Automatic algorithms for disease diagnosis are being thoroughly researched for use in clinical settings. They usually rely on pre-identified biomarkers to highlight the existence of certain problems. However, finding such biomarkers for neurodevelopmental disorders such as Autism Spectrum Disorder (ASD) has challenged researchers for many years. With enough data and computational power, machine learning (ML) algorithms can be used to interpret the data and extract the best biomarkers from thousands of candidates. In this study, we used the fMRI data of 816 individuals enrolled in the Autism Brain Imaging Data Exchange (ABIDE) to introduce a new biomarker extraction pipeline for ASD that relies on the use of graph theoretical metrics of fMRI-based functional connectivity to inform a support vector machine (SVM). Furthermore, we split the dataset into 5 age groups to account for the effect of aging on functional connectivity. Our methodology achieved better results than most state-of-the-art investigations on this dataset with the best model for the >30 years age group achieving an accuracy, sensitivity, and specificity of 95, 97, and 95%, respectively. Our results suggest that measures of centrality provide the highest contribution to the classification power of the models.

Phase-amplitude coupling (PAC), a type of cross-frequency coupling (CFC) where the phase of a low-frequency rhythm modulates the amplitude of a higher frequency, is becoming an important indicator of information transmission in the brain. However, the neurobiological mechanisms underlying its generation remain undetermined. A realistic, yet tractable computational model of the phenomenon is thus needed. Here we analyze a neural mass model of a cortical column, comprising fourteen neuronal populations distributed across four layers (L2/3, L4, L5 and L6). A control analysis showed that the conditional transfer entropy (cTE) measure is able to correctly estimate the flow of information between neuronal populations. Then, we computed cTE from the phases to the amplitudes of the oscillations generated in the cortical column. This approach provides information regarding directionality by distinguishing PAC from APC (amplitude-phase coupling), i.e. the information transfer from amplitudes to phases, and can be used to estimate other types of CFC such as amplitude-amplitude coupling (AAC) and phase-phase coupling (PPC). While experiments often only focus on one or two PAC combinations (e.g., theta-gamma or alpha-gamma), we found that a cortical column can simultaneously generate almost all possible PAC combinations, depending on connectivity parameters, time constants, and external inputs. PAC interactions with and without an anatomical equivalent (direct and indirect interactions, respectively) were analyzed. We found that the strength of PAC between two populations was strongly correlated with the strength of the effective connections between the populations and, on average, did not depend on whether the PAC connection was direct or indirect. When considering a cortical column circuit as a complex network, we found that neuronal populations making indirect PAC connections had, on average, higher local clustering coefficient, efficiency, and betweenness centrality than populations making direct connections and populations not involved in PAC connections. This suggests that their interactions were more effective when transmitting information. Since approximately 60% of the obtained interactions represented indirect connections, our results highlight the importance of the topology of cortical circuits for the generation of the PAC phenomenon. Finally, our results demonstrated that indirect PAC interactions can be explained by a cascade of direct CFC and same-frequency band interactions, suggesting that PAC analysis of experimental data should be accompanied by the estimation of other types of frequency interactions for an integrative understanding of the phenomenon. For many decades, the study of oscillatory brain activity focused on the separate analysis of its different frequency bands (from delta to gamma). However, neurons, and neuronal populations are nonlinear systems, and a sinusoidal input will produce new frequency components in their output. This induces cross-frequency coupling (CFC) between any two sources (e.g. neuronal populations, or brain regions) when there are bidirectional connections between them, as is often the case in the brain. Cascades of nonlinear sources can also produce CFC between sources that are not directly connected. Although several types of CFC are possible, there is an increasing interest in phase-amplitude coupling (PAC), the phenomenon where the amplitude of a high frequency oscillation (e.g. gamma) is modulated by the phase of a lower frequency (e.g. theta). PAC has been hypothesized to mediate the integration of distributed information in the brain, but the exact local and global mechanisms responsible for this processing remain unknown. Here we focus on the generation of PAC at the local scale, in the cortical column, and study how the biophysics of the neuronal populations involved, influence the generation of the phenomenon. Our results highlight the importance of the topology of the cortical column network on the generation of PAC, and show that indirect PAC connections can be predicted by a cascade of direct same-frequency coupling (SFC) and CFC connections.

Brain stimulation can modulate the activity of neural circuits impaired by Alzheimer’s disease (AD), having promising clinical benefit. However, all individuals with the same condition currently receive identical brain stimulation, with limited theoretical basis for this generic approach. In this study, we introduce a control theory framework for obtaining exogenous signals that revert pathological electroencephalographic activity in AD at a minimal energetic cost, while reflecting patients’ biological variability. We used anatomical networks obtained from diffusion magnetic resonance images acquired by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) as mediators for the interaction between Duffing oscillators. The nonlinear nature of the brain dynamics is preserved, given that we extend the so-called state-dependent Riccati equation control to reflect the stimulation objective in the high-dimensional neural system. By considering nonlinearities in our model, we identified regions for which control inputs fail to correct abnormal activity. There are changes to the way stimulated regions are ranked in terms of the energetic cost of controlling the entire network, from a linear to a nonlinear approach. We also found that limbic system and basal ganglia structures constitute the top target locations for stimulation in AD. Patients with highly integrated anatomical networks–namely, networks having low average shortest path length, high global efficiency–are the most suitable candidates for the propagation of stimuli and consequent success on the control task. Other diseases associated with alterations in brain dynamics and the self-control mechanisms of the brain can be addressed through our framework. This work aims to close the knowledge gap between theory and experiment in brain stimulation. Previous modeling approaches for stimulation have overlooked the nonlinear dynamical nature of the brain and failed to shed light on efficient mechanisms for the exogenous control of the brain. Amid the current efforts for developing personalized medicine, we introduce a framework for producing tailored stimulation signals, based on individual neuroimaging data and innovative modeling. This is the first time, to our knowledge, that brain stimulation for the most common cause of dementia, Alzheimer’s disease, is theoretically addressed. Our approach leads to the identification of potential target regions and subjects to successfully respond to brain stimulation therapies and yields various disease-reverting signals. Although focused on Alzheimer’s in this study, our methodology could be applied to other clinical conditions characterized by abnormalities in brain dynamics, like epilepsy and Parkinson’s, the treatment of which can benefit from the use of optimal control strategies.

Phase-amplitude coupling (PAC), the phenomenon where the amplitude of a high frequency oscillation is modulated by the phase of a lower frequency oscillation, is attracting an increasing interest in the neuroscience community due to its potential relevance for understanding healthy and pathological information processing in the brain. PAC is a diverse phenomenon, having been experimentally detected in at least ten combinations of rhythms: delta-theta, delta-alpha, delta-beta, delta-gamma, theta-alpha, theta-beta, theta-gamma, alpha-beta, alpha-gamma, and beta-gamma. However, a complete understanding of the biophysical mechanisms generating this diversity is lacking. Here we review computational models of PAC generation that range from detailed models of neuronal networks, where each cell is described by Hodgkin-Huxley-type equations, to neural mass models (NMMs) where only the average activities of neuronal populations are considered. We argue that NMMs are an appropriate mathematical framework (due to the small number of parameters and variables involved and the richness of the dynamics they can generate) to study the PAC phenomenon.

The identification of community structure in graphs continues to attract great interest in several fields. Network neuroscience is particularly concerned with this problem considering the key roles communities play in brain processes and functionality. Most methods used for community detection in brain graphs are based on the maximization of a parameter-dependent modularity function that often obscures the physical meaning and hierarchical organization of the partitions of network nodes. In this work, we present a new method able to detect communities at different scales in a natural, unrestricted way. First, to obtain an estimation of the information flow in the network we release random walkers to freely move over it. The activity of the walkers is separated into oscillatory modes by using empirical mode decomposition. After grouping nodes by their co-occurrence at each time scale, k-modes clustering returns the desired partitions. Our algorithm was first tested on benchmark graphs with favorable performance. Next, it was applied to real and simulated anatomical and/or functional connectomes in the macaque and human brains. We found a clear hierarchical repertoire of community structures in both the anatomical and the functional networks. The observed partitions range from the evident division in two hemispheres -in which all processes are managed globally- to specialized communities seemingly shaped by physical proximity and shared function. Additionally, the spatial scales of a network's community structure (characterized by a measure we term within-communities path length) appear inversely proportional to the oscillatory modes' average frequencies. The proportionality constant may constitute a network-specific propagation velocity for the information flow. Our results stimulate the research of hierarchical community organization in terms of temporal scales of information flow in the brain network.

Modulation of the amplitude of high-frequency cortical field activity locked to changes in the phase of a slower brain rhythm is known as phase-amplitude coupling (PAC). The study of this phenomenon has been gaining traction in neuroscience because of several reports on its appearance in normal and pathological brain processes in humans as well as across different mammalian species. This has led to the suggestion that PAC may be an intrinsic brain process that facilitates brain inter-area communication across different spatiotemporal scales. Several methods have been proposed to measure the PAC process, but few of these enable detailed study of its time course. It appears that no studies have reported details of PAC dynamics including its possible directional delay characteristic. Here, we study and characterize the use of a novel information theoretic measure that may address this limitation: local transfer entropy. We use both simulated and actual intracranial electroencephalographic data. In both cases, we observe initial indications that local transfer entropy can be used to detect the onset and offset of modulation process periods revealed by mutual information estimated phase-amplitude coupling (MIPAC). We review our results in the context of current theories about PAC in brain electrical activity, and discuss technical issues that must be addressed to see local transfer entropy more widely applied to PAC analysis. The current work sets the foundations for further use of local transfer entropy for estimating PAC process dynamics, and extends and complements our previous work on using local mutual information to compute PAC (MIPAC).