Rich dynamics and functional organization on topographically designed neuronal networks in vitro.

Neuronal cultures are a prominent experimental tool to understand complex functional organization in neuronal assemblies. However, neurons grown on flat surfaces exhibit a strongly coherent bursting behavior with limited functionality. To approach the functional richness of naturally formed neuronal circuits, here we studied neuronal networks grown on polydimethylsiloxane (PDMS) topographical patterns shaped as either parallel tracks or square valleys. We followed the evolution of spontaneous activity in these cultures along 20 days in vitro using fluorescence calcium imaging. The networks were characterized by rich spatiotemporal activity patterns that comprised from small regions of the culture to its whole extent. Effective connectivity analysis revealed the emergence of spatially compact functional modules that were associated with both the underpinned topographical features and predominant spatiotemporal activity fronts. Our results show the capacity of spatial constraints to mold activity and functional organization, bringing new opportunities to comprehend the structure-function relationship in living neuronal circuits.

Dynamic and Functional Alterations of Neuronal Networks In Vitro upon Physical Damage: A Proof of Concept.

There is a growing technological interest in combining biological neuronal networks with electronic ones, specifically for biological computation, human-machine interfacing and robotic implants. A major challenge for the development of these technologies is the resilience of the biological networks to physical damage, for instance, when used in harsh environments. To tackle this question, here, we investigated the dynamic and functional alterations of rodent cortical networks grown in vitro that were physically damaged, either by sequentially removing groups of neurons that were central for information flow or by applying an incision that cut the network in half. In both cases, we observed a remarkable capacity of the neuronal cultures to cope with damage, maintaining their activity and even reestablishing lost communication pathways. We also observed-particularly for the cultures cut in half-that a reservoir of healthy neurons surrounding the damaged region could boost resilience by providing stimulation and a communication bridge across disconnected areas. Our results show the remarkable capacity of neuronal cultures to sustain and recover from damage, and may be inspirational for the development of future hybrid biological-electronic systems.

Spontaneous brain activity in healthy aging: An overview through fluctuations and regional homogeneity.

Introduction: This study aims to explore whole-brain resting-state spontaneous brain activity using fractional amplitude of low-frequency fluctuation (fALFF) and regional homogeneity (ReHo) strategies to find differences among age groups within a population ranging from middle age to older adults. Methods: The sample comprised 112 healthy persons (M = 68.80, SD = 7.99) aged 48-89 who were split into six age groups (< 60, 60-64, 65-69, 70-74, 75-79, and ≥ 80). Fractional amplitude of low-frequency fluctuation and ReHo analyses were performed and were compared among the six age groups, and the significant results commonly found across groups were correlated with the gray matter volume of the areas and the age variable. Results: Increased activity was found using fALFF in the superior temporal gyrus and inferior frontal gyrus when comparing the first group and the fifth. Regarding ReHo analysis, Group 6 showed increased ReHo in the temporal lobe (hippocampus), right and left precuneus, right caudate, and right and left thalamus depending on the age group. Moreover, significant correlations between age and fALFF and ReHo clusters, as well as with their gray matter volume were found, meaning that the higher the age, the higher the regional synchronization, the lower the fALFF activation, and the lower gray matter of the right thalamus. Conclusion: Both techniques have been shown to be valuable and usable tools for disentangling brain changes in activation in a very low interval of years in healthy aging.

Network change point detection in resting-state functional connectivity dynamics of mild cognitive impairment patients / Detección de puntos de cambios en redes de conectividad funcional dinámica en situación de reposo en pacientes con deterioro cognitivo leve

BACKGROUND/OBJECTIVE: This study aims to characterize the differences on the short-term temporal network dynamics of the undirected and weighted wholebrain functional connectivity between healthy aging individuals and people with mild cognitive impairment (MCI). The Network Change Point Detection algorithm was applied to identify the significant change points in the resting-state fMRI register, and we analyzed the fluctuations in the topological properties of the subnetworks between significant change points. METHOD: Ten MCI patients matched by gender and age in 1:1 ratio to healthy controls screened during patient recruitment. A neuropsychological evaluation was done to both groups as well as functional magnetic images were obtained with a Philips 3.0T. All the images were preprocessed and statistically analyzed through dynamic point estimation tools. RESULTS: No statistically significant differences were found between groups in the number of significant change points in the functional connectivity networks. However, an interaction effect of age and state was detected on the intra-participant variability of the network strength. CONCLUSIONS: The progression of states was associated to higher variability in the patient's group. Additionally, higher performance in the prospective and retrospective memory scale was associated with higher median network strength

ANTECEDENTES/OBJETIVO: Este estudio tiene como objetivo caracterizar las diferencias en la red dinámica de conectividad funcional no dirigida entre un grupo de personas sanas y otro con deterioro cognitivo leve. Se aplicó un algoritmo de detección de puntos de cambio en redes complejas para identificarlos en registros fMRI en estado de reposo y se analizaron las fluctuaciones en las propiedades topológicas de las subredes entre puntos de cambio significativos. MÉTODO: Diez pacientes emparejados por sexo y edad en proporción 1:1 a controles sanos. Se realizó una evaluación neuropsicológica a ambos grupos y se obtuvieron imágenes funcionales con un Philips Ingenia 3.0T. Todas las imágenes fueron preprocesadas y analizadas estadísticamente a través de herramientas de estimación dinámica de puntos. RESULTADOS: No se encontraron diferencias estadísticamente significativas entre ambos grupos en el número de puntos de cambio en las redes de conectividad funcional. Se detectó un efecto de interacción entre edad y la variabilidad intra-sujeto en algunos indicadores de complejidad (strength) de la red dinámica. CONCLUSIONES: La progresión de la conectividad se asoció a una mayor variabilidad en el grupo de pacientes. Además, se puede asociar un mayor rendimiento en la escala de memoria prospectiva y retrospectiva con un mayor valor de la mediana de strength de la red

Network change point detection in resting-state functional connectivity dynamics of mild cognitive impairment patients.

Background/Objective: This study aims to characterize the differences on the short-term temporal network dynamics of the undirected and weighted whole-brain functional connectivity between healthy aging individuals and people with mild cognitive impairment (MCI). The Network Change Point Detection algorithm was applied to identify the significant change points in the resting-state fMRI register, and we analyzed the fluctuations in the topological properties of the sub-networks between significant change points. Method: Ten MCI patients matched by gender and age in 1:1 ratio to healthy controls screened during patient recruitment. A neuropsychological evaluation was done to both groups as well as functional magnetic images were obtained with a Philips 3.0T. All the images were preprocessed and statistically analyzed through dynamic point estimation tools. Results: No statistically significant differences were found between groups in the number of significant change points in the functional connectivity networks. However, an interaction effect of age and state was detected on the intra-participant variability of the network strength. Conclusions: The progression of states was associated to higher variability in the patient's group. Additionally, higher performance in the prospective and retrospective memory scale was associated with higher median network strength.

Antecedentes/Objetivo: Este estudio tiene como objetivo caracterizar las diferencias en la red dinámica de conectividad funcional no dirigida entre un grupo de personas sanas y otro con deterioro cognitivo leve. Se aplicó un algoritmo de detección de puntos de cambio en redes complejas para identificarlos en registros fMRI en estado de reposo y se analizaron las fluctuaciones en las propiedades topológicas de las subredes entre puntos de cambio significativos. Método: Diez pacientes emparejados por sexo y edad en proporción 1:1 a controles sanos. Se realizó una evaluación neuropsicológica a ambos grupos y se obtuvieron imágenes funcionales con un Philips Ingenia 3.0T. Todas las imágenes fueron preprocesadas y analizadas estadísticamente a través de herramientas de estimación dinámica de puntos. Resultados: No se encontraron diferencias estadísticamente significativas entre ambos grupos en el número de puntos de cambio en las redes de conectividad funcional. Se detectó un efecto de interacción entre edad y la variabilidad intra-sujeto en algunos indicadores de complejidad (strength) de la red dinámica. Conclusiones: La progresión de la conectividad se asoció a una mayor variabilidad en el grupo de pacientes. Además, se puede asociar un mayor rendimiento en la escala de memoria prospectiva y retrospectiva con un mayor valor de la mediana de strength de la red.

Resting-state functional dynamic connectivity and healthy aging: a sliding-window network analysis / Conectividad dinámica funcional en situación de reposo y envejecimiento sano: análisis de redes mediante ventanas móviles

BACKGROUND: Graph theory has been widely used to study structural and functional brain connectivity changes in healthy aging, and occasionally with clinical samples; in both cases, during task-related and resting-state experiments. Recent studies have focused their interest on dynamic changes during a resting-state fMRI register in order to identify differences in non-stationary patterns associated with the aging process. The objective of this study was to characterize resting-state fMRI network dynamics in order to study the healthy aging process. METHOD: 114 healthy older adults were measured in a resting-state paradigm using fMRI. A sliding-window approach to graph theory was used to measure the mean degree, average path length, clustering coefficient, and small-worldness of each subnetwork, and the impact of age and time in each graph measure was assessed. RESULTS: A combined effect of age and time was detected in mean degree, average path length, and small-worldness, where participants aged 75 to 79 showed a curvilinear trend with reduced network density and increased small-world coefficient in the middle of the register. CONCLUSION: An effect of age was observed on average path length, with younger participants showing slightly lower scores

ANTECEDENTES: la Teoría de Grafos se ha utilizado para estudiar los cambios de la conectividad cerebral en el envejecimiento sano. Trabajos recientes han centrado su interés en los cambios dinámicos en registro fMRI en estado de reposo para identificar patrones no estacionarios en el proceso de envejecimiento. Este artículo tiene como objetivo caracterizar la dinámica de la red fMRI para estudiar envejecimiento saludable. MÉTODO: se registraron 114 adultos sanos mayores de 65 años en un paradigma de estado de reposo mediante señal fMRI. Se usó Teoría de Grafos para medir el grado medio de conectividad, la longitud promedio de las conexiones, el coeficiente de agrupamiento y el small-world de cada subred. Se evaluó el impacto de la edad y el tiempo en cada medida de grafo. RESULTADOS: se detectó un efecto combinado de la edad y el tiempo en diversas medidas, los participantes de 75 a 79 años mostraron una tendencia curvilínea de la densidad y agrupación de red reducidas, pero un coeficiente small-world mayor en las ventanas centrales. CONCLUSIÓN: se observó un efecto de la edad en la longitud promedio y los participantes más jóvenes mostraron puntuaciones más bajas en los indicadores de red

Resting-state functional dynamic connectivity and healthy aging: A sliding-window network analysis.

BACKGROUND: Graph theory has been widely used to study structural and functional brain connectivity changes in healthy aging, and occasionally with clinical samples; in both cases, during task-related and resting-state experiments. Recent studies have focused their interest on dynamic changes during a resting-state fMRI register in order to identify differences in non-stationary patterns associated with the aging process. The objective of this study was to characterize resting-state fMRI network dynamics in order to study the healthy aging process. METHOD: 114 healthy older adults were measured in a resting-state paradigm using fMRI. A sliding-window approach to graph theory was used to measure the mean degree, average path length, clustering coefficient, and small-worldness of each subnetwork, and the impact of age and time in each graph measure was assessed. RESULTS: A combined effect of age and time was detected in mean degree, average path length, and small-worldness, where participants aged 75 to 79 showed a curvilinear trend with reduced network density and increased small-world coefficient in the middle of the register. CONCLUSION: An effect of age was observed on average path length, with younger participants showing slightly lower scores.

Resting-State Functional Connectivity Dynamics in Healthy Aging: An Approach Through Network Change Point Detection.

This study aims at assessing the impact of age on the short-term temporal dynamics of the topological properties of the undirected and weighted whole-brain functional connectivity (FC) networks. We studied the association between the participant's age and the number of significant change points detected through the Network Change Point Detection algorithm. Secondary, we defined state as the resting-state functional magnetic resonance imaging (rs-fMRI) subsequence between two significant change points, obtaining the FC network in each state and participant and characterized their network topological properties. The data comprise the rs-fMRI sequences of 114 healthy individuals combined from 3 different studies conducted at the Department of Medicine, School of Medicine and Health Sciences, University of Barcelona. Participants were healthy people in the absence of any pathology that could interfere with the scanning procedures, as well as any chronic illness that implied a short-lived situation. Topological properties of everyone's FC networks were characterized by their network strength, transitivity, characteristic path length, and small-worldness, analyzing the effect of age in those observed distributions. To that effect, we constructed a mixed linear model for each network topological property with age, state, and state duration as the linear predictors. Several statistically significant relationships have been estimated between the indicators of the FC networks that show a certain regular pattern of change in the networks during the time of registration at the resting fMRI paradigm. These dynamic changes seem to be related to the age of each group studied. Healthy aging could be characterized by FC dynamics patterns.

Functional interactions in patients with hemianopia: A graph theory-based connectivity study of resting fMRI signal.

The assessment of task-independent functional connectivity (FC) after a lesion causing hemianopia remains an uncovered topic and represents a crucial point to better understand the neural basis of blindsight (i.e. unconscious visually triggered behavior) and visual awareness. In this light, we evaluated functional connectivity (FC) in 10 hemianopic patients and 10 healthy controls in a resting state paradigm. The main aim of this study is twofold: first of all we focused on the description and assessment of density and intensity of functional connectivity and network topology with and without a lesion affecting the visual pathway, and then we extracted and statistically compared network metrics, focusing on functional segregation, integration and specialization. Moreover, a study of 3-cycle triangles with prominent connectivity was conducted to analyze functional segregation calculated as the area of each triangle created connecting three neighboring nodes. To achieve these purposes we applied a graph theory-based approach, starting from Pearson correlation coefficients extracted from pairs of regions of interest. In these analyses we focused on the FC extracted by the whole brain as well as by four resting state networks: The Visual (VN), Salience (SN), Attention (AN) and Default Mode Network (DMN), to assess brain functional reorganization following the injury. The results showed a general decrease in density and intensity of functional connections, that leads to a less compact structure characterized by decrease in functional integration, segregation and in the number of interconnected hubs in both the Visual Network and the whole brain, despite an increase in long-range inter-modules connections (occipito-frontal connections). Indeed, the VN was the most affected network, characterized by a decrease in intra- and inter-network connections and by a less compact topology, with less interconnected nodes. Surprisingly, we observed a higher functional integration in the DMN and in the AN regardless of the lesion extent, that may indicate a functional reorganization of the brain following the injury, trying to compensate for the general reduced connectivity. Finally we observed an increase in functional specialization (lower between-network connectivity) and in inter-networks functional segregation, which is reflected in a less compact network topology, highly organized in functional clusters. These descriptive findings provide new insight on the spontaneous brain activity in hemianopic patients by showing an alteration in the intrinsic architecture of a large-scale brain system that goes beyond the impairment of a single RSN.

Estimation of Brain Functional Connectivity in Patients with Mild Cognitive Impairment.

Mild cognitive impairment is defined as greater cognitive decline than expected for a person at a particular age and is sometimes considered a stage between healthy aging and Alzheimer's disease or other dementia syndromes. It is known that functional connectivity patterns change in people with this diagnosis. We studied functional connectivity patterns and functional segregation in a resting-state fMRI paradigm comparing 10 MCI patients and 10 healthy controls matched by education level, age and sex. Ninety ROIs from the automated anatomical labeling (AAL) atlas were selected for functional connectivity analysis. A correlation matrix was created for each group, and a third matrix with the correlation coefficient differences between the two matrices was created. Functional segregation was analyzed with the 3-cycle method, which is novel in studies of this topic. Finally, cluster analyses were also performed. Our results showed that the two correlation matrices were visually similar but had many differences related to different cognitive functions. Differences were especially apparent in the anterior default mode network (DMN), while the visual resting-state network (RSN) showed no differences between groups. Differences in connectivity patterns in the anterior DMN should be studied more extensively to fully understand its role in the differentiation of healthy aging and an MCI diagnosis.

Age-related changes in resting-state functional connectivity in older adults.

Age-related changes in the brain connectivity of healthy older adults have been widely studied in recent years, with some differences in the obtained results. Most of these studies showed decreases in general functional connectivity, but they also found increases in some particular regions and areas. Frequently, these studies compared young individuals with older subjects, but few studies compared different age groups only in older populations. The purpose of this study is to analyze whole-brain functional connectivity in healthy older adult groups and its network characteristics through functional segregation. A total of 114 individuals, 48 to 89 years old, were scanned using resting-state functional magnetic resonance imaging in a resting state paradigm and were divided into six different age groups (< 60, 60-64, 65-69, 70-74, 75-79, ≥ 80 years old). A partial correlation analysis, a pooled correlation analysis and a study of 3-cycle regions with prominent connectivity were conducted. Our results showed progressive diminution in the functional connectivity among different age groups and this was particularly pronounced between 75 and 79 years old. The oldest group (≥ 80 years old) showed a slight increase in functional connectivity compared to the other groups. This occurred possibly because of compensatory mechanism in brain functioning. This study provides information on the brain functional characteristics of every age group, with more specific information on the functional progressive decline, and supplies methodological tools to study functional connectivity characteristics. Approval for the study was obtained from the ethics committee of the Comisión de Bioética de la Universidad de Barcelona (approval No. PSI2012-38257) on June 5, 2012, and from the ethics committee of the Barcelona's Hospital Clínic (approval No. 2009-5306 and 2011-6604) on October 22, 2009 and April 7, 2011 respectively.