevertheless, the overall predictive power of our models is relatively modest, and further research is needed to identify factors associated with subsequent behavioral problems in this population.