Brain Architecture Research Articles

Exploratory correlation of the human structural connectome with non-MRI variables in Alzheimer's disease.

Discovery of the associations between brain structural connectivity and clinical and demographic variables can help to better understand the vulnerability and resilience of the brain architecture to neurodegenerative diseases and to discover biomarkers. We used four diffusion-MRI databases, three related to Alzheimer's disease (AD), to exploratorily correlate structural connections between 85 brain regions with non-MRI variables, while stringently correcting the significance values for multiple testing and ruling out spurious correlations via careful visual inspection. We repeated the analysis with brain connectivity augmented with multi-synaptic neural pathways. We found 85 and 101 significant relationships with direct and augmented connectivity, respectively, which were generally stronger for the latter. Age was consistently linked to decreased connectivity, and healthier clinical scores were generally linked to increased connectivity. Our findings help to elucidate which structural brain networks are affected in AD and aging and highlight the importance of including indirect connections.

Altered intrinsic functional brain architecture in patients with functional constipation: a surface-based network study.

Functional constipation (FCon) is a common functional gastrointestinal disorder (FGID). Studies have indicated a higher likelihood of psychiatric disorders, such as anxiety, depression, sleep disturbances, and impaired concentration, among patients with FCon. However, the underlying pathophysiological mechanisms responsible for these symptoms in FCon patients remain to be fully elucidated. The human brain is a complex network architecture with several fundamental organizational properties. Neurological interactions between gut symptoms and psychiatric issues may be closely associated with these complex networks. In the present study, a total of 35 patients with FCon and 40 healthy controls (HC) were recruited for a series of clinical examinations and resting-state functional magnetic imaging (RS-fMRI). We employed the surface-based analysis (SBA) approach, utilizing the Schaefer cortical parcellation template and Tikhonov regularization. Graph theoretical analysis (GTA) and functional connectivity (FC) analysis of RS-fMRI were conducted to investigate the aberrant network alterations between the two groups. Additionally, correlation analyses were performed between the network indices and clinical variables in patients with FCon. At the global level, we found altered topological properties and networks in patients with FCon, mainly including the significantly increased clustering coefficient (CP), local efficiency (Eloc), and shortest path length (LP), whereas the decreased global efficiency (Eglob) compared to HC. At the regional level, patients with FCon exhibited increased nodal efficiency in the frontoparietal network (FPN). Furthermore, FC analysis demonstrated several functional alterations within and between the Yeo 7 networks, particularly including visual network (VN), limbic network (LN), default mode network (DMN), and somatosensory-motor network (SMN) in sub-network and large-scale network analysis. Correlation analysis revealed that there were no significant associations between the network metrics and clinical variables in the present study. These results highlight the altered topological architecture of functional brain networks associated with visual perception abilities, emotion regulation, sensorimotor processing, and attentional control, which may contribute to effectively targeted treatment modalities for patients with FCon.

Associations of BDNF/BDNF-AS SNPs with Depression, Schizophrenia, and Bipolar Disorder.

Brain-Derived Neurotrophic Factor (BDNF) is crucial for various aspects of neuronal development and function, including synaptic plasticity, neurotransmitter release, and supporting neuronal differentiation, growth, and survival. It is involved in the formation and preservation of dopaminergic, serotonergic, GABAergic, and cholinergic neurons, facilitating efficient stimulus transmission within the synaptic system and contributing to learning, memory, and overall cognition. Furthermore, BDNF demonstrates involvement in neuroinflammation and showcases neuroprotective effects. In contrast, BDNF antisense RNA (BDNF-AS) is linked to the regulation and control of BDNF, facilitating its suppression and contributing to neurotoxicity, apoptosis, and decreased cell viability. This review article aims to comprehensively overview the significance of single nucleotide polymorphisms (SNPs) in BDNF/BDNF-AS genes within psychiatric conditions, with a specific focus on their associations with depression, schizophrenia, and bipolar disorder. The independent influence of each BDNF/BDNF-AS gene variation, as well as the interplay between SNPs and their linkage disequilibrium, environmental factors, including early-life experiences, and interactions with other genes, lead to alterations in brain architecture and function, shaping vulnerability to mental health disorders. The potential translational applications of BDNF/BDNF-AS polymorphism knowledge can revolutionize personalized medicine, predict disease susceptibility, treatment outcomes, and guide the selection of interventions tailored to individual patients.

A lamprey neural cell type atlas illuminates the origins of the vertebrate brain

The vertebrate brain emerged more than ~500 million years ago in common evolutionary ancestors. To systematically trace its cellular and molecular origins, we established a spatially resolved cell type atlas of the entire brain of the sea lamprey—a jawless species whose phylogenetic position affords the reconstruction of ancestral vertebrate traits—based on extensive single-cell RNA-seq and in situ sequencing data. Comparisons of this atlas to neural data from the mouse and other jawed vertebrates unveiled various shared features that enabled the reconstruction of cell types, tissue structures and gene expression programs of the ancestral vertebrate brain. However, our analyses also revealed key tissues and cell types that arose later in evolution. For example, the ancestral brain was probably devoid of cerebellar cell types and oligodendrocytes (myelinating cells); our data suggest that the latter emerged from astrocyte-like evolutionary precursors in the jawed vertebrate lineage. Altogether, our work illuminates the cellular and molecular architecture of the ancestral vertebrate brain and provides a foundation for exploring its diversification during evolution.

Neuroprotective evaluation of Marsilea quadrifolia L. and Salvinia molesta D.S Mitchel in aluminium chloride induced Alzheimer disease

Phenolic compounds are very effective for the cure of various neurological and pathological diseases. Current study was conducted to estimate the Phenolic compounds through HPLC and to perform the anti-Alzheimer activity from two aquatic Leptosporangiate ferns; Marsilea quadrifolia L. and Salvinia molesta D. Crushed leaves were subjected to Microwave Assisted Extraction to prepare plant leave ethanolic extract of plants under study. Aluminum chloride induced Alzheimer’s disease model in rats by estimating behavioural and biochemical parameters were measured for ethanolic extract of both plants. Different behavioural tests were performed for neuromuscular coordination estimation and hole board test for exploratory behaviour were performed. The levels of AChE inhibitory activity and antioxidant enzymes were estimated on brain homogenates and Histopathological analysis were also performed. Phenolic compounds of leaf extracts were noted for HPLC chromatograms of standard compounds with Gallic acid (33.76 ± 0.08) higher in M. quadrifolia L. and Salicylic acid (12.45 ± 0.07) higher in S. molesta D. S Mitchel. Histopathological analysis showed that M. quadrifolia and S. molesta reversed the neurofibrillary tangles, degenerative changes, neuronal loss and neuroinflammation in the brain architecture. Both ferns at a dose of 500 mg/kg and 1000mg/kg significantly improved the Aluminium chloride induced neurotoxicity by modulating cognitive disabilities and motor dysfunctions, and normalized the biochemical alteration of acetylcholinesterase and antioxidant enzymes. In conclusion, both plants M. quadrifolia and S. molesta improved behavioural and biochemical parameters and therefore will be effective in treatment of neurodegenerative disorders via countless underlying mechanistic pathways.

Intrinsic neural network dynamics underlying the ability to down-regulate emotions in male perpetrators of intimate partner violence against women

Research has pointed to difficulties in emotion regulation as a risk factor for perpetrating intimate partner violence against women (IPVAW). While efforts have been made to understand the brain mechanisms underlying emotion regulation strategies such as reappraisal, little is known about the intrinsic neural dynamics supporting this strategy in male perpetrators. Resting-state functional magnetic resonance imaging was used to characterise the network dynamics underlying reappraisal. Spectral dynamic causal modelling was performed to examine the effective connectivity (EC) within a predefined reappraisal-related brain network. 26 men convicted for an IPVAW crime [male perpetrators] were compared to 29 men convicted of other crimes [other offenders] and 29 men with no criminal records [non-offenders]. The ability to down-regulate emotions in response to IPVAW stimuli was used as a covariate to explore its association with male perpetrators' EC. The analysis revealed that (1) compared to non-offenders, both convicted groups exhibited increased EC within prefrontal areas, enhanced EC from prefrontal to temporoparietal regions and decreased EC in the opposite direction; (2) male perpetrators compared to other offenders showed increased EC from temporoparietal to prefrontal regions and, increased EC from the supplementary motor area to frontal areas; (3) connections involving dorsolateral prefrontal cortex were found to be potential predictors of the ability to down-regulate emotions. The study provides a deeper characterisation of the brain architecture of the processes that underlie IPVAW. This knowledge could inform the work of adaptive emotion regulation strategies in intervention programmes for male perpetrators in order to reduce the high recidivism rates.

A Study to Evaluate the Neuroprotective property of Aqueous Extract of Mentha piperita Leaves on Haloperidol Induced Parkinsonism in Experimental rats

The main objective of the proposed study was designed to investigate the neuroprotective property of aqueous extract of the Mentha piperita leaves (AEMPL) against haloperidol induced Parkinsonism in experimental animals. Rats were divided into 5 groups (n=6 animals). Group 1 received vehicle control, Group 2 received Haloperidol (1mg/kg, i.p.), Group 3receivedstandard drug Sinemet (125mg/kg p.o.), Group4andGroup5treated with lower (100mg/kg, p.o.) and higher (250mg/kg, p.o.) doses of AEMPL respectively for 14 days. Later motor co-ordination (rota-rod), locomotor activity (actophotometer) and catalepsy bar test was performed and also brain histopathological examination was also done. Both the lower and higher doses of aqueous extract of Mentha piperita leaves showed dose dependent, extremely significant increases in locomotor activity by increasing number of cuts, decreases fall off time and also decreases in latency period in metal bar test, histopathological examination shows reduction in neuronal loss and normal brain architecture was observed when compared haloperidol treated group. Hence Mentha piperita shows neuroprotective activity because of potential anti-oxidant property. The obtained result was comparable with that of the standard drug levodopa+carbidopa (Sinemet). The outcome of the present study provides the evidence that the aqueous extract of Mentha piperita leaves reported that it has dose dependent beneficial neuroprotective effect against haloperidol induced Parkinson’s disease in experimental rats.

Ex-utero third trimester developmental changes in functional brain network organization in infants born very and extremely preterm.

The latter half of gestation is a period of rapid brain development, including the formation of fundamental functional brain network architecture. Unlike in-utero fetuses, infants born very and extremely preterm undergo these critical maturational changes in the extrauterine environment, with growing evidence suggesting this may result in altered brain networks. To date, however, the development of functional brain architecture has been unexplored. From a prospective cohort of preterm infants, graph parameters were calculated for fMRI scans acquired prior to reaching term equivalent age. Eight graph properties were calculated, Clustering Coefficient (C), Characteristic Path Length (L), Modularity (Q), Local Efficiency (LE), Global Efficiency (GE), Normalized Clustering (λ), Normalized Path Length (γ), and Small-Worldness (σ). Properties were first compared to values generated from random and lattice networks and cost efficiency was evaluated. Subsequently, linear mixed effect models were used to assess relationship with postmenstrual age and infant sex. A total of 111 fMRI scans were acquired from 85 preterm infants born at a mean GA 28.93 ± 2.8. Infants displayed robust small world properties as well as both locally and globally efficient networks. Regression models found that GE increased while L, Q, λ, γ, and σ decreased with increasing postmenstrual age following multiple comparison correction (r2Adj range 0.143-0.401, p < 0048), with C and LE exhibited trending increases with age. This is the first direct investigation on the extra-uterine formation of functional brain architecture in preterm infants. Importantly, our results suggest that changes in functional architecture with increasing age exhibit a different trajectory relative to in utero fetus. Instead, they exhibit developmental changes more similar to the early postnatal period in term born infants.

Abnormal static and dynamic functional network connectivity of the whole-brain in children with generalized tonic-clonic seizures.

Generalized tonic-clonic seizures (GTCS) are a subtype of generalized seizures exhibiting bursts of bilaterally synchronous generalized spike-wave discharges. Numerous neuroimaging studies have reported aberrant functional activity and topological organization of brain network in epilepsy patients with GTCS, but most studies have focused on adults. However, the effect of GTCS on the spatial and temporal properties of brain function in children remains unclear. The present study aimed to explore whole-brain static (sFC) and dynamic functional connectivity (dFC) in children with GTCS. Twenty-three children with GTCS and 32 matched healthy controls (HCs) were recruited for the present study. Resting-state functional magnetic resonance imaging (MRI) data were collected for each subject. The group independent component analysis method was used to obtain independent components (ICs). Then, sFC and dFC methods were applied and the differences in functional connectivity (FC) were compared between the children with GTCS and the HCs. Additionally, we investigated the correlations between the dFC indicators and epilepsy duration. Compared to HCs, GTCS patients exhibited a significant decrease in sFC strengths among most networks. The K-means clustering method was implemented for dFC analysis, and the optimal number of clusters was estimated: two discrete connectivity configurations, State 1 (strong connection) and State 2 (weak connection). The decreased dFC mainly occurred in State 1, especially the dFC between the visual network (VIS) and somatomotor network (SMN); but the increased dFC mainly occurred in State 2 among most networks in GTCS children. In addition, GTCS children showed significantly shorter mean dwell time and lower fractional windows in stronger connected State 1, while GTCS children showed significantly longer mean dwell time in weaker connected State 2. In addition, the dFC properties, including mean dwell time and fractional windows, were significantly correlated with epilepsy duration. Our results indicated that GTCS epilepsy not only alters the connectivity strength but also changes the temporal properties of connectivity in networks in the whole brain. These findings also emphasized the differences in sFC and dFC in children with GTCS. Combining sFC and dFC methods may provide more comprehensive understanding of the abnormal changes in brain architecture in children with GTCS.

Effect of memristor’s potentiation-depression curves peculiarities in the convergence of physical perceptrons

Neuromorphic computing aims to emulate the architecture and information processing mechanisms of the mammalian brain. This includes the implementation by hardware of neural networks. Oxide-based memristor arrays with cross-bar architecture appear as a possible physical implementation of neural networks. In this paper, we obtain experimental potentiation-depression (P-D) curves on different manganite-based memristive systems and simulate the learning process of perceptrons for character recognition. We analyze how the specific characteristics of the P-D curves affect the convergence time -characterized by the EPOCHs-to-convergence (ETC) parameter- of the network. Our work shows that ETC is reduced for systems displaying P-D curves with relatively low granularity and non-linear and asymmetric response. In addition, we also show that noise injection during the synaptic weight actualization further reduces the ETC. The results obtained here are expected to contribute to the optimization of hardware neural networks based on memristors cross-bar arrays.

Pushing the boundaries of brain organoids to study Alzheimer's disease.

Progression of Alzheimer's disease (AD) entails deterioration or aberrant function of multiple brain cell types, eventually leading to neurodegeneration and cognitive decline. Defining how complex cell-cell interactions become dysregulated in AD requires novel human cell-based in vitro platforms that could recapitulate the intricate cytoarchitecture and cell diversity of the human brain. Brain organoids (BOs) are 3D self-organizing tissues that partially resemble the human brain architecture and can recapitulate AD-relevant pathology. In this review, we highlight the versatile applications of different types of BOs to model AD pathogenesis, including amyloid-β and tau aggregation, neuroinflammation, myelin breakdown, vascular dysfunction, and other phenotypes, as well as to accelerate therapeutic development for AD.

Individual-level brain morphological similarity networks: Current methodologies and applications.

The human brain is an extremely complex system in which neurons, clusters of neurons, or regions are connected to form a complex network. With the development of neuroimaging techniques, magnetic resonance imaging (MRI)-based brain networks play a key role in our understanding of the intricate architecture of human brain. Among them, the structural MRI-based brain morphological network approach has attracted increasing attention due to the advantages in data acquisition, image quality, and in revealing the structural organizing principles intrinsic to the brain. This review is to summarize the methodology and related applications of individual-level morphological networks. There have been a growing number of studies related to brain morphological similarity networks. Conventional morphological networks are intersubject covariance networks constructed using a certain morphological indicator of a group of subjects; individual-level morphological networks, on the other hand, measure the morphological similarity between brain regions for individual brains and can reflect the morphological information of single subjects. In recent years, individual morphological networks have demonstrated significant worth in exploring the topological changes of the human brain under both normal and disease conditions. Such studies provided novel perspectives for understanding human brain development and exploring the pathological mechanisms of neuropsychiatric disorders. This paper mainly focuses on the studies of brain morphological networks at the individual level, introduces several ways for network construction, reviews representative work in this field, and finally points out current problems and future directions.

3D Functional Neuronal Networks in Free-Standing Bioprinted Hydrogel Constructs.

The composition, elasticity, and organization of the extracellular matrix within the central nervous system contribute to the architecture and function of the brain. From an in vitro modeling perspective, soft biomaterials are needed to mimic the 3D neural microenvironments. While many studies have investigated 3D culture and neural network formation in bulk hydrogel systems, these approaches have limited ability to position cells to mimic sophisticated brain architectures. In this study, cortical neurons and astrocytes acutely isolated from the brains of rats are bioprinted in a hydrogel to form 3D neuronal constructs. Successful bioprinting of cellular and acellular strands in a multi-bioink approach allows the subsequent formation of gray- and white-matter tracts reminiscent of cortical structures. Immunohistochemistry shows the formation of dense, 3D axon networks. Calcium signaling and extracellular electrophysiology in these 3D neuronal networks confirm spontaneous activity in addition to evoked activities under pharmacological and electrical stimulation. The system and bioprinting approaches are capable of fabricating soft, free-standing neuronal structures of different bioink and cell types with high resolution and throughput, which provide a promising platform for understanding fundamental questions of neural networks, engineering neuromorphic circuits, and for in vitro drug screening.

The neurobiology of insulin-like growth factor I: From neuroprotection to modulation of brain states.

After decades of research in the neurobiology of IGF-I, its role as a prototypical neurotrophic factor is undisputed. However, many of its actions in the adult brain indicate that this growth factor is not only involved in brain development or in the response to injury. Following a three-layer assessment of its role in the central nervous system, we consider that at the cellular level, IGF-I is indeed a bona fide neurotrophic factor, modulating along ontogeny the generation and function of all the major types of brain cells, contributing to sculpt brain architecture and adaptive responses to damage. At the circuit level, IGF-I modulates neuronal excitability and synaptic plasticity at multiple sites, whereas at the system level, IGF-I intervenes in energy allocation, proteostasis, circadian cycles, mood, and cognition. Local and peripheral sources of brain IGF-I input contribute to a spatially restricted, compartmentalized, and timed modulation of brain activity. To better define these variety of actions, we consider IGF-I a modulator of brain states. This definition aims to reconcile all aspects of IGF-I neurobiology, and may provide a new conceptual framework in the design of future research on the actions of this multitasking neuromodulator in the brain.

Associations between infant amygdala functional connectivity and social engagement following a stressor: A preliminary investigation.

Functional architecture of the infant brain, especially functional connectivity (FC) within the amygdala network and between the amygdala and other networks (i.e., default-mode [DMN] and salience [SAL] networks), provides a neural basis for infant socioemotional functioning. Yet, little is known about the extent to which early within- and between-network amygdala FC are related to infant stress recovery across the first year of life. In this study, we examined associations between amygdala FC (i.e., within-network amygdala connectivity, and between-network amygdala connectivity with the DMN and SAL) at 3 months and infant recovery from a mild social stressor at 3, 6 and 9 months. At 3 months, thirty-five infants (13 girls) underwent resting-state functional magnetic resonance imaging during natural sleep. Infants and their mothers completed the still-face paradigm at 3, 6, and 9 months, and infant stress recovery was assessed at each time point as the proportion of infant social engagement during the reunion episode. Bivariate correlations indicated that greater positive within-network amygdala FC and greater positive amygdala-SAL FC, but not amygdala-DMN FC, at 3 months predicted lower levels of stress recovery at 3 and 6 months, but were nonsignificant at 9 months. These findings provide preliminary evidence that early functional synchronization within the amygdala network, as well as segregation between the amygdala and the SAL, may contribute to infant stress recovery in the context of infant-mother interaction.

Imaging the Human Brain on Oral Contraceptives

Oral contraceptives (OCs) are the most popular form of birth control in the United States and in European countries. However, little is known about the extent OCs affect the brain’s function and morphology, although it is known that endogenous sex hormones shape the brain across the life span. Here, we reviewed studies that investigated structural gray and white matter in women using OCs in comparison to naturally cycling women. We focused on neuroimaging methods used to quantify structural gray and white matter changes: structural (sMRI) and diffusion MRI (dMRI). Relatively few imaging studies have been performed to answer the question of the effect of OCs on brain architecture. Studies have reported morphometric abnormalities in whole brain, cortical, and subcortical gray and white matter with no consistent pattern. Rather, findings in gray and white matter seem to be dependent on whether women using OCs and naturally cycling women were split into groups (active/inactive intake phase vs. follicular/luteal phase). There is a lack of sMRI and dMRI studies in this field of research. However, current studies demonstrate that it is important to compare women according to the follicular and luteal phase, as well as the active and inactive intake phase of OCs. Future studies with standardized protocols and larger sample sizes will allow an in-depth characterization of the effect of OCs on the brain. Furthermore, longitudinal studies comparing naturally cycling women to women using OCs over time and at different life stages are of particular importance.

White matter changes in fetal brains with ventriculomegaly.

Ventriculomegaly (VM) is a fetal brain malformation which may present independently (isolated form) or in association with different cerebral malformations, genetic syndromes or other pathologies (non-isolated form). This paper aims to study the effect of ventriculomegaly on the internal tridimensional architecture of fetal brains by way of Klingler's dissection. Ventriculomegaly was diagnosed using fetal ultrasonography during pregnancy and subsequently confirmed by necropsy. Taking into consideration the diameter of the lateral ventricle (measured at the level of the atrium), the brains were divided into two groups: moderate ventriculomegaly (with atrial diameter between 13 and 15 mm) and severe ventriculomegaly (with atrial diameter above 15 mm). The results of each dissection were described and illustrated, then compared with age-matched reference brains. In the pathological brains, fascicles in direct contact with the enlarged ventricles were found to be thinner and displaced inferiorly, the opening of the uncinate fasciculus was wider, the fornix was no longer in contact with the corpus callosum and the convexity of the corpus callosum was inverted. We have studied the prevalence of neurodevelopmental delay in children born with ventriculomegaly in the literature and discovered that a normal developmental outcome was found in over 90% of the mild VM cases, approximately 75% of the moderate and 60% in severe VM, with the correlated neurological impairments ranging from attention deficits to psychiatric disorders.

Deep ultraviolet fluorescence microscopy of three-dimensional structures in the mouse brain

Three-dimensional (3D) imaging at cellular resolution improves our understanding of the brain architecture and is crucial for structural and functional integration as well as for the understanding of normal and pathological conditions in the brain. We developed a wide-field fluorescent microscope for 3D imaging of the brain structures using deep ultraviolet (DUV) light. This microscope allowed fluorescence imaging with optical sectioning due to the large absorption at the surface of the tissue and hence low tissue penetration of DUV light. Multiple channels of fluorophore signals were detected using single or a combination of dyes emitting fluorescence in the visible range of spectrum upon DUV excitation. Combination of this DUV microscope with microcontroller-based motorized stage enabled wide-field imaging of a coronal section of the cerebral hemisphere in mouse for deciphering cytoarchitecture of each substructure in detail. We extended this by integrating vibrating microtome which allowed serial block-face imaging of the brain structure such as the habenula in mouse. Acquired images were with resolution high enough for quantification of the cell numbers and density in the mouse habenula. Upon block-face imaging of the tissues covering entire extent of the cerebral hemisphere of the mouse brain, acquired data were registered and segmented for quantification of cell number in each brain regions. Results in the current analysis indicated that this novel microscope could be a convenient tool for large-scale 3D analysis of the brain in mice.

Spatiotemporal dynamics of functional connectivity and association with molecular architecture in schizophrenia.

Schizophrenia is a self-disorder characterized by disrupted brain dynamics and architectures of multiple molecules. This study aims to explore spatiotemporal dynamics and its association with psychiatric symptoms. Resting-state functional magnetic resonance imaging data were collected from 98 patients with schizophrenia. Brain dynamics included the temporal and spatial variations in functional connectivity density and association with symptom scores were evaluated. Moreover, the spatial association between dynamics and receptors/transporters according to prior molecular imaging in healthy subjects was examined. Patients demonstrated decreased temporal variation and increased spatial variation in perceptual and attentional systems. However, increased temporal variation and decreased spatial variation were revealed in higher order networks and subcortical networks in patients. Specifically, spatial variation in perceptual and attentional systems was associated with symptom severity. Moreover, case-control differences were associated with dopamine, serotonin and mu-opioid receptor densities, serotonin reuptake transporter density, dopamine transporter density, and dopamine synthesis capacity. Therefore, this study implicates the abnormal dynamic interactions between the perceptual system and cortical core networks; in addition, the subcortical regions play a role in the dynamic interaction among the cortical regions in schizophrenia. These convergent findings support the importance of brain dynamics and emphasize the contribution of primary information processing to the pathological mechanism underlying schizophrenia.

On temporal scale-free non-periodic stimulation and its mechanisms as an infinite improbability drive of the brain's functional connectogram.

Rationalized development of electrical stimulation (ES) therapy is of paramount importance. Not only it will foster new techniques and technologies with increased levels of safety, efficacy, and efficiency, but it will also facilitate the translation from basic research to clinical practice. For such endeavor, design of new technologies must dialogue with state-of-the-art neuroscientific knowledge. By its turn, neuroscience is transitioning-a movement started a couple of decades earlier-into adopting a new conceptual framework for brain architecture, in which time and thus temporal patterns plays a central role in the neuronal representation of sampled data from the world. This article discusses how neuroscience has evolved to understand the importance of brain rhythms in the overall functional architecture of the nervous system and, consequently, that neuromodulation research should embrace this new conceptual framework. Based on such support, we revisit the literature on standard (fixed-frequency pulsatile stimuli) and mostly non-standard patterns of ES to put forward our own rationale on how temporally complex stimulation schemes may impact neuromodulation strategies. We then proceed to present a low frequency, on average (thus low energy), scale-free temporally randomized ES pattern for the treatment of experimental epilepsy, devised by our group and termed NPS (Non-periodic Stimulation). The approach has been shown to have robust anticonvulsant effects in different animal models of acute and chronic seizures (displaying dysfunctional hyperexcitable tissue), while also preserving neural function. In our understanding, accumulated mechanistic evidence suggests such a beneficial mechanism of action may be due to the natural-like characteristic of a scale-free temporal pattern that may robustly compete with aberrant epileptiform activity for the recruitment of neural circuits. Delivering temporally patterned or random stimuli within specific phases of the underlying oscillations (i.e., those involved in the communication within and across brain regions) could both potentiate and disrupt the formation of neuronal assemblies with random probability. The usage of infinite improbability drive here is obviously a reference to the "The Hitchhiker's Guide to the Galaxy" comedy science fiction classic, written by Douglas Adams. The parallel is that dynamically driving brain functional connectogram, through neuromodulation, in a manner that would not favor any specific neuronal assembly and/or circuit, could re-stabilize a system that is transitioning to fall under the control of a single attractor. We conclude by discussing future avenues of investigation and their potentially disruptive impact on neurotechnology, with a particular interest in NPS implications in neural plasticity, motor rehabilitation, and its potential for clinical translation.