Person:

Santarnecchi, Emiliano

Our brain is a complex system of interconnected regions spontaneously organized into distinct networks. The integration of information between and within these networks is a continuous process that can be observed even when the brain is at rest, i.e. not engaged in any particular task. Moreover, such spontaneous dynamics show predictive value over individual cognitive profile and constitute a potential marker in neurological and psychiatric conditions, making its understanding of fundamental importance in modern neuroscience. Here we present a theoretical and mathematical model based on an extension of evolutionary game theory on networks (EGN), able to capture brain's interregional dynamics by balancing emulative and non-emulative attitudes among brain regions. This results in the net behavior of nodes composing resting-state networks identified using functional magnetic resonance imaging (fMRI), determining their moment-to-moment level of activation and inhibition as expressed by positive and negative shifts in BOLD fMRI signal. By spontaneously generating low-frequency oscillatory behaviors, the EGN model is able to mimic functional connectivity dynamics, approximate fMRI time series on the basis of initial subset of available data, as well as simulate the impact of network lesions and provide evidence of compensation mechanisms across networks. Results suggest evolutionary game theory on networks as a new potential framework for the understanding of human brain network dynamics.

Background: The absence of efficient treatments capable to promote central nervous system recovery in patients in vegetative state (VS) due to a severe acquired brain injury highlights the need of exploring alternative neuromodulatory treatments that can lead to neurobehavioral gains. Some encouraging preliminary observations suggest that transcranial direct current stimulation could be effective in disorders of consciousness (DoC) patients, especially when applied on the dorsolateral prefrontal cortex (DLPFC) in patients with minimally conscious state (MCS) but not in those with VS. Objective: The primary aim of the present study was to verify if the application of transcranial random noise stimulation (tRNS) on the DLPFC might favor improvements of consciousness recovery in subacute VS-UWS. Methods: Nine patients with DoC due to traumatic brain injury (n = 1), anoxia (n = 3), and vascular damage (n = 5), have undergone a randomized, double-blind, sham-controlled, neuromodulatory trial with tRNS of bilateral DLPFC. All patients were in a post-acute phase and the DoC onset ranged from 30 days to 4 months. The diagnosis of DoC was based on internationally established criteria from the Multi-Society Task Force on PVS, and classified as VS or MCS using the JFK Coma Recovery Scale-Revised scores (CRS-R). We used CRS-R, Synek Scale, Ad-Hoc semi-quantitative scale and the Clinical Global Impression-Improvement scale to measure behavioral and electrophysiological changes during tRNS intervention. All patients were also treated with daily conventional rehabilitation treatment. Results: No significant differences emerged between active and sham groups regarding improvements of level of consciousness, as well as on electroencephalographic data. Only one patient showed emergence from VS-UWS, evolving from VS to MCS after the tRNS stimulation, at a distance of 3 weeks from the enrolment into the study. Conclusion: Repeated applications of tRNS of the DLPFC, even if applied in a subacute phase of VS-UWS state, did not modify behavioral and neurophysiological outcomes differently than sham stimulation.

Laminar heterotopia is a rare condition consisting in an extra layer of gray matter under properly migrated cortex; it configures an atypical presentation of periventricular nodular heterotopia (PNH) or a double cortex (DC) syndrome. We conducted an original functional MRI (fMRI) analysis in a drug-resistant epilepsy patient with “double-cortex”-like malformation to reveal her functional connectivity (FC) as well as a wide genetic analysis to identify possible genetic substrates. Heterotopias were segmented into region of interests (ROIs), whose voxel-wise FC was compared to that of (i) its normally migrated counterpart, (ii) its contralateral homologous, and (iii) those of 30 age-matched healthy controls. Extensive genetic analysis was conducted to screen cortical malformations-associated genes. Compared to healthy controls, both laminar heterotopias and the overlying cortex showed significant reduction of FC with the contralateral hemisphere. Two heterozygous variants of uncertain clinical significance were found, involving autosomal recessive disease-causing genes, FAT4 and COL18A1. This first FC analysis of a unique case of “double-cortex”-like malformation revealed a hemispheric connectivity segregation both in the laminar cortex as in the correctly migrated one, with a new pattern of genes’ mutations. Our study suggests the altered FC could have an electrophysiological and functional impact on large-scale brain networks, and the involvement of not yet identified genes in “double-cortex”-like malformation with a possible role of rare variants in recessive genes as pathogenic cofactors.

Insomnia might occur as result of increased cognitive and physiological arousal caused by acute or long acting stressors and associated cognitive rumination. This might lead to alterations in brain connectivity patterns as those captured by functional connectivity fMRI analysis, leading to potential insight about primary insomnia (PI) pathophysiology as well as the impact of long-term exposure to sleep deprivation. We investigated changes of voxel-wise connectivity patterns in a sample of 17 drug-naïve PI patients and 17 age-gender matched healthy controls, as well as the relationship between brain connectivity and age of onset, illness duration, and severity. Results showed a significant increase in resting-state functional connectivity of the bilateral visual cortex in PI patients, associated with decreased connectivity between the visual cortex and bilateral temporal pole. Regression with clinical scores originally unveiled a pattern of increased local connectivity as measured by intrinsic connectivity contrast (ICC), specifically resembling the default mode network (DMN). Additionally, age of onset was found to be correlated with the connectivity of supplementary motor area (SMA), and the strength of DMN←→SMA connectivity was significantly correlated with both age of onset (R2 = 41%) and disease duration (R2 = 21%). Chronic sleep deprivation, but most importantly early insomnia onset, seems to have a significant disruptive effect over the physiological negative correlation between DMN and SMA, a well-known fMRI marker of attention performance in humans. This suggests the need for more in-depth investigations on the prevention and treatment of connectivity changes and associated cognitive and psychological deficits in PI patients.