Brain Waves Analysis Via a Non-Parametric Bayesian Mixture of Autoregressive Kernels.

The standard approach to analyzing brain electrical activity is to examine the spectral density function (SDF) and identify frequency bands, defined a priori, that have the most substantial relative contributions to the overall variance of the signal. However, a limitation of this approach is that the precise frequency and bandwidth of oscillations are not uniform across different cognitive demands. Thus, these bands should not be arbitrarily set in any analysis. To overcome this limitation, the Bayesian mixture auto-regressive decomposition (BMARD) method is proposed, as a data-driven approach that identifies (i) the number of prominent spectral peaks, (ii) the frequency peak locations, and (iii) their corresponding bandwidths (or spread of power around the peaks). Using the BMARD method, the standardized SDF is represented as a Dirichlet process mixture based on a kernel derived from second-order auto-regressive processes which completely characterize the location (peak) and scale (bandwidth) parameters. A Metropolis-Hastings within the Gibbs algorithm is developed for sampling the posterior distribution of the mixture parameters. Simulations demonstrate the robust performance of the proposed method. Finally, the BMARD method is applied to analyze local field potential (LFP) activity from the hippocampus of laboratory rats across different conditions in a non-spatial sequence memory experiment, to identify the most prominent frequency bands and examine the link between specific patterns of brain oscillatory activity and trial-specific cognitive demands.

Proximal CA1 20-40 Hz power dynamics reflect trial-specific information processing supporting nonspatial sequence memory.

The hippocampus is known to play a critical role in processing information about temporal context. However, it remains unclear how hippocampal oscillations are involved, and how their functional organization is influenced by connectivity gradients. We examined local field potential activity in CA1 as rats performed a nonspatial odor sequence memory task. We found that odor sequence processing epochs were characterized by distinct spectral profiles and proximodistal CA1 gradients of theta and 20-40 Hz power than track running epochs. We also discovered that 20-40 Hz power was predictive of sequence memory performance, particularly in proximal CA1 and during the plateau of high power observed in trials in which animals had to maintain their decision until instructed to respond. Altogether, these results provide evidence that dynamics of 20-40 Hz power along the CA1 axis are linked to trial-specific processing of nonspatial information critical to order judgments and are consistent with a role for 20-40 Hz power in gating information processing.

Hippocampal ensembles represent sequential relationships among an extended sequence of nonspatial events.

The hippocampus is critical to the temporal organization of our experiences. Although this fundamental capacity is conserved across modalities and species, its underlying neuronal mechanisms remain unclear. Here we recorded hippocampal activity as rats remembered an extended sequence of nonspatial events unfolding over several seconds, as in daily life episodes in humans. We then developed statistical machine learning methods to analyze the ensemble activity and discovered forms of sequential organization and coding important for order memory judgments. Specifically, we found that hippocampal ensembles provide significant temporal coding throughout nonspatial event sequences, differentiate distinct types of task-critical information sequentially within events, and exhibit theta-associated reactivation of the sequential relationships among events. We also demonstrate that nonspatial event representations are sequentially organized within individual theta cycles and precess across successive cycles. These findings suggest a fundamental function of the hippocampal network is to encode, preserve, and predict the sequential order of experiences.

Regularized matrix data clustering and its application to image analysis.

We propose a novel regularized mixture model for clustering matrix-valued data. The proposed method assumes a separable covariance structure for each cluster and imposes a sparsity structure (eg, low rankness, spatial sparsity) for the mean signal of each cluster. We formulate the problem as a finite mixture model of matrix-normal distributions with regularization terms, and then develop an expectation maximization type of algorithm for efficient computation. In theory, we show that the proposed estimators are strongly consistent for various choices of penalty functions. Simulation and two applications on brain signal studies confirm the excellent performance of the proposed method including a better prediction accuracy than the competitors and the scientific interpretability of the solution.

A Hierarchical Bayesian Model for Differential Connectivity in Multi-trial Brain Signals.

There is a strong interest in the neuroscience community to measure brain connectivity and develop methods that can differentiate connectivity across patient groups and across different experimental stimuli. The development of such statistical tools is critical to understand the dynamics of functional relationships among brain structures supporting memory encoding and retrieval. However, the challenge comes from the need to incorporate within-condition similarity with between-conditions heterogeneity in modeling connectivity, as well as how to provide a natural way to conduct trial- and condition-level inference on effective connectivity. A Bayesian hierarchical vector autoregressive (BH-VAR) model is proposed to characterize brain connectivity and infer differences in connectivity across conditions. Within-condition connectivity similarity and between-conditions connectivity heterogeneity are accounted for by the priors on trial-specific models. In addition to the fully Bayesian framework, an alternative two-stage computation approach is also proposed which still allows straightforward uncertainty quantification of between-trial conditions via MCMC posterior sampling, but provides a fast approximate procedure for the estimation of trial-specific VAR parameters. A novel aspect of the approach is the use of a frequency-specific measure, partial directed coherence (PDC), to characterize effective connectivity under the Bayesian framework. More specifically, PDC allows inferring directionality and explaining the extent to which the present oscillatory activity at a certain frequency in a sender channel influences the future oscillatory activity in a specific receiver channel relative to all possible receivers in the brain network. The proposed model is applied to a large electrophysiological dataset collected as rats performed a complex sequence memory task. This unique dataset includes local field potentials (LFPs) activity recorded from an array of electrodes across hippocampal region CA1 while animals were presented with multiple trials from two main conditions. The proposed modeling approach provided novel insights into hippocampal connectivity during memory performance. Specifically, it separated CA1 into two functional units, a lateral and a medial segment, each showing stronger functional connectivity to itself than to the other. This approach also revealed that information primarily flowed in a lateral-to-medial direction across trials (within-condition), and suggested this effect was stronger on one trial condition than the other (between-conditions effect). Collectively, these results indicate that the proposed model is a promising approach to quantify the variation of functional connectivity, both within- and between-conditions, and thus should have broad applications in neuroscience research.

Evolutionary State-Space Model and Its Application to Time-Frequency Analysis of Local Field Potentials.

We propose an evolutionary state space model (E-SSM) for analyzing high dimensional brain signals whose statistical properties evolve over the course of a non-spatial memory experiment. Under E-SSM, brain signals are modeled as mixtures of components (e.g., AR(2) process) with oscillatory activity at pre-defined frequency bands. To account for the potential non-stationarity of these components (since the brain responses could vary throughout the entire experiment), the parameters are allowed to vary over epochs. Compared with classical approaches such as independent component analysis and filtering, the proposed method accounts for the entire temporal correlation of the components and accommodates non-stationarity. For inference purpose, we propose a novel computational algorithm based upon using Kalman smoother, maximum likelihood and blocked resampling. The E-SSM model is applied to simulation studies and an application to a multi-epoch local field potentials (LFP) signal data collected from a non-spatial (olfactory) sequence memory task study. The results confirm that our method captures the evolution of the power for different components across different phases in the experiment and identifies clusters of electrodes that behave similarly with respect to the decomposition of different sources. These findings suggest that the activity of different electrodes does change over the course of an experiment in practice; treating these epoch recordings as realizations of an identical process could lead to misleading results. In summary, the proposed method underscores the importance of capturing the evolution in brain responses over the study period.

Flexible Bayesian Dynamic Modeling of Correlation and Covariance Matrices.

Modeling correlation (and covariance) matrices can be challenging due to the positive-definiteness constraint and potential high-dimensionality. Our approach is to decompose the covariance matrix into the correlation and variance matrices and propose a novel Bayesian framework based on modeling the correlations as products of unit vectors. By specifying a wide range of distributions on a sphere (e.g. the squared-Dirichlet distribution), the proposed approach induces flexible prior distributions for covariance matrices (that go beyond the commonly used inverse-Wishart prior). For modeling real-life spatio-temporal processes with complex dependence structures, we extend our method to dynamic cases and introduce unit-vector Gaussian process priors in order to capture the evolution of correlation among components of a multivariate time series. To handle the intractability of the resulting posterior, we introduce the adaptive Δ-Spherical Hamiltonian Monte Carlo. We demonstrate the validity and flexibility of our proposed framework in a simulation study of periodic processes and an analysis of rat's local field potential activity in a complex sequence memory task.

The hippocampus, prefrontal cortex, and perirhinal cortex are critical to incidental order memory.

Considerable research in rodents and humans indicates the hippocampus and prefrontal cortex are essential for remembering temporal relationships among stimuli, and accumulating evidence suggests the perirhinal cortex may also be involved. However, experimental parameters differ substantially across studies, which limits our ability to fully understand the fundamental contributions of these structures. In fact, previous studies vary in the type of temporal memory they emphasize (e.g., order, sequence, or separation in time), the stimuli and responses they use (e.g., trial-unique or repeated sequences, and incidental or rewarded behavior), and the degree to which they control for potential confounding factors (e.g., primary and recency effects, or order memory deficits secondary to item memory impairments). To help integrate these findings, we developed a new paradigm testing incidental memory for trial-unique series of events, and concurrently assessed order and item memory in animals with damage to the hippocampus, prefrontal cortex, or perirhinal cortex. We found that this new approach led to robust order and item memory, and that hippocampal, prefrontal and perirhinal damage selectively impaired order memory. These findings suggest the hippocampus, prefrontal cortex and perirhinal cortex are part of a broad network of structures essential for incidentally learning the order of events in episodic memory.

Nonspatial sequence coding varies along the CA1 transverse axis.

The hippocampus plays a critical role in the memory for sequences of events, a defining feature of episodic memory. To shed light on the fundamental mechanisms supporting this capacity, we recently recorded neural activity in CA1 as rats performed a nonspatial odor sequence memory task. Our main finding was that, while the animals' location and behavior remained constant, a proportion of CA1 neurons fired differentially to odors depending on whether they were presented in or out of sequence (sequence cells). Here, we further examined if such sequence coding varied along the distal-to-proximal axis of the dorsal CA1 region (distal: toward subiculum; proximal: toward CA3). Differences in information processing along this axis have been suggested by recent anatomical and electrophysiological evidence that odor information may be more strongly represented in the distal segment, whereas spatial information may be more strongly represented in the proximal segment. Recorded neurons were grouped into four arbitrary sections of dorsal CA1, ranging from distal to proximal. We found that, although sequence cell coding was observed across the distal-to-proximal extent of CA1 from which we recorded, it was significantly higher in intermediate CA1, a region with more balanced anatomical input from lateral and medial entorhinal regions. More specifically, in that particular segment of CA1, we observed a significant increase in the magnitude of sequence coding of all cells, as well as in the sequential information content of sequence cells. Importantly, a different pattern was observed when examining the distribution of spatial coding from the same electrodes. Consistent with previous reports, our results suggest that spatial information was more strongly represented in the proximal section of CA1 (higher proportion of cells with place fields). These findings indicate that nonspatial sequence memory coding is not uniformly distributed along the transverse axis of CA1, and that this distribution does not simply follow the expected gradient based on the stimulus modality or the degree of spatial selectivity. Instead, the observed distribution suggests this form of sequence coding may be associated with convergent input from lateral and medial entorhinal regions, which is present throughout the proximodistal axis but greater in intermediate CA1.

Nonspatial Sequence Coding in CA1 Neurons.

The hippocampus is critical to the memory for sequences of events, a defining feature of episodic memory. However, the fundamental neuronal mechanisms underlying this capacity remain elusive. While considerable research indicates hippocampal neurons can represent sequences of locations, direct evidence of coding for the memory of sequential relationships among nonspatial events remains lacking. To address this important issue, we recorded neural activity in CA1 as rats performed a hippocampus-dependent sequence-memory task. Briefly, the task involves the presentation of repeated sequences of odors at a single port and requires rats to identify each item as "in sequence" or "out of sequence". We report that, while the animals' location and behavior remained constant, hippocampal activity differed depending on the temporal context of items-in this case, whether they were presented in or out of sequence. Some neurons showed this effect across items or sequence positions (general sequence cells), while others exhibited selectivity for specific conjunctions of item and sequence position information (conjunctive sequence cells) or for specific probe types (probe-specific sequence cells). We also found that the temporal context of individual trials could be accurately decoded from the activity of neuronal ensembles, that sequence coding at the single-cell and ensemble level was linked to sequence memory performance, and that slow-gamma oscillations (20-40 Hz) were more strongly modulated by temporal context and performance than theta oscillations (4-12 Hz). These findings provide compelling evidence that sequence coding extends beyond the domain of spatial trajectories and is thus a fundamental function of the hippocampus. SIGNIFICANCE STATEMENT: The ability to remember the order of life events depends on the hippocampus, but the underlying neural mechanisms remain poorly understood. Here we addressed this issue by recording neural activity in hippocampal region CA1 while rats performed a nonspatial sequence memory task. We found that hippocampal neurons code for the temporal context of items (whether odors were presented in the correct or incorrect sequential position) and that this activity is linked with memory performance. The discovery of this novel form of temporal coding in hippocampal neurons advances our fundamental understanding of the neurobiology of episodic memory and will serve as a foundation for our cross-species, multitechnique approach aimed at elucidating the neural mechanisms underlying memory impairments in aging and dementia.

Memory for sequences of events impaired in typical aging.

Typical aging is associated with diminished episodic memory performance. To improve our understanding of the fundamental mechanisms underlying this age-related memory deficit, we previously developed an integrated, cross-species approach to link converging evidence from human and animal research. This novel approach focuses on the ability to remember sequences of events, an important feature of episodic memory. Unlike existing paradigms, this task is nonspatial, nonverbal, and can be used to isolate different cognitive processes that may be differentially affected in aging. Here, we used this task to make a comprehensive comparison of sequence memory performance between younger (18-22 yr) and older adults (62-86 yr). Specifically, participants viewed repeated sequences of six colored, fractal images and indicated whether each item was presented "in sequence" or "out of sequence." Several out of sequence probe trials were used to provide a detailed assessment of sequence memory, including: (i) repeating an item from earlier in the sequence ("Repeats"; e.g., AB A: DEF), (ii) skipping ahead in the sequence ("Skips"; e.g., AB D: DEF), and (iii) inserting an item from a different sequence into the same ordinal position ("Ordinal Transfers"; e.g., AB 3: DEF). We found that older adults performed as well as younger controls when tested on well-known and predictable sequences, but were severely impaired when tested using novel sequences. Importantly, overall sequence memory performance in older adults steadily declined with age, a decline not detected with other measures (RAVLT or BPS-O). We further characterized this deficit by showing that performance of older adults was severely impaired on specific probe trials that required detailed knowledge of the sequence (Skips and Ordinal Transfers), and was associated with a shift in their underlying mnemonic representation of the sequences. Collectively, these findings provide unambiguous evidence that the capacity to remember sequences of events is fundamentally affected by typical aging.

A Sequence of events model of episodic memory shows parallels in rats and humans.

A critical feature of episodic memory is the ability to remember the order of events as they occurred in time, a capacity shared across species including humans, nonhuman primates, and rodents. Accumulating evidence suggests that this capacity depends on a network of structures including the hippocampus and the prefrontal cortex, but their respective contributions remain poorly understood. As addressing this important issue will require converging evidence from complementary investigative techniques, we developed a cross-species, nonspatial sequence memory task suitable for behavioral and neurophysiological studies in rodents and in humans. The task involves the repeated presentation of sequences of items (odors in rats and images in humans) and requires subjects to make a judgment as to whether each item is presented "in sequence" or "out of sequence." To shed light on the cognitive processes and sequence representations supporting performance, different types of "out of sequence" probe trials were used including: (i) repeating an item from earlier in the sequence (Repeats; e.g., ABAD), (ii) skipping ahead in the sequence (Skips; e.g., ABD), and (iii) inserting an item from a different sequence into the same ordinal position (Ordinal Transfers; e.g., A2CD). We found a remarkable similarity in the performance of rats and humans, particularly in the pattern of results across probe trial types. Thus, the results suggest that rats and humans not only remember the sequences of events, but also use similar underlying cognitive processes and mnemonic representations. This strong cross-species correspondence validates this task for use in future basic and clinical interdisciplinary studies aimed at examining the neural mechanisms underlying episodic memory.

Critical role of the hippocampus in memory for elapsed time.

Episodic memory includes information about how long ago specific events occurred. Since most of our experiences have overlapping elements, remembering this temporal context is crucial for distinguishing individual episodes. The discovery of timing signals in hippocampal neurons, including evidence of "time cells" and of gradual changes in ensemble activity over long timescales, strongly suggests that the hippocampus is important for this capacity. However, behavioral evidence that the hippocampus is critical for the memory of elapsed time is lacking. This is possibly because previous studies have used time durations in the range of seconds when assessing hippocampal dependence, a timescale known to require corticostriatal circuits. Here we developed a nonspatial paradigm to test the hypothesis that the hippocampus is critical for keeping track of elapsed time over several minutes. We report that rats have a robust ability to remember durations at this timescale. We then determined the role of the hippocampus using infusions of fluorophore-conjugated muscimol, a GABAA agonist. We found that the hippocampus was essential for discriminating smaller, but not larger, temporal differences (measured in log units), consistent with a role in temporal pattern separation. Importantly, this effect was observed at long (minutes) but not short (seconds) timescales, suggesting an interplay of temporal resolution and timescale in determining hippocampal dependence. These results offer compelling evidence that the hippocampus plays a critical role in remembering how long ago events occurred.

The evolution of episodic memory.

One prominent view holds that episodic memory emerged recently in humans and lacks a "(neo)Darwinian evolution" [Tulving E (2002) Annu Rev Psychol 53:1-25]. Here, we review evidence supporting the alternative perspective that episodic memory has a long evolutionary history. We show that fundamental features of episodic memory capacity are present in mammals and birds and that the major brain regions responsible for episodic memory in humans have anatomical and functional homologs in other species. We propose that episodic memory capacity depends on a fundamental neural circuit that is similar across mammalian and avian species, suggesting that protoepisodic memory systems exist across amniotes and, possibly, all vertebrates. The implication is that episodic memory in diverse species may primarily be due to a shared underlying neural ancestry, rather than the result of evolutionary convergence. We also discuss potential advantages that episodic memory may offer, as well as species-specific divergences that have developed on top of the fundamental episodic memory architecture. We conclude by identifying possible time points for the emergence of episodic memory in evolution, to help guide further research in this area.

A preclinical cognitive test battery to parallel the National Institute of Health Toolbox in humans: bridging the translational gap.

A major goal of animal research is to identify interventions that can promote successful aging and delay or reverse age-related cognitive decline in humans. Recent advances in standardizing cognitive assessment tools for humans have the potential to bring preclinical work closer to human research in aging and Alzheimer's disease. The National Institute of Health (NIH) has led an initiative to develop a comprehensive Toolbox for Neurologic Behavioral Function (NIH Toolbox) to evaluate cognitive, motor, sensory and emotional function for use in epidemiologic and clinical studies spanning 3 to 85 years of age. This paper aims to analyze the strengths and limitations of animal behavioral tests that can be used to parallel those in the NIH Toolbox. We conclude that there are several paradigms available to define a preclinical battery that parallels the NIH Toolbox. We also suggest areas in which new tests may benefit the development of a comprehensive preclinical test battery for assessment of cognitive function in animal models of aging and Alzheimer's disease.

Recognition memory for social and non-social odors: differential effects of neurotoxic lesions to the hippocampus and perirhinal cortex.

The contributions of the hippocampus (HC) and perirhinal cortex (PER) to recognition memory are currently topics of debate in neuroscience. Here we used a rapidly-learned (seconds) spontaneous novel odor recognition paradigm to assess the effects of pre-training N-methyl-D-aspartate lesions to the HC or PER on odor recognition memory. We tested memory for both social and non-social odor stimuli. Social odors were acquired from conspecifics, while non-social odors were household spices. Conspecific odor stimuli are ethologically-relevant and have a high degree of overlapping features compared to non-social household spices. Various retention intervals (5 min, 20 min, 1h, 24h, or 48 h) were used between study and test phases, each with a unique odor pair, to assess changes in novelty preference over time. Consistent with findings in other paradigms, modalities, and species, we found that HC lesions yielded no significant recognition memory deficits. In contrast, PER lesions caused significant deficits for social odor recognition memory at long retention intervals, demonstrating a critical role for PER in long-term memory for social odors. PER lesions had no effect on memory for non-social odors. The results are consistent with a general role for PER in long-term recognition memory for stimuli that have a high degree of overlapping features, which must be distinguished by conjunctive representations.

The neurobiology of memory based predictions.

Recent findings indicate that, in humans, the hippocampal memory system is involved in the capacity to imagine the future as well as remember the past. Other studies have suggested that animals may also have the capacity to recall the past and plan for the future. Here, we will consider data that bridge between these sets of findings by assessing the role of the hippocampus in memory and prediction in rats. We will argue that animals have the capacity for recollection and that the hippocampus plays a central and selective role in binding information in the service of recollective memory. Then we will consider examples of transitive inference, a paradigm that requires the integration of overlapping memories and flexible use of the resulting relational memory networks for generating predictions in novel situations. Our data show that animals have the capacity for transitive inference and that the hippocampus plays a central role in the ability to predict outcomes of events that have not yet occurred.

Cognitive aging: a common decline of episodic recollection and spatial memory in rats.

In humans, recognition memory declines with aging, and this impairment is characterized by a selective loss in recollection of previously studied items contrasted with relative sparing of familiarity for items in the study list. Rodent models of cognitive aging have focused on water maze learning and have demonstrated an age-associated loss in spatial, but not cued memory. The current study examined odor recognition memory in young and aged rats and compared performance in recognition with that in water maze learning. In the recognition task, young rats used both recollection and familiarity. In contrast, the aged rats showed a selective loss of recollection and relative sparing of familiarity, similar to the effects of hippocampal damage. Furthermore, performance on the recall component, but not the familiarity component, of recognition was correlated with spatial memory and recollection was poorer in aged rats that were also impaired in spatial memory. These results extend the pattern of impairment in recollection and relative sparing of familiarity observed in human cognitive aging to rats, and suggest a common age-related impairment in both spatial learning and the recollective component of nonspatial recognition memory.