Quantitative Biology

The diversity of cognitive deficits and neuropathological processes associated with dementias has encouraged divergence in pathophysiological explanations of disease. Here, we review an alternative framework that emphasises convergent critical features of pathophysiology, rather than the loss of memory centres or language centres, or singular neurotransmitter systems. Cognitive deficits are interpreted in the light of advances in normative accounts of brain function, based on predictive coding in hierarchical neural networks. The predicting coding rests on Bayesian integration of beliefs and sensory evidence, with hierarchical predictions and prediction errors, for memory, perception, speech and behaviour. We describe how analogous impairments in predictive coding in parallel neurocognitive systems can generate diverse clinical phenomena, in neurodegenerative dementias. The review presents evidence from behavioural and neurophysiological studies of perception, language, memory and decision-making. The re-formulation of cognitive deficits in dementia in terms of predictive coding has several advantages. It brings diverse clinical phenomena into a common framework, such as linking cognitive and movement disorders; and it makes specific predictions on cognitive physiology that support translational and experimental medicine studies. The insights into complex human cognitive disorders from the predictive coding model may therefore also inform future therapeutic strategies.

An implanted device for brain-responsive neurostimulation (RNS System) is approved as an effective treatment to reduce seizures in adults with medically-refractory focal epilepsy. Clinical trials of the RNS System demonstrate population-level reduction in average seizure frequency, but therapeutic response is highly variable. Recent evidence links seizures to cyclical fluctuations in underlying risk. We tested the hypothesis that effectiveness of responsive neurostimulation varies based on current state within cyclical risk fluctuations. We analyzed retrospective data from 25 adults with medically-refractory focal epilepsy implanted with the RNS System. Chronic electrocorticography was used to record electrographic seizures, and hidden Markov models decoded seizures into fluctuations in underlying risk. State-dependent associations of RNS System stimulation parameters with changes in risk were estimated. Higher charge density was associated with improved outcomes, both for remaining in a low seizure risk state and for transitioning from a high to a low seizure risk state. The effect of stimulation frequency depended on initial seizure risk state: when starting in a low risk state, higher stimulation frequencies were associated with remaining in a low risk state, but when starting in a high risk state, lower stimulation frequencies were associated with transition to a low risk state. Findings were consistent across bipolar and monopolar stimulation configurations. The impact of RNS on seizure frequency exhibits state-dependence, such that stimulation parameters which are effective in one seizure risk state may not be effective in another. These findings represent conceptual advances in understanding the therapeutic mechanism of RNS, and directly inform current practices of RNS tuning and the development of next-generation neurostimulation systems.

Continuous adaptation allows survival in an ever-changing world. Adjustments in the synaptic coupling strength between neurons are essential for this capability, setting us apart from simpler, hard-wired organisms. How these changes can be mathematically described at the phenomenological level, as so called "plasticity rules", is essential both for understanding biological information processing and for developing cognitively performant artificial systems. We suggest an automated approach for discovering biophysically plausible plasticity rules based on the definition of task families, associated performance measures and biophysical constraints. By evolving compact symbolic expressions we ensure the discovered plasticity rules are amenable to intuitive understanding, fundamental for successful communication and human-guided generalization. We successfully apply our approach to typical learning scenarios and discover previously unknown mechanisms for learning efficiently from rewards, recover efficient gradient-descent methods for learning from target signals, and uncover various functionally equivalent STDP-like rules with tuned homeostatic mechanisms.

Electrical synapses play a major role in setting up neuronal synchronization, but the precise mechanisms whereby these synapses contribute to synchrony are subtle and remain elusive. To investigate these mechanisms mean-field theories for quadratic integrate-and-fire neurons with electrical synapses have been recently put forward. Still, the validity of these theories is controversial since they assume that the neurons produce unrealistic, symmetric spikes, ignoring the well-known impact of spike shape on synchronization. Here we show that the assumption of symmetric spikes can be relaxed in such theories. The resulting mean-field equations reveal a dual role of electrical synapses: First, they equalize membrane potentials favoring the emergence of synchrony. Second, electrical synapses act as "virtual chemical synapses", which can be either excitatory or inhibitory depending upon the spike shape. Our results offer a precise mathematical explanation of the intricate effect of electrical synapses in collective synchronization. This reconciles previous theoretical and numerical works, and confirms the suitability of recent low-dimensional mean-field theories to investigate electrically coupled neuronal networks.

Phenomics is concerned with detailed description of all aspects of organisms, from their physical foundations at genetic, molecular and cellular level, to behavioural and psychological traits. Neuropsychiatric phenomics, endorsed by NIMH, provides such broad perspective to understand mental disorders. It is clear that learning sciences also need similar approach that will integrate efforts to understand cognitive processes from the perspective of the brain development, in temporal, spatial, psychological and social aspects. The brain is a substrate shaped by genetic, epigenetic, cellular and environmental factors including education, individual experiences and personal history, culture, social milieu. Learning sciences should thus be based on the foundation of neurocognitive phenomics. A brief review of selected aspects of such approach is presented, outlining new research directions. Central, peripheral and motor processes in the brain are linked to the inventory of the learning styles.

In his 1952 paper "The chemical basis of morphogenesis", Alan M. Turing presented a model for the formation of skin patterns. While it took several decades, the model has been validated by finding corresponding natural phenomena, e.g. in the skin pattern formation of zebrafish. More surprising, seemingly unrelated pattern formations can also be studied via the model, like e.g. the formation of plant patches around termite hills. In 1984, David A. Young proposed a discretization of Turing's model, reducing it to an activator/inhibitor process on a discrete domain. From this model, the concept of three-dimensional Turing-like patterns was derived. In this paper, we consider this generalization to pattern-formation in three-dimensional space. We are particularly interested in classifying the different arising sub-structures of the patterns. By providing examples for the different structures, we prove a conjecture regarding these structures within the setup of three-dimensional Turing-like pattern. Furthermore, we investigate - guided by visual experiments - how these sub-structures are distributed in the parameter space of the discrete model. We found two-fold versions of zero- and one-dimensional sub-structures as well as two-dimensional sub-structures and use our experimental findings to formulate several conjectures for three-dimensional Turing-like patterns and higher-dimensional cases.

Acquisition of bimanual motor skills, critical in several applications ranging from robotic teleoperations to surgery, is associated with a protracted learning curve. Brain connectivity based on functional Near Infrared Spectroscopy (fNIRS) data has shown promising results in distinguishing experts from novice surgeons. However, it is less well understood how expertise-related disparity in brain connectivity is modulated by dynamic temporal demands experienced during a surgical task. In this study, we use fNIRS to examine the interplay between frontal and motor brain regions in a cohort of surgical residents of varying expertise performing a laparoscopic surgical task under temporal demand. The results demonstrate that prefrontal-motor connectivity in senior residents is more resilient to time pressure. Furthermore, certain global characteristics of brain connectomes, such as the small-world index, may be used to detect the presence of an underlying stressor.

Diagnosing Autism Spectrum Disorder (ASD) is a challenging problem, and is based purely on behavioral descriptions of symptomology (DSM-5/ICD-10), and requires informants to observe children with disorder across different settings (e.g. home, school). Numerous limitations (e.g., informant discrepancies, lack of adherence to assessment guidelines, informant biases) to current diagnostic practices have the potential to result in over-, under-, or misdiagnosis of the disorder. Advances in neuroimaging technologies are providing a critical step towards a more objective assessment of the disorder. Prior research provides strong evidence that structural and functional magnetic resonance imaging (MRI) data collected from individuals with ASD exhibit distinguishing characteristics that differ in local and global spatial, and temporal neural-patterns of the brain. Our proposed deep-learning model ASD-DiagNet exhibits consistently high accuracy for classification of ASD brain scans from neurotypical scans. We have for the first time integrated traditional machine-learning and deep-learning techniques that allows us to isolate ASD biomarkers from MRI data sets. Our method, called Auto-ASD-Network, uses a combination of deep-learning and Support Vector Machines (SVM) to classify ASD scans from neurotypical scans. Such interpretable models would help explain the decisions made by deep-learning techniques leading to knowledge discovery for neuroscientists, and transparent analysis for clinicians.

A freely walking fly visits roughly 100 stereotyped states in a strongly non-Markovian sequence. To explore these dynamics, we develop a generalization of the information bottleneck method, compressing the large number of behavioral states into a more compact description that maximally preserves the correlations between successive states. Surprisingly, preserving these short time correlations with a compression into just two states captures the long ranged correlations seen in the raw data. Having reduced the behavior to a binary sequence, we describe the distribution of these sequences by an Ising model with pairwise interactions, which is the maximum entropy model that matches the two-point correlations. Matching the correlation function at longer and longer times drives the resulting model toward the Ising model with inverse square interactions and near zero magnetic field. The emergence of this statistical physics problem from the analysis real data on animal behavior is unexpected.

Studying and understanding the computational primitives of our neural system requires for a diverse and complementary set of techniques. In this work, we use the Neuro-robotic Platform (NRP)to evaluate the vestibulo ocular cerebellar adaptatIon (Vestibulo-ocular reflex, VOR)mediated by two STDP mechanisms located at the cerebellar molecular layer and the vestibular nuclei respectively. This simulation study adopts an experimental setup (rotatory VOR)widely used by neuroscientists to better understand the contribution of certain specific cerebellar properties (i.e. distributed STDP, neural properties, coding cerebellar topology, etc.)to r-VOR adaptation. The work proposes and describes an embodiment solution for which we endow a simulated humanoid robot (iCub)with a spiking cerebellar model by means of the NRP, and we face the humanoid to an r-VOR task. The results validate the adaptive capabilities of the spiking cerebellar model (with STDP)in a perception-action closed-loop (r- VOR)causing the simulated iCub robot to mimic a human behavior.