Geometric constraints on human brain function.

The anatomy of the brain necessarily constrains its function, but precisely how remains unclear. The classical and dominant paradigm in neuroscience is that neuronal dynamics are driven by interactions between discrete, functionally specialized cell populations connected by a complex array of axonal fibres1-3. However, predictions from neural field theory, an established mathematical framework for modelling large-scale brain activity4-6, suggest that the geometry of the brain may represent a more fundamental constraint on dynamics than complex interregional connectivity7,8. Here, we confirm these theoretical predictions by analysing human magnetic resonance imaging data acquired under spontaneous and diverse task-evoked conditions. Specifically, we show that cortical and subcortical activity can be parsimoniously understood as resulting from excitations of fundamental, resonant modes of the brain's geometry (that is, its shape) rather than from modes of complex interregional connectivity, as classically assumed. We then use these geometric modes to show that task-evoked activations across over 10,000 brain maps are not confined to focal areas, as widely believed, but instead excite brain-wide modes with wavelengths spanning over 60 mm. Finally, we confirm predictions that the close link between geometry and function is explained by a dominant role for wave-like activity, showing that wave dynamics can reproduce numerous canonical spatiotemporal properties of spontaneous and evoked recordings. Our findings challenge prevailing views and identify a previously underappreciated role of geometry in shaping function, as predicted by a unifying and physically principled model of brain-wide dynamics.

Cortical depth-dependent modeling of visual hemodynamic responses.

A physiologically based three-dimensional (3D) hemodynamic model is developed to predict the experimentally observed blood oxygen level dependent (BOLD) responses versus the cortical depth induced by visual stimuli. Prior 2D approximations are relaxed in order to analyze 3D blood flow dynamics as a function of cortical depth. Comparison of the predictions with experimental data for evoked stimuli demonstrates that the full 3D model performs at least as well as previous approaches while remaining parsimonious. In particular, the 3D model requires significantly fewer assumptions and model parameters than previous models such that there is no longer need to define depth-specific parameter values for spatial spreading, peak amplitude, and hemodynamic velocity.

Brain dynamics and structure-function relationships via spectral factorization and the transfer function.

It is shown how the brain's linear transfer function provides a means to systematically analyze brain connectivity and dynamics, and to infer connectivity, eigenmodes, and activity measures such as spectra, evoked responses, coherence, and causality, all of which are widely used in brain monitoring. In particular, the Wilson spectral factorization algorithm is outlined and used to efficiently obtain linear transfer functions from experimental two-point correlation functions. The algorithm is tested on a series of brain-like structures of increasing complexity which include time delays, asymmetry, two-dimensionality, and complex network connectivity. These tests are used to verify the algorithm is suitable for application to brain dynamics, specify sampling requirements for experimental time series, and to verify that its runtime is short enough to obtain accurate results for systems of similar size to current experiments. The results can equally well be applied to inference of the transfer function in complex linear systems other than brains.

Feasibility of functional magnetic resonance imaging of ocular dominance and orientation preference in primary visual cortex.

A recent hemodynamic model is extended and applied to simulate and explore the feasibility of detecting ocular dominance (OD) and orientation preference (OP) columns in primary visual cortex by means of functional magnetic resonance imaging (fMRI). The stimulation entails a short oriented bar stimulus being presented to one eye and mapped to cortical neurons with corresponding OD and OP selectivity. Activated neurons project via patchy connectivity to excite other neurons with similar OP in nearby visual fields located preferentially along the direction of stimulus orientation. The resulting blood oxygen level dependent (BOLD) response is estimated numerically via the model's spatiotemporal hemodynamic response function. The results are then used to explore the feasibility of detecting spatial OD-OP modulation, either directly measuring BOLD or by using Wiener deconvolution to filter the image and estimate the underlying neural activity. The effect of noise is also considered and it is estimated that direct detection can be robust for fMRI resolution of around 0.5 mm, whereas detection with Wiener deconvolution is possible at a broader range from 0.125 mm to 1 mm resolution. The detection of OD-OP features is strongly dependent on hemodynamic parameters, such as low velocity and high damping reduce response spreads and result in less blurring. The short-bar stimulus that gives the most detectable response is found to occur when neural projections are at 45 relative to the edge of local OD boundaries, which provides a constraint on the OD-OP architecture even when it is not fully resolved.

Modeling melanopsin-mediated effects of light on circadian phase, melatonin suppression, and subjective sleepiness.

A physiologically based model of arousal dynamics is improved to incorporate the effects of the light spectrum on circadian phase resetting, melatonin suppression, and subjective sleepiness. To account for these nonvisual effects of light, melanopic irradiance replaces photopic illuminance that was used previously in the model. The dynamic circadian oscillator is revised according to the melanopic irradiance definition and tested against experimental circadian phase resetting dose-response and phase response data. Melatonin suppression function is recalibrated against melatonin dose-response data for monochromatic and polychromatic light sources. A new light-dependent term is introduced into the homeostatic weight component of subjective sleepiness to represent the direct alerting effect of light; the new term responds to light change in a time-dependent manner and is calibrated against experimental data. The model predictions are compared to a total of 14 experimental studies containing 26 data sets for 14 different spectral light profiles. The revised melanopic model shows on average 1.4 times lower prediction error for circadian phase resetting compared to the photopic-based model, 3.2 times lower error for melatonin suppression, and 2.1 times lower error for subjective sleepiness. Overall, incorporating melanopic irradiance allowed simulation of wavelength-dependent responses to light and could explain the majority of the observations. Moving forward, models of circadian phase resetting and the direct effects of light on alertness and sleep need to use nonvisual photoreception-based measures of light, for example, melanopic irradiance, instead of the traditionally used illuminance based on the visual system.

Quantitative theory of deep brain stimulation of the subthalamic nucleus for the suppression of pathological rhythms in Parkinson's disease.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is modeled to explore the mechanisms of this effective, but poorly understood, treatment for motor symptoms of drug-refractory Parkinson's disease and dystonia. First, a neural field model of the corticothalamic-basal ganglia (CTBG) system is developed that reproduces key clinical features of Parkinson's disease, including its characteristic 4-8 Hz and 13-30 Hz electrophysiological signatures. Deep brain stimulation of the STN is then modeled and shown to suppress the pathological 13-30 Hz (beta) activity for physiologically realistic and optimized stimulus parameters. This supports the idea that suppression of abnormally coherent activity in the CTBG system is a major factor in DBS therapy for Parkinson's disease, by permitting normal dynamics to resume. At high stimulus intensities, nonlinear effects in the target population mediate wave-wave interactions between resonant beta activity and the stimulus pulse train, leading to complex spectral structure that shows remarkable similarity to that seen in steady-state evoked potential experiments.

NFTsim: Theory and Simulation of Multiscale Neural Field Dynamics.

A user ready, portable, documented software package, NFTsim, is presented to facilitate numerical simulations of a wide range of brain systems using continuum neural field modeling. NFTsim enables users to simulate key aspects of brain activity at multiple scales. At the microscopic scale, it incorporates characteristics of local interactions between cells, neurotransmitter effects, synaptodendritic delays and feedbacks. At the mesoscopic scale, it incorporates information about medium to large scale axonal ranges of fibers, which are essential to model dissipative wave transmission and to produce synchronous oscillations and associated cross-correlation patterns as observed in local field potential recordings of active tissue. At the scale of the whole brain, NFTsim allows for the inclusion of long range pathways, such as thalamocortical projections, when generating macroscopic activity fields. The multiscale nature of the neural activity produced by NFTsim has the potential to enable the modeling of resulting quantities measurable via various neuroimaging techniques. In this work, we give a comprehensive description of the design and implementation of the software. Due to its modularity and flexibility, NFTsim enables the systematic study of an unlimited number of neural systems with multiple neural populations under a unified framework and allows for direct comparison with analytic and experimental predictions. The code is written in C++ and bundled with Matlab routines for a rapid quantitative analysis and visualization of the outputs. The output of NFTsim is stored in plain text file enabling users to select from a broad range of tools for offline analysis. This software enables a wide and convenient use of powerful physiologically-based neural field approaches to brain modeling. NFTsim is distributed under the Apache 2.0 license.

A unified model of melatonin, 6-sulfatoxymelatonin, and sleep dynamics.

A biophysical model of the key aspects of melatonin synthesis and excretion has been developed, which is able to predict experimental dynamics of melatonin in plasma and saliva, and of its urinary metabolite 6-sulfatoxymelatonin (aMT6s). This new model is coupled to an established model of arousal dynamics, which predicts sleep and circadian dynamics based on light exposure and times of wakefulness. The combined model thus predicts melatonin levels over the sleep-wake/dark-light cycle and enables prediction of melatonin-based circadian phase markers, such as dim light melatonin onset (DLMO) and aMT6s acrophase under conditions of normal sleep and circadian misalignment. The model is calibrated and tested against group average data from 10 published experimental studies and is found to reproduce quantitatively the key dynamics of melatonin and aMT6s, including the timing of release and amplitude, as well as response to controlled lighting and shift work.

Recruiting neural field theory for data augmentation in a motor imagery brain-computer interface.

We introduce a novel approach to training data augmentation in brain-computer interfaces (BCIs) using neural field theory (NFT) applied to EEG data from motor imagery tasks. BCIs often suffer from limited accuracy due to a limited amount of training data. To address this, we leveraged a corticothalamic NFT model to generate artificial EEG time series as supplemental training data. We employed the BCI competition IV '2a' dataset to evaluate this augmentation technique. For each individual, we fitted the model to common spatial patterns of each motor imagery class, jittered the fitted parameters, and generated time series for data augmentation. Our method led to significant accuracy improvements of over 2% in classifying the "total power" feature, but not in the case of the "Higuchi fractal dimension" feature. This suggests that the fit NFT model may more favorably represent one feature than the other. These findings pave the way for further exploration of NFT-based data augmentation, highlighting the benefits of biophysically accurate artificial data.

Neural field theory of adaptive effects on auditory evoked responses and mismatch negativity in multifrequency stimulus sequences.

Physiologically based neural field theory (NFT) of the corticothalamic system, including adaptation, is used to calculate the responses evoked by trains of auditory stimuli that differ in frequency. In oddball paradigms, fully distinguishable frequencies lead to different standard (common stimulus) and deviant (rare stimulus) responses; the signal obtained by subtracting the standard response from the deviant is termed the mismatch negativity (MMN). In this analysis, deviant responses are found to correspond to unadapted cortex, whereas the part of auditory cortex that processes the standard stimuli adapts over several stimulus presentations until the final standard response form is achieved. No higher-order memory processes are invoked. In multifrequency experiments, the deviant response approaches the standard one as the deviant frequency approaches that of the standard and analytic criteria for this effect to be obtained. It is shown that these criteria can also be used to understand adaptation in random tone sequences. A method of probing MMNs and adaptation in random tone sequences is suggested to makes more use of such data.

Biophysical mechanisms of multistability in resting-state cortical rhythms.

The human alpha (8-12 Hz) rhythm is one of the most prominent, robust, and widely studied attributes of ongoing cortical activity. Contrary to the prevalent notion that it simply "waxes and wanes," spontaneous alpha activity bursts erratically between two distinct modes of activity. We now establish a mechanism for this multistable phenomenon in resting-state cortical recordings by characterizing the complex dynamics of a biophysical model of macroscopic corticothalamic activity. This is achieved by studying the predicted activity of cortical and thalamic neuronal populations in this model as a function of its dynamic stability and the role of nonspecific synaptic noise. We hence find that fluctuating noisy inputs into thalamic neurons elicit spontaneous bursts between low- and high-amplitude alpha oscillations when the system is near a particular type of dynamical instability, namely a subcritical Hopf bifurcation. When the postsynaptic potentials associated with these noisy inputs are modulated by cortical feedback, the SD of power within each of these modes scale in proportion to their mean, showing remarkable concordance with empirical data. Our state-dependent corticothalamic model hence exhibits multistability and scale-invariant fluctuations-key features of resting-state cortical activity and indeed, of human perception, cognition, and behavior-thus providing a unified account of these apparently divergent phenomena.

Analytic Model for Feature Maps in the Primary Visual Cortex.

A compact analytic model is proposed to describe the combined orientation preference (OP) and ocular dominance (OD) features of simple cells and their mutual constraints on the spatial layout of the combined OP-OD map in the primary visual cortex (V1). This model consists of three parts: (i) an anisotropic Laplacian (AL) operator that represents the local neural sensitivity to the orientation of visual inputs; and (ii) obtain a receptive field (RF) operator that models the anisotropic spatial projection from nearby neurons to a given V1 cell over scales of a few tenths of a millimeter and combines with the AL operator to give an overall OP operator; and (iii) a map that describes how the parameters of these operators vary approximately periodically across V1. The parameters of the proposed model maximize the neural response at a given OP with an OP tuning curve fitted to experimental results. It is found that the anisotropy of the AL operator does not significantly affect OP selectivity, which is dominated by the RF anisotropy, consistent with Hubel and Wiesel's original conclusions that orientation tuning width of V1 simple cell is inversely related to the elongation of its RF. A simplified and idealized OP-OD map is then constructed to describe the approximately periodic local OP-OD structure of V1 in a compact form. It is shown explicitly that the OP map can be approximated by retaining its dominant spatial Fourier coefficients, which are shown to suffice to reconstruct its basic spatial structure. Moreover, this representation is a suitable form to analyze observed OP maps compactly and to be used in neural field theory (NFT) for analyzing activity modulated by the OP-OD structure of V1. Application to independently simulated V1 OP structure shows that observed irregularities in the map correspond to a spread of dominant coefficients in a circle in Fourier space. In addition, there is a strong bias toward two perpendicular directions when only a small patch of local map is included. The bias is decreased as the amount of V1 included in the Fourier transform is increased.

The music of the hemispheres: Cortical eigenmodes as a physical basis for large-scale brain activity and connectivity patterns.

Neuroscience has had access to high-resolution recordings of large-scale cortical activity and structure for decades, but still lacks a generally adopted basis to analyze and interrelate results from different individuals and experiments. Here it is argued that the natural oscillatory modes of the cortex-cortical eigenmodes-provide a physically preferred framework for systematic comparisons across experimental conditions and imaging modalities. In this framework, eigenmodes are analogous to notes of a musical instrument, while commonly used statistical patterns parallel frequently played chords. This intuitive perspective avoids problems that often arise in neuroimaging analyses, and connects to underlying mechanisms of brain activity. We envisage this approach will lead to novel insights into whole-brain function, both in existing and prospective datasets, and facilitate a unification of empirical findings across presently disparate analysis paradigms and measurement modalities.

Thalamocortical changes in major depression probed by deconvolution and physiology-based modeling.

Auditory event-related potentials (ERPs) have been extensively studied in patients with depression, but most studies have focused on purely phenomenological analysis methods, such as component scoring. In contrast, this study applies two recently developed physiology-based methods-fitting using a thalamocortical model of neuronal activity and waveform deconvolution - to data from a selective-attention task in four subject groups (49 patients with melancholic depression, 34 patients with non-melancholic depression, 111 participants with subclinical depressed mood, and 98 healthy controls), to yield insight into physiological differences in attentional processing between participants with major depression and controls. This approach found evidence that: participants with depressed mood, regardless of clinical status, shift from excitation in the thalamocortical system towards inhibition; that clinically depressed participants have decreased relative response amplitude between target and standard waveforms; and that patients with melancholic depression also have increased thalamocortical delays. These findings suggest possible physiological mechanisms underlying different depression subtypes, and may eventually prove useful in motivating new physiology-based diagnostic methods.

Firing responses of bursting neurons with delayed feedback.

Thalamic neurons, which play important roles in the genesis of rhythmic activities of the brain, show various bursting behaviors, particularly modulated by complex thalamocortical feedback via cortical neurons. As a first step to explore this complex neural system and focus on the effects of the feedback on the bursting behavior, a simple loop structure delayed in time and scaled by a coupling strength is added to a recent mean-field model of bursting neurons. Depending on the coupling strength and delay time, the modeled neurons show two distinct response patterns: one entrained to the unperturbed bursting frequency of the neurons and one entrained to the resonant frequency of the loop structure. Transitions between these two patterns are explored in the model's parameter space via extensive numerical simulations. It is found that at a fixed loop delay, there is a critical coupling strength at which the dominant response frequency switches from the unperturbed bursting frequency to the loop-induced one. Furthermore, alternating occurrence of these two response frequencies is observed when the delay varies at fixed coupling strength. The results demonstrate that bursting is coupled with feedback to yield new dynamics, which will provide insights into such effects in more complex neural systems.

Mammalian sleep dynamics: how diverse features arise from a common physiological framework.

Mammalian sleep varies widely, ranging from frequent napping in rodents to consolidated blocks in primates and unihemispheric sleep in cetaceans. In humans, rats, mice and cats, sleep patterns are orchestrated by homeostatic and circadian drives to the sleep-wake switch, but it is not known whether this system is ubiquitous among mammals. Here, changes of just two parameters in a recent quantitative model of this switch are shown to reproduce typical sleep patterns for 17 species across 7 orders. Furthermore, the parameter variations are found to be consistent with the assumptions that homeostatic production and clearance scale as brain volume and surface area, respectively. Modeling an additional inhibitory connection between sleep-active neuronal populations on opposite sides of the brain generates unihemispheric sleep, providing a testable hypothetical mechanism for this poorly understood phenomenon. Neuromodulation of this connection alone is shown to account for the ability of fur seals to transition between bihemispheric sleep on land and unihemispheric sleep in water. Determining what aspects of mammalian sleep patterns can be explained within a single framework, and are thus universal, is essential to understanding the evolution and function of mammalian sleep. This is the first demonstration of a single model reproducing sleep patterns for multiple different species. These wide-ranging findings suggest that the core physiological mechanisms controlling sleep are common to many mammalian orders, with slight evolutionary modifications accounting for interspecies differences.

Neural Field Theory of Evoked Response Sequences and Mismatch Negativity With Adaptation.

Physiologically based neural field theory of the corticothalamic system is used to calculate the responses evoked by trains of auditory stimuli that correspond to different cortical locations via the tonotopic map. The results are shown to account for standard and deviant evoked responses to frequent and rare stimuli, respectively, in the auditory oddball paradigms widely used in human cognitive studies, and the so-called mismatch negativity between them. It also reproduces a wide range of other effects and variants, including the mechanism by which a change in standard responses relative to deviants can develop through adaptation, different responses when two deviants are presented in a row or a standard is presented after two deviants, relaxation of standard responses back to deviant form after a stimulus-free period, and more complex sequences. Some cases are identified in which adaptation does not account for the whole difference between standard and deviant responses. The results thus provide a systematic means to determine how much of the response is due to adaptation in the system comprising the primary auditory cortex and medial geniculate nucleus, and how much requires involvement of higher-level processing.

Modal-Polar Representation of Evoked Response Potentials in Multiple Arousal States.

An expansion of the corticothalamic transfer function into eigenmodes and resonant poles is used to derive a simple formula for evoked response potentials (ERPs) in various states of arousal. The transfer function corresponds to the cortical response to an external stimulus, which encodes all the information and properties of the linear system. This approach links experimental observations of resonances and characteristic timescales in brain activity with physically based neural field theory (NFT). The present work greatly simplifies the formula of the analytical ERP, and separates its spatial part (eigenmodes) from the temporal part (poles). Within this framework, calculations involve contour integrations that yield an explicit expression for ERPs. The dominant global mode is considered explicitly in more detail to study how the ERP varies with time in this mode and to illustrate the method. For each arousal state in sleep and wake, the resonances of the system are determined and it is found that five poles are sufficient to study the main dynamics of the system in waking eyes-open and eyes-closed states. Similarly, it is shown that six poles suffice to reproduce ERPs in rapid-eye movement sleep, sleep state 1, and sleep state 2 states, whereas just four poles suffice to reproduce the dynamics in slow wave sleep. Thus, six poles are sufficient to preserve the main global ERP dynamics of the system for all states of arousal. These six poles correspond to the dominant resonances of the system at slow-wave, alpha, and beta frequencies. These results provide the basis for simplified analytic treatment of brain dynamics and link observations more closely to theory.

Determination of Dynamic Brain Connectivity via Spectral Analysis.

Spectral analysis based on neural field theory is used to analyze dynamic connectivity via methods based on the physical eigenmodes that are the building blocks of brain dynamics. These approaches integrate over space instead of averaging over time and thereby greatly reduce or remove the temporal averaging effects, windowing artifacts, and noise at fine spatial scales that have bedeviled the analysis of dynamical functional connectivity (FC). The dependences of FC on dynamics at various timescales, and on windowing, are clarified and the results are demonstrated on simple test cases, demonstrating how modes provide directly interpretable insights that can be related to brain structure and function. It is shown that FC is dynamic even when the brain structure and effective connectivity are fixed, and that the observed patterns of FC are dominated by relatively few eigenmodes. Common artifacts introduced by statistical analyses that do not incorporate the physical nature of the brain are discussed and it is shown that these are avoided by spectral analysis using eigenmodes. Unlike most published artificially discretized "resting state networks" and other statistically-derived patterns, eigenmodes overlap, with every mode extending across the whole brain and every region participating in every mode-just like the vibrations that give rise to notes of a musical instrument. Despite this, modes are independent and do not interact in the linear limit. It is argued that for many purposes the intrinsic limitations of covariance-based FC instead favor the alternative of tracking eigenmode coefficients vs. time, which provide a compact representation that is directly related to biophysical brain dynamics.

Bistability and non-Gaussian fluctuations in spontaneous cortical activity.

The brain is widely assumed to be a paradigmatic example of a complex, self-organizing system. As such, it should exhibit the classic hallmarks of nonlinearity, multistability, and "nondiffusivity" (large coherent fluctuations). Surprisingly, at least at the very large scale of neocortical dynamics, there is little empirical evidence to support this, and hence most computational and methodological frameworks for healthy brain activity have proceeded very reasonably from a purely linear and diffusive perspective. By studying the temporal fluctuations of power in human resting-state electroencephalograms, we show that, although these simple properties may hold true at some temporal scales, there is strong evidence for bistability and nondiffusivity in key brain rhythms. Bistability is manifest as nonclassic bursting between high- and low-amplitude modes in the alpha rhythm. Nondiffusivity is expressed through the irregular appearance of high amplitude "extremal" events in beta rhythm power fluctuations. The statistical robustness of these observations was confirmed through comparison with Gaussian-rendered phase-randomized surrogate data. Although there is a good conceptual framework for understanding bistability in cortical dynamics, the implications of the extremal events challenge existing frameworks for understanding large-scale brain systems.