NSF DARE-transforming modeling in neurorehabilitation: perspectives and opportunities from US funding agencies.

In recognition of the importance and timeliness of computational models for accelerating progress in neurorehabilitation, the U.S. National Science Foundation (NSF) and the National Institutes of Health (NIH) sponsored a conference in March 2023 at the University of Southern California that drew global participation from engineers, scientists, clinicians, and trainees. This commentary highlights promising applications of computational models to understand neurorehabilitation ("Using computational models to understand complex mechanisms in neurorehabilitation" section), improve rehabilitation care in the context of digital twin frameworks ("Using computational models to improve delivery and implementation of rehabilitation care" section), and empower future interdisciplinary workforces to deliver higher-quality clinical care using computational models ("Using computational models in neurorehabilitation requires an interdisciplinary workforce" section). The authors describe near-term gaps and opportunities, all of which encourage interdisciplinary team science. Four major opportunities were identified including (1) deciphering the relationship between engineering figures of merit-a term commonly used by engineers to objectively quantify the performance of a device, system, method, or material relative to existing state of the art-and clinical outcome measures, (2) validating computational models from engineering and patient perspectives, (3) creating and curating datasets that are made publicly accessible, and (4) developing new transdisciplinary frameworks, theories, and models that incorporate the complexities of the nervous and musculoskeletal systems. This commentary summarizes U.S. funding opportunities by two Federal agencies that support computational research in neurorehabilitation. The NSF has funding programs that support high-risk/high-reward research proposals on computational methods in neurorehabilitation informed by theory- and data-driven approaches. The NIH supports the development of new interventions and therapies for a wide range of nervous system injuries and impairments informed by the field of computational modeling. The conference materials can be found at https://dare2023.usc.edu/ .

On the Role of Theory and Modeling in Neuroscience.

In recent years, the field of neuroscience has gone through rapid experimental advances and a significant increase in the use of quantitative and computational methods. This growth has created a need for clearer analyses of the theory and modeling approaches used in the field. This issue is particularly complex in neuroscience because the field studies phenomena that cross a wide range of scales and often require consideration at varying degrees of abstraction, from precise biophysical interactions to the computations they implement. We argue that a pragmatic perspective of science, in which descriptive, mechanistic, and normative models and theories each play a distinct role in defining and bridging levels of abstraction, will facilitate neuroscientific practice. This analysis leads to methodological suggestions, including selecting a level of abstraction that is appropriate for a given problem, identifying transfer functions to connect models and data, and the use of models themselves as a form of experiment.

Bayesian optimization of distributed neurodynamical controller models for spatial navigation.

Dynamical systems models for controlling multi-agent swarms have demonstrated advances toward resilient, decentralized navigation algorithms. We previously introduced the NeuroSwarms controller, in which agent-based interactions were modeled by analogy to neuronal network interactions, including attractor dynamics and phase synchrony, that have been theorized to operate within hippocampal place-cell circuits in navigating rodents. This complexity precludes linear analyses of stability, controllability, and performance typically used to study conventional swarm models. Further, tuning dynamical controllers by manual or grid-based search is often inadequate due to the complexity of objectives, dimensionality of model parameters, and computational costs of simulation-based sampling. Here, we present a framework for tuning dynamical controller models of autonomous multi-agent systems with Bayesian optimization. Our approach utilizes a task-dependent objective function to train Gaussian process surrogate models to achieve adaptive and efficient exploration of a dynamical controller model's parameter space. We demonstrate this approach by studying an objective function selecting for NeuroSwarms behaviors that cooperatively localize and capture spatially distributed rewards under time pressure. We generalized task performance across environments by combining scores for simulations in multiple mazes with distinct geometries. To validate search performance, we compared high-dimensional clustering for high- vs. low-likelihood parameter points by visualizing sample trajectories in 2-dimensional embeddings. Our findings show that adaptive, sample-efficient evaluation of the self-organizing behavioral capacities of complex systems, including dynamical swarm controllers, can accelerate the translation of neuroscientific theory to applied domains.

Cognitive swarming in complex environments with attractor dynamics and oscillatory computing.

Neurobiological theories of spatial cognition developed with respect to recording data from relatively small and/or simplistic environments compared to animals' natural habitats. It has been unclear how to extend theoretical models to large or complex spaces. Complementarily, in autonomous systems technology, applications have been growing for distributed control methods that scale to large numbers of low-footprint mobile platforms. Animals and many-robot groups must solve common problems of navigating complex and uncertain environments. Here, we introduce the NeuroSwarms control framework to investigate whether adaptive, autonomous swarm control of minimal artificial agents can be achieved by direct analogy to neural circuits of rodent spatial cognition. NeuroSwarms analogizes agents to neurons and swarming groups to recurrent networks. We implemented neuron-like agent interactions in which mutually visible agents operate as if they were reciprocally connected place cells in an attractor network. We attributed a phase state to agents to enable patterns of oscillatory synchronization similar to hippocampal models of theta-rhythmic (5-12 Hz) sequence generation. We demonstrate that multi-agent swarming and reward-approach dynamics can be expressed as a mobile form of Hebbian learning and that NeuroSwarms supports a single-entity paradigm that directly informs theoretical models of animal cognition. We present emergent behaviors including phase-organized rings and trajectory sequences that interact with environmental cues and geometry in large, fragmented mazes. Thus, NeuroSwarms is a model artificial spatial system that integrates autonomous control and theoretical neuroscience to potentially uncover common principles to advance both domains.

Hippocampal Place Cells Encode Local Surface-Texture Boundaries.

The cognitive map is often assumed to be a Euclidean map that isometrically represents the real world (i.e., the Euclidean distance between any two locations in the physical world should be preserved on the cognitive map). However, accumulating evidence suggests that environmental boundaries can distort the mental representations of physical space. For example, the distance between two locations can be remembered as longer than the true physical distance if the locations are separated by a boundary. While this overestimation is observed under different experimental conditions, even when the boundary is formed by flat surface cues, its physiological basis is not well understood. We examined the neural representation of flat surface cue boundaries, and of the space segregated by these boundaries, by recording place cell activity from CA1 and CA3 while rats foraged on a circular track or square platforms with inhomogeneous surface textures. About 40% of the place field edges concentrated near the boundaries on the circular track (significantly above the chance level 33%). Similarly, place field edges were more prevalent near boundaries on the platforms than expected by chance. In both one- and two-dimensional environments, the population vectors of place cell activity changed more abruptly with distance between locations that crossed cue boundaries than between locations within a bounded region. These results show that the locations of surface boundaries were evident as enhanced decorrelations of the neural representations of locations to either side of the boundaries. This enhancement might underlie the cognitive phenomenon of overestimation of distances across boundaries.

Spatial synchronization codes from coupled rate-phase neurons.

During spatial navigation, the frequency and timing of spikes from spatial neurons including place cells in hippocampus and grid cells in medial entorhinal cortex are temporally organized by continuous theta oscillations (6-11 Hz). The theta rhythm is regulated by subcortical structures including the medial septum, but it is unclear how spatial information from place cells may reciprocally organize subcortical theta-rhythmic activity. Here we recorded single-unit spiking from a constellation of subcortical and hippocampal sites to study spatial modulation of rhythmic spike timing in rats freely exploring an open environment. Our analysis revealed a novel class of neurons that we termed 'phaser cells,' characterized by a symmetric coupling between firing rate and spike theta-phase. Phaser cells encoded space by assigning distinct phases to allocentric isocontour levels of each cell's spatial firing pattern. In our dataset, phaser cells were predominantly located in the lateral septum, but also the hippocampus, anteroventral thalamus, lateral hypothalamus, and nucleus accumbens. Unlike the unidirectional late-to-early phase precession of place cells, bidirectional phase modulation acted to return phaser cells to the same theta-phase along a given spatial isocontour, including cells that characteristically shifted to later phases at higher firing rates. Our dynamical models of intrinsic theta-bursting neurons demonstrated that experience-independent temporal coding mechanisms can qualitatively explain (1) the spatial rate-phase relationships of phaser cells and (2) the observed temporal segregation of phaser cells according to phase-shift direction. In open-field phaser cell simulations, competitive learning embedded phase-code entrainment maps into the weights of downstream targets, including path integration networks. Bayesian phase decoding revealed error correction capable of resetting path integration at subsecond timescales. Our findings suggest that phaser cells may instantiate a subcortical theta-rhythmic loop of spatial feedback. We outline a framework in which location-dependent synchrony reconciles internal idiothetic processes with the allothetic reference points of sensory experience.

Clock-Generated Temporal Codes Determine Synaptic Plasticity to Control Sleep.

Neurons use two main schemes to encode information: rate coding (frequency of firing) and temporal coding (timing or pattern of firing). While the importance of rate coding is well established, it remains controversial whether temporal codes alone are sufficient for controlling behavior. Moreover, the molecular mechanisms underlying the generation of specific temporal codes are enigmatic. Here, we show in Drosophila clock neurons that distinct temporal spike patterns, dissociated from changes in firing rate, encode time-dependent arousal and regulate sleep. From a large-scale genetic screen, we identify the molecular pathways mediating the circadian-dependent changes in ionic flux and spike morphology that rhythmically modulate spike timing. Remarkably, the daytime spiking pattern alone is sufficient to drive plasticity in downstream arousal neurons, leading to increased firing of these cells. These findings demonstrate a causal role for temporal coding in behavior and define a form of synaptic plasticity triggered solely by temporal spike patterns.

Attentive scanning behavior drives one-trial potentiation of hippocampal place fields.

The hippocampus is thought to have a critical role in episodic memory by incorporating the sensory input of an experience onto a spatial framework embodied by place cells. Although the formation and stability of place fields requires exploration, the interaction between discrete exploratory behaviors and the specific, immediate and persistent modifications of neural representations required by episodic memory has not been established. We recorded place cells in rats and found that increased neural activity during exploratory head-scanning behaviors predicted the formation and potentiation of place fields on the next pass through that location, regardless of environmental familiarity and across multiple testing days. These results strongly suggest that, during the attentive behaviors that punctuate exploration, place cell activity mediates the one-trial encoding of ongoing experiences necessary for episodic memory.

Sensory feedback, error correction, and remapping in a multiple oscillator model of place-cell activity.

Mammals navigate by integrating self-motion signals ("path integration") and occasionally fixing on familiar environmental landmarks. The rat hippocampus is a model system of spatial representation in which place cells are thought to integrate both sensory and spatial information from entorhinal cortex. The localized firing fields of hippocampal place cells and entorhinal grid-cells demonstrate a phase relationship with the local theta (6-10 Hz) rhythm that may be a temporal signature of path integration. However, encoding self-motion in the phase of theta oscillations requires high temporal precision and is susceptible to idiothetic noise, neuronal variability, and a changing environment. We present a model based on oscillatory interference theory, previously studied in the context of grid cells, in which transient temporal synchronization among a pool of path-integrating theta oscillators produces hippocampal-like place fields. We hypothesize that a spatiotemporally extended sensory interaction with external cues modulates feedback to the theta oscillators. We implement a form of this cue-driven feedback and show that it can retrieve fixed points in the phase code of position. A single cue can smoothly reset oscillator phases to correct for both systematic errors and continuous noise in path integration. Further, simulations in which local and global cues are rotated against each other reveal a phase-code mechanism in which conflicting cue arrangements can reproduce experimentally observed distributions of "partial remapping" responses. This abstract model demonstrates that phase-code feedback can provide stability to the temporal coding of position during navigation and may contribute to the context-dependence of hippocampal spatial representations. While the anatomical substrates of these processes have not been fully characterized, our findings suggest several signatures that can be evaluated in future experiments.

Modular realignment of entorhinal grid cell activity as a basis for hippocampal remapping.

Hippocampal place fields, the local regions of activity recorded from place cells in exploring rodents, can undergo large changes in relative location during remapping. This process would appear to require some form of modulated global input. Grid-cell responses recorded from layer II of medial entorhinal cortex in rats have been observed to realign concurrently with hippocampal remapping, making them a candidate input source. However, this realignment occurs coherently across colocalized ensembles of grid cells (Fyhn et al., 2007). The hypothesized entorhinal contribution to remapping depends on whether this coherence extends to all grid cells, which is currently unknown. We study whether dividing grid cells into small numbers of independently realigning modules can both account for this localized coherence and allow for hippocampal remapping. To do this, we construct a model in which place-cell responses arise from network competition mediated by global inhibition. We show that these simulated responses approximate the sparsity and spatial specificity of hippocampal activity while fully representing a virtual environment without learning. Place-field locations and the set of active place cells in one environment can be independently rearranged by changes to the underlying grid-cell inputs. We introduce new measures of remapping to assess the effectiveness of grid-cell modularity and to compare shift realignments with other geometric transformations of grid-cell responses. Complete hippocampal remapping is possible with a small number of shifting grid modules, indicating that entorhinal realignment may be able to generate place-field randomization despite substantial coherence.

Lexico-semantic structure and the word-frequency effect in recognition memory.

The word-frequency effect (WFE) in recognition memory refers to the finding that more rare words are better recognized than more common words. We demonstrate that a familiarity-discrimination model operating on data from a semantic word-association space yields a robust WFE in data on both hit rates and false-alarm rates. Our modeling results suggest that word frequency is encoded in the semantic structure of language, and that this encoding contributes to the WFE observed in item-recognition experiments.