Developing a hippocampal neural prosthetic to facilitate human memory encoding and recall of stimulus features and categories.

Objective: Here, we demonstrate the first successful use of static neural stimulation patterns for specific information content. These static patterns were derived by a model that was applied to a subject's own hippocampal spatiotemporal neural codes for memory. Approach: We constructed a new model of processes by which the hippocampus encodes specific memory items via spatiotemporal firing of neural ensembles that underlie the successful encoding of targeted content into short-term memory. A memory decoding model (MDM) of hippocampal CA3 and CA1 neural firing was computed which derives a stimulation pattern for CA1 and CA3 neurons to be applied during the encoding (sample) phase of a delayed match-to-sample (DMS) human short-term memory task. Main results: MDM electrical stimulation delivered to the CA1 and CA3 locations in the hippocampus during the sample phase of DMS trials facilitated memory of images from the DMS task during a delayed recognition (DR) task that also included control images that were not from the DMS task. Across all subjects, the stimulated trials exhibited significant changes in performance in 22.4% of patient and category combinations. Changes in performance were a combination of both increased memory performance and decreased memory performance, with increases in performance occurring at almost 2 to 1 relative to decreases in performance. Across patients with impaired memory that received bilateral stimulation, significant changes in over 37.9% of patient and category combinations was seen with the changes in memory performance show a ratio of increased to decreased performance of over 4 to 1. Modification of memory performance was dependent on whether memory function was intact or impaired, and if stimulation was applied bilaterally or unilaterally, with nearly all increase in performance seen in subjects with impaired memory receiving bilateral stimulation. Significance: These results demonstrate that memory encoding in patients with impaired memory function can be facilitated for specific memory content, which offers a stimulation method for a future implantable neural prosthetic to improve human memory.

Corrigendum: Patterned hippocampal stimulation facilitates memory in patients with a history of head impact and/or brain injury.

[This corrects the article DOI: 10.3389/fnhum.2022.933401.].

Patterned Hippocampal Stimulation Facilitates Memory in Patients With a History of Head Impact and/or Brain Injury.

RATIONALE: Deep brain stimulation (DBS) of the hippocampus is proposed for enhancement of memory impaired by injury or disease. Many pre-clinical DBS paradigms can be addressed in epilepsy patients undergoing intracranial monitoring for seizure localization, since they already have electrodes implanted in brain areas of interest. Even though epilepsy is usually not a memory disorder targeted by DBS, the studies can nevertheless model other memory-impacting disorders, such as Traumatic Brain Injury (TBI). METHODS: Human patients undergoing Phase II invasive monitoring for intractable epilepsy were implanted with depth electrodes capable of recording neurophysiological signals. Subjects performed a delayed-match-to-sample (DMS) memory task while hippocampal ensembles from CA1 and CA3 cell layers were recorded to estimate a multi-input, multi-output (MIMO) model of CA3-to-CA1 neural encoding and a memory decoding model (MDM) to decode memory information from CA3 and CA1 neuronal signals. After model estimation, subjects again performed the DMS task while either MIMO-based or MDM-based patterned stimulation was delivered to CA1 electrode sites during the encoding phase of the DMS trials. Each subject was sorted (post hoc) by prior experience of repeated and/or mild-to-moderate brain injury (RMBI), TBI, or no history (control) and scored for percentage successful delayed recognition (DR) recall on stimulated vs. non-stimulated DMS trials. The subject's medical history was unknown to the experimenters until after individual subject memory retention results were scored. RESULTS: When examined compared to control subjects, both TBI and RMBI subjects showed increased memory retention in response to both MIMO and MDM-based hippocampal stimulation. Furthermore, effects of stimulation were also greater in subjects who were evaluated as having pre-existing mild-to-moderate memory impairment. CONCLUSION: These results show that hippocampal stimulation for memory facilitation was more beneficial for subjects who had previously suffered a brain injury (other than epilepsy), compared to control (epilepsy) subjects who had not suffered a brain injury. This study demonstrates that the epilepsy/intracranial recording model can be extended to test the ability of DBS to restore memory function in subjects who previously suffered a brain injury other than epilepsy, and support further investigation into the beneficial effect of DBS in TBI patients.

Altered adult neurogenesis and gliogenesis in patients with mesial temporal lobe epilepsy.

The hippocampus is the most common seizure focus in people. In the hippocampus, aberrant neurogenesis plays a critical role in the initiation and progression of epilepsy in rodent models, but it is unknown whether this also holds true in humans. To address this question, we used immunofluorescence on control healthy hippocampus and surgical resections from mesial temporal lobe epilepsy (MTLE), plus neural stem-cell cultures and multi-electrode recordings of ex vivo hippocampal slices. We found that a longer duration of epilepsy is associated with a sharp decline in neuronal production and persistent numbers in astrogenesis. Further, immature neurons in MTLE are mostly inactive, and are not observed in cases with local epileptiform-like activity. However, immature astroglia are present in every MTLE case and their location and activity are dependent on epileptiform-like activity. Immature astroglia, rather than newborn neurons, therefore represent a potential target to continually modulate adult human neuronal hyperactivity.

Accelerating input-output model estimation with parallel computing for testing hippocampal memory prostheses in human.

BACKGROUND: Hippocampal memory prosthesis is defined as a closed-loop biomimetic system that can be used for restoration and enhancement of memory functions impaired in diseases or injuries. To build such a prosthesis, we have developed two types of input-output models, i.e., a multi-input multi-output (MIMO) model for predicting output spike trains based on input spikes, and a double-layer multi-resolution memory decoding (MD) model for classifying spatio-temporal patterns of spikes into memory categories. Both models can achieve high prediction accuracy using human hippocampal spikes data and can be used to derive electrical stimulation patterns to test the hippocampal memory prosthesis. METHODS: However, testing hippocampal memory prostheses in human epilepsy patients with such models has to be performed within a much shorter time window (48-72 h) due to clinical limitations. To solve this problem, we have developed parallelization strategies to decompose the overall model estimation task into multiple independent sub-tasks involving different outputs and cross-validation folds. These sub-tasks are then accomplished in parallel on different computer nodes to reduce model estimation time. RESULTS: Implementing both parallel schemes with a high-performance computer cluster, we successfully reduced the computing time of model estimations from hundreds of hours to tens of hours. COMPARISON WITH EXISTING METHOD: We have tested the two parallel computing schemes for both MIMO and MD models with data collected from 11 human subjects. The performances of the parallel schemes are compared with the performance of the non-parallel scheme. CONCLUSION: Such strategies allow us to complete the modeling procedure within the required time frame to further test input-output model-driven electrical stimulations for the hippocampal memory prosthesis. It has important implications to test the model-based DBS intraoperatively and developing clinically viable hippocampal memory prostheses.

A Double-Layer Multi-Resolution Classification Model for Decoding Spatiotemporal Patterns of Spikes With Small Sample Size.

We build a double-layer, multiple temporal-resolution classification model for decoding single-trial spatiotemporal patterns of spikes. The model takes spiking activities as input signals and binary behavioral or cognitive variables as output signals and represents the input-output mapping with a double-layer ensemble classifier. In the first layer, to solve the underdetermined problem caused by the small sample size and the very high dimensionality of input signals, B-spline functional expansion and L1-regularized logistic classifiers are used to reduce dimensionality and yield sparse model estimations. A wide range of temporal resolutions of neural features is included by using a large number of classifiers with different numbers of B-spline knots. Each classifier serves as a base learner to classify spatiotemporal patterns into the probability of the output label with a single temporal resolution. A bootstrap aggregating strategy is used to reduce the estimation variances of these classifiers. In the second layer, another L1-regularized logistic classifier takes outputs of first-layer classifiers as inputs to generate the final output predictions. This classifier serves as a meta-learner that fuses multiple temporal resolutions to classify spatiotemporal patterns of spikes into binary output labels. We test this decoding model with both synthetic and experimental data recorded from rats and human subjects performing memory-dependent behavioral tasks. Results show that this method can effectively avoid overfitting and yield accurate prediction of output labels with small sample size. The double-layer, multi-resolution classifier consistently outperforms the best single-layer, single-resolution classifier by extracting and utilizing multi-resolution spatiotemporal features of spike patterns in the classification.

Bridging Hierarchies in Multi-Scale Models of Neural Systems: Look-Up Tables Enable Computationally Efficient Simulations of Non-linear Synaptic Dynamics.

Synapses are critical actors of neuronal transmission as they form the basis of chemical communication between neurons. Accurate computational models of synaptic dynamics may prove important in elucidating emergent properties across hierarchical scales. Yet, in large-scale neuronal network simulations, synapses are often modeled as highly simplified linear exponential functions due to their small computational footprint. However, these models cannot capture the complex non-linear dynamics that biological synapses exhibit and thus, are insufficient in representing synaptic behavior accurately. Existing detailed mechanistic synapse models can replicate these non-linear dynamics by modeling the underlying kinetics of biological synapses, but their high complexity prevents them from being a suitable option in large-scale models due to long simulation times. This motivates the development of more parsimonious models that can capture the complex non-linear dynamics of synapses accurately while maintaining a minimal computational cost. We propose a look-up table approach that stores precomputed values thereby circumventing most computations at runtime and enabling extremely fast simulations for glutamatergic receptors AMPAr and NMDAr. Our results demonstrate that this methodology is capable of replicating the dynamics of biological synapses as accurately as the mechanistic synapse models while offering up to a 56-fold increase in speed. This powerful approach allows for multi-scale neuronal networks to be simulated at large scales, enabling the investigation of how low-level synaptic activity may lead to changes in high-level phenomena, such as memory and learning.

A sparse multiscale nonlinear autoregressive model for seizure prediction.

Objectives.Accurate seizure prediction is highly desirable for medical interventions such as responsive electrical stimulation. We aim to develop a classification model that can predict seizures by identifying preictal states, i.e. the precursor of a seizure, based on multi-channel intracranial electroencephalography (iEEG) signals.Approach.A two-level sparse multiscale classification model was developed to classify interictal and preictal states from iEEG data. In the first level, short time-scale linear dynamical features were extracted as autoregressive (AR) model coefficients; arbitrary (usually long) time-scale linear and nonlinear dynamical features were extracted as Laguerre-Volterra AR model coefficients; root-mean-square error of model prediction was used as a feature representing model unpredictability. In the second level, all features were fed into a sparse classifier to discriminate the iEEG data between interictal and preictal states.Main results. The two-level model can accurately classify seizure states using iEEG data recorded from ten canine and human subjects. Adding arbitrary (usually long) time-scale and nonlinear features significantly improves model performance compared with the conventional AR modeling approach. There is a high degree of variability in the types of features contributing to seizure prediction across different subjects.Significance. This study suggests that seizure generation may involve distinct linear/nonlinear dynamical processes caused by different underlying neurobiological mechanisms. It is necessary to build patient-specific classification models with a wide range of dynamical features.

Topographic Organization of Correlation Along the Longitudinal and Transverse Axes in Rat Hippocampal CA3 Due to Excitatory Afferents.

The topographic organization of afferents to the hippocampal CA3 subfield are well-studied, but their role in influencing the spatiotemporal dynamics of population activity is not understood. Using a large-scale, computational neuronal network model of the entorhinal-dentate-CA3 system, the effects of the perforant path, mossy fibers, and associational system on the propagation and transformation of network spiking patterns were investigated. A correlation map was constructed to characterize the spatial structure and temporal evolution of pairwise correlations which underlie the emergent patterns found in the population activity. The topographic organization of the associational system gave rise to changes in the spatial correlation structure along the longitudinal and transverse axes of the CA3. The resulting gradients may provide a basis for the known functional organization observed in hippocampus.

A Computational Model of Mitochondria Motility in Axons.

Mitochondria play a critical role in regulating cellular processes including ATP production, intracellular calcium signaling and generation of reactive oxidative species (ROS). Neurons rely on mitochondrial function to perform a range of complex processes, and mitochondrial dysfunctions have been shown to have an impact in pathologies of the nervous system. Yet, neurons contain a finite number of mitochondria, and their location is known to change in response to a number of factors including age and cellular activity, thereby impacting neuronal response. In this paper, we introduce a novel computational model of mitochondria motility that focuses on their movements along the axon. We describe the biological processes involved and the main parameters of the model. We use the model to investigate how some of these parameters affect the ability of mitochondria to position themselves in regions of high energy demand. Finally, we discuss the significance of our work and its downstream applications in further understanding pathologies of the nervous system such as Alzheimer's disease, and help identify potential novel therapeutic targets.

Accelerating Estimation of a Multi-Input Multi-Output Model of the Hippocampus with a Parallel Computing Strategy.

To build hippocampal memory prosthesis for restoring memory functions, we previously developed and implemented a multi-input multi-output (MIMO) nonlinear dynamic model of the hippocampus. This model can successfully predict hippocampal output spike activities based on input spike activities, and thus be used to drive microstimulation to bypass the damaged hippocampal region. Building such a MIMO model involves estimations of a large number of model coefficients, which typically takes hundreds of hours using a single personal computer. In practice, however, due to the requirement of medical care and clinical trials, the modeling processes must be completed within 72 hours after the recording, so that models can be used to drive stimulations. To solve this problem, we utilized a parallelization strategy to divide the whole MIMO model computation involving iterative estimation and optimization into independent computing tasks that can be performed simultaneously in multiple computer nodes. Such a strategy was implemented on the high-performance computing cluster at the University of Southern California. It reduced the model estimation time to tens of hours and thus allowed us to complete the modeling process within the required time frame to further test model-driven electrical stimulation for the hippocampal memory prosthesis.

A Computational Model of the Cholinergic Modulation of CA1 Pyramidal Cell Activity.

Dysfunction in cholinergic modulation has been linked to a variety of cognitive disorders including Alzheimer's disease. The important role of this neurotransmitter has been explored in a variety of experiments, yet many questions remain unanswered about the contribution of cholinergic modulation to healthy hippocampal function. To address this question, we have developed a model of CA1 pyramidal neuron that takes into consideration muscarinic receptor activation in response to changes in extracellular concentration of acetylcholine and its effects on cellular excitability and downstream intracellular calcium dynamics. This model incorporates a variety of molecular agents to accurately simulate several processes heretofore ignored in computational modeling of CA1 pyramidal neurons. These processes include the inhibition of ionic channels by phospholipid depletion along with the release of calcium from intracellular stores (i.e., the endoplasmic reticulum). This paper describes the model and the methods used to calibrate its behavior to match experimental results. The result of this work is a compartmental model with calibrated mechanisms for simulating the intracellular calcium dynamics of CA1 pyramidal cells with a focus on those related to release from calcium stores in the endoplasmic reticulum. From this model we also make various predictions for how the inhibitory and excitatory responses to cholinergic modulation vary with agonist concentration. This model expands the capabilities of CA1 pyramidal cell models through the explicit modeling of molecular interactions involved in healthy cognitive function and disease. Through this expanded model we come closer to simulating these diseases and gaining the knowledge required to develop novel treatments.

Admittance Method for Estimating Local Field Potentials Generated in a Multi-Scale Neuron Model of the Hippocampus.

Significant progress has been made toward model-based prediction of neral tissue activation in response to extracellular electrical stimulation, but challenges remain in the accurate and efficient estimation of distributed local field potentials (LFP). Analytical methods of estimating electric fields are a first-order approximation that may be suitable for model validation, but they are computationally expensive and cannot accurately capture boundary conditions in heterogeneous tissue. While there are many appropriate numerical methods of solving electric fields in neural tissue models, there isn't an established standard for mesh geometry nor a well-known rule for handling any mismatch in spatial resolution. Moreover, the challenge of misalignment between current sources and mesh nodes in a finite-element or resistor-network method volume conduction model needs to be further investigated. Therefore, using a previously published and validated multi-scale model of the hippocampus, the authors have formulated an algorithm for LFP estimation, and by extension, bidirectional communication between discretized and numerically solved volume conduction models and biologically detailed neural circuit models constructed in NEURON. Development of this algorithm required that we assess meshes of (i) unstructured tetrahedral and grid-based hexahedral geometries as well as (ii) differing approaches for managing the spatial misalignment of current sources and mesh nodes. The resulting algorithm is validated through the comparison of Admittance Method predicted evoked potentials with analytically estimated LFPs. Establishing this method is a critical step toward closed-loop integration of volume conductor and NEURON models that could lead to substantial improvement of the predictive power of multi-scale stimulation models of cortical tissue. These models may be used to deepen our understanding of hippocampal pathologies and the identification of efficacious electroceutical treatments.

Generation of Granule Cell Dendritic Morphologies by Estimating the Spatial Heterogeneity of Dendritic Branching.

Biological realism of dendritic morphologies is important for simulating electrical stimulation of brain tissue. By adding point process modeling and conditional sampling to existing generation strategies, we provide a novel means of reproducing the nuanced branching behavior that occurs in different layers of granule cell dendritic morphologies. In this study, a heterogeneous Poisson point process was used to simulate branching events. Conditional distributions were then used to select branch angles depending on the orthogonal distance to the somatic plane. The proposed method was compared to an existing generation tool and a control version of the proposed method that used a homogeneous Poisson point process. Morphologies were generated with each method and then compared to a set of digitally reconstructed neurons. The introduction of a conditionally dependent branching rate resulted in the generation of morphologies that more accurately reproduced the emergent properties of dendritic material per layer, Sholl intersections, and proximal passive current flow. Conditional dependence was critically important for the generation of realistic granule cell dendritic morphologies.

ROOTS: An Algorithm to Generate Biologically Realistic Cortical Axons and an Application to Electroceutical Modeling.

Advances in computation and neuronal modeling have enabled the study of entire neural tissue systems with an impressive degree of biological realism. These efforts have focused largely on modeling dendrites and somas while largely neglecting axons. The need for biologically realistic explicit axonal models is particularly clear for applications involving clinical and therapeutic electrical stimulation because axons are generally more excitable than other neuroanatomical subunits. While many modeling efforts can rely on existing repositories of reconstructed dendritic/somatic morphologies to study real cells or to estimate parameters for a generative model, such datasets for axons are scarce and incomplete. Those that do exist may still be insufficient to build accurate models because the increased geometric variability of axons demands a proportional increase in data. To address this need, a Ruled-Optimum Ordered Tree System (ROOTS) was developed that extends the capability of neuronal morphology generative methods to include highly branched cortical axon terminal arbors. Further, this study presents and explores a clear use-case for such models in the prediction of cortical tissue response to externally applied electric fields. The results presented herein comprise (i) a quantitative and qualitative analysis of the generative algorithm proposed, (ii) a comparison of generated fibers with those observed in histological studies, (iii) a study of the requisite spatial and morphological complexity of axonal arbors for accurate prediction of neuronal response to extracellular electrical stimulation, and (iv) an extracellular electrical stimulation strength-duration analysis to explore probable thresholds of excitation of the dentate perforant path under controlled conditions. ROOTS demonstrates a superior ability to capture biological realism in model fibers, allowing improved accuracy in predicting the impact that microscale structures and branching patterns have on spatiotemporal patterns of activity in the presence of extracellular electric fields.

Multi-Input, Multi-Output Neuronal Mode Network Approach to Modeling the Encoding Dynamics and Functional Connectivity of Neural Systems.

This letter proposes a novel method, multi-input, multi-output neuronal mode network (MIMO-NMN), for modeling encoding dynamics and functional connectivity in neural ensembles such as the hippocampus. Compared with conventional approaches such as the Volterra-Wiener model, linear-nonlinear-cascade (LNC) model, and generalized linear model (GLM), the NMN has several advantages in terms of estimation accuracy, model interpretation, and functional connectivity analysis. We point out the limitations of current neural spike modeling methods, especially the estimation biases caused by the imbalanced class problem when the number of zeros is significantly larger than ones in the spike data. We use synthetic data to test the performance of NMN with a comparison of the traditional methods, and the results indicate the NMN approach could reduce the imbalanced class problem and achieve better predictions. Subsequently, we apply the MIMO-NMN method to analyze data from the human hippocampus. The results indicate that the MIMO-NMN method is a promising approach to modeling neural dynamics and analyzing functional connectivity of multi-neuronal data.

Axonal Anatomy Optimizes Spatial Encoding in the Rat Entorhinal-Dentate System: A Computational Study.

OBJECTIVE: The network architecture connecting neural regions is defined by the organization and anatomical properties of the projecting axons, but its contributions to neural encoding and system function are difficult to study experimentally. METHODS: Using a large-scale, spiking neuronal network model of rat dentate gyrus, the role of the anatomy of the entorhinal-dentate axonal projection was evaluated in the context of spatial encoding by incorporating grid cell activity to provide physiological, spatially-correlated input. The dorso-ventral extents of the entorhinal axon terminal fields were varied to generate different feedforward architectures, and the resulting spatial representations and spatial information scores of the network were evaluated. Position was decoded from the population activity using a point process filter to investigate the contributions of network architecture on spatial encoding. RESULTS: The model predicted the emergence of anatomical gradients within the dentate gyrus for place field size and spatial information along its dorso-ventral axis, which were dependent on the extents of the entorhinal axon terminal fields. The decoding results revealed an optimal performance at an axon terminal field extent of 2 mm that lies within the biological range. CONCLUSION: The axonal anatomy mediates a tradeoff between encoding multiple place field sizes or achieving a high spatial information score, and the combination of both properties is necessary to maximize spatial encoding by a network. SIGNIFICANCE: In total, this paper establishes a mechanistic neuronal network model that, in concert with information-theoretic and statistical methods, can be used to investigate how lower level properties contribute to higher level function.

Pathogenic Processes Underlying Alzheimer's Disease: Modeling the Effects of Amyloid Beta on Synaptic Transmission.

The molecular mechanisms underlying Alzheimer's disease (AD) have been and are still under heavy scrutiny to better understand what leads to the onset and progression of the disease, and to design and develop efficacious therapeutic strategies. These decade-long studies have taught us a lot regarding the various molecular pathways involved in the pathology, but a complete dynamic picture of the underlying pathological mechanisms is still missing.We propose to provide a technological answer to fill this gap by developing and using a computational approach that integrates AD-related experimental findings and their effects on multiple aspects of neuronal function. The present study focuses on implementing one known pathogenic process: the binding of amyloid beta, the hallmark of AD, on NMDA receptors, receptors present in the main type of excitatory synapses in the brain, thereby affecting synaptic transmission and downstream pathways. We describe model implementation and calibration; we then quantify the downstream effects of this disruption both in terms of electrical activity (changes in short-term spiking activity of the postsynaptic neuron), and biochemical pathways activation through changes in calcium dynamics (an important trigger to longer-term changes). The computational approach outlined constitutes an insightful instrument to examine the downstream consequences of multiple pathogenic dysfunctions on higher level observables and sets the path for in-silico discovery and testing of therapeutic agents.

Network Activity Due to Topographic Organization of Schaffer Collaterals in a Large-Scale Model of Rat CA1.

Connectivity between neural regions, particularly in the hippocampus, is seldom all-to-all or random, yet it is the predominant method by which connectivity is implemented in most models of neuronal networks. We have been developing a computational platform for simulating the trisynaptic circuit of rat hippocampus with which we have constructed a large-scale, biologically-realistic, spiking neuronal network model of the entorhinal-dentate-CA3 system. Using the model, we had demonstrated a non-trivial effect of topographic connectivity on network dynamics and function. In this work, we detail the introduction of the CA1 subregion to the large-scale model. Using anatomical data, we constrained the distribution of axon collaterals, i.e., Schaffer collaterals, projected from CA3 to CA1 and preserved the topographic organization of the projections. Using a simplified multi-compartmental model of CA1 pyramidal cells and a single compartment model of CA1 parvalbumin basket cells, that were connected with disynaptic feedforward inhibition and feedback inhibition, we demonstrate the network activity of the CA1 network given a topographic organization of Schaffer collaterals. From this introduction of CA1 to the large-scale model, we can then observe the successive transformation of spatio-temporal, spiking neural activity as it propagates through the trisynaptic circuit.

Application of Parylene-Based Flexible Multi-Electrode Array for Recording From Subcortical Brain Regions From Behaving Rats.

Obtaining multiple single-unit recordings in particular neural networks from behaving animals is crucial for the understanding of cognitive functions of the brain. Attaining stable, chronic recordings from the brain is also the foundation to develop effective cortical prosthetic devices. However, severe immune response caused by micromotion between stiff implants and surrounding brain tissue often limits the lifetime of penetrating, neural recording devices. To reduce the stiffness mismatch between recording devices and brain tissue, we developed a flexible, polymer based multi-electrode array for recording single neuron activities from the rat hippocampus, a major subcortical structure of the rat brain. Parylene C, a biocompatible polymer, was used as the structural and insulation material of the multi-electrode array. 64 platinum (Pt) recording electrodes were placed in groups along each shank to conform to the anatomical distribution of hippocampal principle neurons. The multi-electrode array was chronically implanted in three animals. After recovery, neural activity together with movement traces were collected from the behaving animals.