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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. [ABSTRACT FROM AUTHOR]

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-tomoderate 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. [ABSTRACT FROM AUTHOR]

In order to build hippocampal prostheses for restoring memory functions, we build sparse multi-input, multi-output (MIMO) nonlinear dynamical models of the human hippocampus. Spike trains are recorded from hippocampal CA3 and CA1 regions of epileptic patients performing a variety of memory-dependent delayed match-to-sample (DMS) tasks. Using CA3 and CA1 spike trains as inputs and outputs respectively, sparse generalized Laguerre-Volterra models are estimated with group lasso and local coordinate descent methods to capture the nonlinear dynamics underlying the CA3-CA1 spike train transformations. These models can accurately predict the CA1 spike trains based on the ongoing CA3 spike trains during multiple memory events, e.g., sample presentation, sample response, match presentation and match response, of the DMS task, and thus will serve as the computational basis of human hippocampal memory prostheses. [ABSTRACT FROM PUBLISHER]

This letter examines the results of input-output (nonparametric) modeling based on the analysis of data generated by a mechanism-based (parametric) model of CA3-CA1 neuronal connections in the hippocampus. The motivation is to obtain biological insight into the interpretation of such input-output (Volterra-equivalent) models estimated from synthetic data. The insights obtained may be subsequently used to interpretat input-output models extracted from actual experimental data. Specifically, we found that a simplified parametric model may serve as a useful tool to study the signal transformations in the hippocampal CA3-CA1 regions. Input-output modeling of model-based synthetic data show that GABAergic interneurons are responsible for regulating neuronal excitation, controlling the precision of spike timing, and maintaining network oscillations, in a manner consistent with previous studies. The input-output model obtained from real data exhibits intriguing similarities with its synthetic-data counterpart, demonstrating the importance of a dynamic resonance in the system/model response around 2 Hz to 3 Hz. Using the input-output model from real data as a guide, we may be able to amend the parametric model by incorporating more mechanisms in order to yield better-matching input-output model. The approach we present can also be applied to the study of other neural systems and pathways. [ABSTRACT FROM AUTHOR]

Fractality, represented as self-similar repeating patterns, is ubiquitous in nature and the brain. Dynamic patterns of hippocampal spike trains are known to exhibit multifractal properties during working memory processing; however, it is unclear whether the multifractal properties inherent to hippocampal spike trains reflect active cognitive processing. To examine this possibility, hippocampal neuronal ensembles were recorded from rats before, during and after a spatial working memory task following administration of tetrahydrocannabinol (THC), a memory-impairing component of cannabis. Multifractal detrended fluctuation analysis was performed on hippocampal interspike interval sequences to determine characteristics of monofractal long-range temporal correlations (LRTCs), quantified by the Hurst exponent, and the degree/magnitude of multifractal complexity, quantified by the width of the singularity spectrum. Our results demonstrate that multifractal firing patterns of hippocampal spike trains are a marker of functional memory processing, as they are more complex during the working memory task and significantly reduced following administration of memory impairing THC doses. Conversely, LRTCs are largest during resting state recordings, therefore reflecting different information compared to multifractality. In order to deepen conceptual understanding of multifractal complexity and LRTCs, these measures were compared to classical methods using hippocampal frequency content and firing variability measures. These results showed that LRTCs, multifractality, and theta rhythm represent independent processes, while delta rhythm correlated with multifractality. Taken together, these results provide a novel perspective on memory function by demonstrating that the multifractal nature of spike trains reflects hippocampal microcircuit activity that can be used to detect and quantify cognitive, physiological, and pathological states. [ABSTRACT FROM AUTHOR]

A major factor involved in providing closed loop feedback for control of neural function is to understand how neural ensembles encode online information critical to the final behavioral endpoint. This issue was directly assessed in rats performing a short-term delay memory task in which successful encoding of task information is dependent upon specific spatio-temporal firing patterns recorded from ensembles of CA3 and CA1 hippocampal neurons. Such patterns, extracted by a specially designed nonlinear multi-input multi-output (MIMO) nonlinear mathematical model, were used to predict successful performance online via a closed loop paradigm which regulated trial difficulty (time of retention) as a function of the “strength” of stimulus encoding. The significance of the MIMO model as a neural prosthesis has been demonstrated by substituting trains of electrical stimulation pulses to mimic these same ensemble firing patterns. This feature was used repeatedly to vary “normal” encoding as a means of understanding how neural ensembles can be “tuned” to mimic the inherent process of selecting codes of different strength and functional specificity. The capacity to enhance and tune hippocampal encoding via MIMO model detection and insertion of critical ensemble firing patterns shown here provides the basis for possible extension to other disrupted brain circuitry. [ABSTRACT FROM PUBLISHER]

The successful development of neural prostheses requires an understanding of the neurobiological bases of cognitive processes, i.e., how the collective activity of populations of neurons results in a higher level process not predictable based on knowledge of the individual neurons and/or synapses alone. We have been studying and applying novel methods for representing nonlinear transformations of multiple spike train inputs (multiple time series of pulse train inputs) produced by synaptic and field interactions among multiple subclasses of neurons arrayed in multiple layers of incompletely connected units. We have been applying our methods to study of the hippocampus, a cortical brain structure that has been demonstrated, in humans and in animals, to perform the cognitive function of encoding new long-term (declarative) memories. Without their hippocampi, animals and humans retain a short-term memory (memory lasting approximately 1 min), and long-term memory for information learned prior to loss of hippocampal function. Results of more than 20 years of studies have demonstrated that both individual hippocampal neurons, and populations of hippocampal cells, e.g., the neurons comprising one of the three principal subsystems of the hippocampus, induce strong, higher order, nonlinear transformations of hippocampal inputs into hippocampal outputs. For one synaptic input or for a population of synchronously active synaptic inputs, such a transformation is represented by a sequence of action potential inputs being changed into a different sequence of action potential outputs. In other words, an incoming temporal pattern is transformed into a different, outgoing temporal pattern. For multiple, asynchronous synaptic inputs, such a transformation is represented by a spatiotemporal pattern of action potential inputs being changed into a different spatiotemporal pattern of action potential outputs. Our primary thesis is that the encoding of short-term memories into new, long-term memories represents the collective set of nonlinearities induced by the three or four principal subsystems of the hippocampus, i.e., entorhinal cortex-to-dentate gyrus, dentate gyrus-to-CA3 pyramidal cell region, CA3-to-CA1 pyramidal cell region, and CA1-to-subicular cortex. This hypothesis will be supported by studies using in vivo hippocampal multineuron recordings from animals performing memory tasks that require hippocampal function. The implications for this hypothesis will be discussed in the context of "cognitive prostheses"--neural prostheses for cortical brain regions believed to support cognitive functions, and that often are subject to damage due to stroke, epilepsy, dementia, and closed head trauma. [ABSTRACT FROM AUTHOR]

A modeling approach to characterize the nonlinear dynamic transformations of the dentate gyrus of the hippocampus is presented and experimentally validated. The dentate gyrus is the first region of the hippocampus which receives and integrates sensory information via the perforant path. The perforant path is composed of two distinct pathways: 1) the lateral path and 2) the medial perforant path. The proposed approach examines and captures the short-term dynamic characteristics of these two pathways using a nonparametric, third-order Poisson-Volterra model. The nonlinear characteristics of the two pathways are represented by Poisson-Volterra kernels, which are quantitative descriptors of the nonlinear dynamic transformations. The kernels were computed with experimental data from in vitro hippocampal slices. The electrophysiological activity was measured with custom-made multielectrode arrays, which allowed selective stimulation with random impulse trains and simultaneous recordings of extracellular field potential activity. The results demonstrate that this mathematically rigorous approach is suitable for the multipathway complexity of the hippocampus and yields interpretable models that have excellent predictive capabilities. The resulting models not only accurately predict previously reported electrophysiological descriptors, such as paired pulses, but more important, can be used to predict the electrophysiological activity of dentate granule cells to arbitrary stimulation patterns at the perforant path. [ABSTRACT FROM AUTHOR]

One of the fundamental principles of cortical brain regions, including the hippocampus, is that information is represented in the ensemble firing of populations of neurons, i.e., spatio-temporal patterns of electrophysiological activity. The hippocampus has long been known to be responsible for the formation of declarative, or fact-based, memories. Damage to the hippocampus disrupts the propagation of spatio-temporal patterns of activity through hippocampal internal circuitry, resulting in a severe anterograde amnesia. Developing a neural prosthesis for the damaged hippocampus requires restoring this multiple-input, multiple-output transformation of spatio-temporal patterns of activity. Because the, mechanisms underlying synaptic transmission and generation of electrical activity in neurons are inherently nonlinear, any such prosthesis must be based on a nonlinear multiple-input, multiple-output model. In this paper, we have formulated the transformational process of multi-site propagation of spike activity between two subregions of the hippocampus (CA3 and CA1) as the identification of a multiple-input, multiple-output (MIMO) system, and proposed that it can be decomposed into a series of multiple-input, single-output (MISO) systems. Each MISO system is modeled as a physiologically plausible structure that consists of 1) linear/nonlinear feedforward Volterra kernels modeling synaptic transmission and dendritic integration, 2) a linear feedback Volterra kernel modeling spike-triggered after-potentials, 3) a threshold for spike generation, 4) a summation process for somatic integration, and 5) a noise term representing intrinsic neuronal noise and the contributions of unobserved inputs. Input and output spike trains were recorded from hippocampal CA3 and CA1 regions of rats performing a spatial delayed-nonmatch-to-sample memory task that requires normal hippocampal function. Kernels were expanded with Laguerre basis functions and estimated using a maximum-likelihood method. Complexity of the feedforward kernel was progressively increased to capture higher-order system nonlinear dynamics. Results showed higher prediction accuracies as kernel complexity increased. Self-kernels describe the nonlinearities within each input. Cross-kernels capture the nonlinear interaction between inputs. Second- and third-order nonlinear models were found to successfully predict the CA1 output spike distribution based on CA3 input spike trains. First-order, linear models were shown to be insufficient. [ABSTRACT FROM AUTHOR]

Abstract: Developing a neural prosthesis for the damaged hippocampus requires restoring the transformation of population neural activities performed by the hippocampal circuitry. To bypass a damaged region, output spike trains need to be predicted from the input spike trains and then reinstated through stimulation. We formulate a multiple-input, multiple-output (MIMO) nonlinear dynamic model for the input–output transformation of spike trains. In this approach, a MIMO model comprises a series of physiologically-plausible multiple-input, single-output (MISO) neuron models that consist of five components each: (1) feedforward Volterra kernels transforming the input spike trains into the synaptic potential, (2) a feedback kernel transforming the output spikes into the spike-triggered after-potential, (3) a noise term capturing the system uncertainty, (4) an adder generating the pre-threshold potential, and (5) a threshold function generating output spikes. It is shown that this model is equivalent to a generalized linear model with a probit link function. To reduce model complexity and avoid overfitting, statistical model selection and cross-validation methods are employed to choose the significant inputs and interactions between inputs. The model is applied successfully to the hippocampal CA3–CA1 population dynamics. Such a model can serve as a computational basis for the development of hippocampal prostheses. [Copyright &y& Elsevier]

Very productive collaborative investigations characterized how multineuron hippocampal ensembles recorded in nonhuman primates (NHPs) encode short-term memory necessary for successful performance in a delayed match to sample (DMS) task and utilized that information to devise a unique nonlinear multi-input multi-output (MIMO) memory prosthesis device to enhance short-term memory in real-time during task performance. Investigations have characterized how the hippocampus in primate brain encodes information in a multi-item, rule-controlled, delayed match to sample (DMS) task. The MIMO model was applied via closed loop feedback micro-current stimulation during the task via conformal electrode arrays and enhanced performance of the complex memory requirements. These findings clearly indicate detection of a means by which the hippocampus encodes information and transmits this information to other brain regions involved in memory processing. By employing the nonlinear dynamic multi-input/multi-output (MIMO) model, developed and adapted to hippocampal neural ensemble firing patterns derived from simultaneous recorded multi-neuron CA1 and CA3 activity, it was possible to extract information encoded in the Sample phase of DMS trials that was necessary for successful performance in the subsequent Match phase of the task. The extension of this MIMO model to online delivery of electrical stimulation patterns to the same recording loci that exhibited successful CA1 firing in the DMS Sample Phase provided the means to increase task performance on a trial-by-trial basis. Increased utility of the MIMO model as a memory prosthesis was exhibited by the demonstration of cumulative increases in DMS task performance with repeated MIMO stimulation over many sessions. These results, reported below in this article, provide the necessary demonstrations to further the feasibility of the MIMO model as a memory prosthesis to recover and/or enhance encoding of cognitive information in humans with memory disruptions resulting from brain injury, disease or aging. [ABSTRACT FROM AUTHOR]