NIH - Understanding and Modifying Temporal Dynamics of Coordinated Neural Activity (R01, R21)

The following description was taken from the R01 version of this FOA.

The purpose of this FOA is to lay the groundwork for developing systems-level neuroscience interventions into treatments for cognitive, affective, or social deficits in psychiatric disorders. A rich body of knowledge exists regarding the systems-level coordination of temporal patterns of electrophysiological activity in the brain. One key principle that has emerged from basic systems-level neuroscience is that brain rhythms appear to be necessary for normal cognition, including phase-amplitude coupling of slow and fast rhythms, spike-phase correlations such as hippocampal theta precession, and the re-activation of previously experienced neural activity on specific oscillatory frequencies. On the clinical side, cognitive symptoms in particular are among the least tractable and most disabling problems across a wide range of brain disorders, including autism and schizophrenia, because they affect the ability to live independently, such as holding a job and managing a bank account. Almost none of the existing treatments for neuropsychiatric illnesses were developed for the purpose of modulating systems-level coordination of neural activity, yet this is the level at which brain processes such as attention, memory, and social processing emerge. Even for medications that are based on a rational understanding of single-gene disorders, such as Fragile X, Rett, or Angelman syndromes, it has been surprisingly difficult to ameliorate cognitive, affective, or social symptoms in patients with these disorders. However, these medications act at the molecular level, and they might not have a useful effect at the systems level. Therefore, it might be advantageous and even necessary to begin to address cognitive, affective, and social domains of function with a greater consideration of the systems-level electrophysiological patterns, and to test whether modulating these patterns can improve function. The key idea is to evaluate any intervention, whether pharmacological or not, at the systems level rather than exclusively at the molecular level. Evaluating interventions at the systems level might be helpful regardless of whether the interventions themselves are at the genetic, molecular, or cellular level via pharmacology or gene editing, or whether the intervention is at the systems level such as electrical or magnetic stimulation. The purpose of this FOA is to seek applications that use active manipulations to address at least one, and ideally more, of the following points: (1) in animals or humans, determine which parameters of neural coordination, when manipulated in isolation, improve particular aspects of cognitive, affective, or social processing; (2) in animals or humans, determine how particular abnormalities at the cellular or molecular level, such as specific receptor dysfunction, affect the coordination of electrophysiological patterns during behavior; (3) determine whether in vivo, systems-level electrophysiological changes in behaving animals predict analogous electrophysiological and cognitive improvements in normal humans or clinical populations; and (4) use systems-level computational modeling to develop a principled understanding of the function and mechanisms by which oscillatory and other electrophysiological patterns unfold across the brain (cortically and subcortically) to impact cognitive, affective, or social processing.

Background

Cognition appears to emerge at the level of populations of neurons, with information represented and organized as action potentials and network events that are temporally coordinated across brain areas. For example, there have been notable advances in our basic understanding of the role of local field potential (LFP) oscillations and large-scale coordination of neural networks in learning and memory. In rodents, particular patterns of temporal dynamics have been shown to proportionally improve or worsen working memory, and particular LFP oscillatory bands predict episodic/relational learning. Theta phase precession is another well-known precise temporal code that might be required for optimal cognition, and the precise reactivation of neural activity during hippocampal sharp wave ripples is also a temporally coordinated representation that might be necessary for memory consolidation or decision making.

From a disease standpoint, electrophysiological aberrations exist in many brain disorders, and recent findings suggest that modulating electrophysiological patterns could potentially have therapeutic benefit. In schizophrenia, findings have suggested that systems-level electrophysiological endophenotypes are modifiable and that such modifications have the potential to improve cognition. In autism, the modest amounts of electrophysiological data that exist in patients and model organisms suggest that this disorder also has disruptions in temporal coordination of neural signals, and that electrophysiological patterns at the level of neural populations might represent an intermediate, modifiable phenotype. Furthermore, rationally-developed pharmacological interventions are being tested for autism spectrum disorders, whose effect on temporal dynamics of electrophysiological patterns might be instructive to examine, especially if the treatments are directed at the cognitive impairments that lead to significant functional deficits for some patients.

These basic and translational findings should be expanded to better understand the brain algorithms that implement learning, memory consolidation, attention, reasoning, affect regulation, and social interactions. The patterns of neural coordination can also be brought to bear on areas of translation such as pre-clinical target validation studies in animals or, in humans, as treatment effectiveness biomarkers or as stratification variables. Work in non-human primates is also highly encouraged, as it would provide a bridge between rodent and human work with regard to neuroanatomy and cognitive capabilities.

The underlying premise of this funding opportunity is that cognitive, affective, and social dysfunction may result in part from compromised systems-level electrophysiological patterns; that these patterns are necessary for normal brain function; and therefore, treatments whose goal is to improve these domains of function might be more effective if they improve the underlying aberrant electrophysiological patterns.

Research Objectives

Applications should address at least one, and ideally more, of the following topic areas:

Topic 1: Temporal dynamics of neural patterns that impact cognition, affect, or social behavior. In animals or humans, determine which aspects of temporal coordination of systems-level neural activity affect particular domains of function such as working memory, long-term memory, relational/spatial processing, attention, cognitive control, decision making, affect regulation, or social cognition. Projects should manipulate specific aspects of the electrophysiological patterns (e.g., the power of oscillatory frequencies during particular task periods, or the degree of phase-amplitude coupling of particular frequency pairs) to determine what parameters, if manipulated appropriately, might yield the most robust and reliable improvements in behavior. Active manipulations proposed in grant applications that address Topic 1 can consist of electrical or magnetic brain stimulation, optogenetics, pharmacological compounds including novel or existing medications if well justified, or other modalities. Novel interventions are encouraged if they might provide greater temporal and/or spatial resolution. It is expected that applications provide a strong scientific rationale for the specific biological intervention chosen, and why it is expected to selectively alter electrophysiological measures in a particular direction. All projects should include measures of neural activity at the systems level during awake behavior.
Topic 2: Understanding how molecular aberrations lead to systems-level discoordination. In animals or humans, understand how particular abnormalities at the cellular or molecular level, such as glutamate or GABA receptor dysfunction, affect the coordination of electrophysiological patterns during cognitive, affective, or social processing. Single-gene disorders in particular, such as Fragile X or Rett syndromes, might be a good opportunity to study such mechanistic questions in the context of systems level dynamics, but the case can also be made for neuropsychiatric disorders of more heterogeneous etiology. The emphasis can be on discovering ways to rescue the systems-level discoordination with either molecular/cellular interventions (e.g., pharmacology, genomic interventions), or with neurophysiology manipulations such as patterned electrical or optogenetic stimulation. The outcomes should be measured at both the systems electrophysiology level and at the behavioral level.
Topic 3: Animal-to-human translation. Determine whether the changes in neural coordination patterns that improve cognition in animals predict analogous electrophysiological and cognitive improvements in normal humans and/or clinical populations. A key goal is to understand the translational value of systems electrophysiology in pre-clinical models, to know whether an electrophysiological pattern identified in a relevant model system is predictive of a similarly aberrant pattern in patients, and whether the effects of any interventions in animals are predictive of their effects in humans. Another goal is to characterize aberrant electrophysiological patterns during cognition in clinical patients, although electrophysiological recordings in humans, if it does not have an active intervention, should be accompanied by parallel work in animals that includes active interventions. It is expected that, to the greatest extent possible, identical interventions (e.g., the same pharmacological compounds, or comparably patterned electrical stimulation in model animals and humans) and tasks (e.g., equivalent working memory tasks) will be used. A related question of interest is whether any existing or novel medications are able to modify neural coordination patterns, and whether this mediates any improvement in cognition, affect, or social interaction.
Topic 4: Computational modeling. Develop a biologically realistic computational model to allow a principled understanding of the algorithms and mechanisms by which neural coordination patterns across brain areas affect cognitive, affective, and social processing. The computational models can cross levels, such as from the biophysical level to systems-level emergent properties, and they can also be top-down, such as mathematically describing and manipulating higher-order parameters of oscillatory coordination in relation to information processing and behavioral output. Projects that address the topic of computational modeling should also include work in animals or in humans, provide testable predictions, and be closely informed by the results.

There are two goals with this Topic. One goal is to reach a mechanistic understanding of how rhythmic patterns support information processing in the brain in the service of cognitive, affective, and social processing, and, relatedly, what algorithms are being implemented in the brain for each type of processing, including, but not limited to, spatial navigation, non-spatial relational processing (e.g., transitive inference), manipulation of items in working memory, social interaction, emotion regulation, decision making, and other cognitive domains of function. A second goal is to understand how modifying a neural pattern in one region of the network affects the patterns in other brain regions. This work can include modeling how brain stimulation at the scalp might affect oscillations and information processing subcortically (e.g., in the hippocampus), or in other cortical areas. The purpose of this is to understand network-level ramifications of local changes in oscillatory dynamics. Applications can address one or more of these goals.

Examples of research topics include, but are not limited to:

An example of Topic 1 would be to conduct electrophysiological recordings in an animal relevant to neuropsychiatric disease during a spatial working memory task and to determine what systems-level aspects of the electrophysiological patterns could be modified to improve task behavior. The goal could be, for example, to examine whether theta precession, phase-amplitude coupling, sharp-wave ripples, or other neural patterns are aberrant. Are there particular patterns of electrical stimulation that would improve theta precession, and would this improve spatial as well as non-spatial relational processing? What is the mechanism by which the changed neural pattern improves behavior? Methods for altering neural patterns could include pharmacological intervention, optogenetic methods, patterned electrical stimulation, or other methods, as long as the method allows for understanding what aspects of the temporal dynamics are the drivers of behavioral improvements, such as changes in amplitude of particular oscillatory frequencies, the co-modulation of particular frequencies, or other characteristics of oscillatory patterns and spike timing.
Another example of Topic 1 would be to use patterned brain stimulation to test whether higher-level cognition could be improved in tasks such as transitive inference. For example, could sharp wave ripples be triggered to occur artificially, and might this improve an aspect of cognition? Can the fidelity of replay be improved? Work of this type would be especially encouraged in nonhuman primates because of more relevant brain anatomy and the possibility for more complex behavioral tasks.
An example of Topic 2 would be to determine how over-activation of metabotropic glutamate signaling, or GABA receptor dysfunction in FMR1 knockout animals leads to particular changes in neural patterns and cognition, and which interventions could correct the systems-level neural coordination during an otherwise impaired behavior.
An example of Topic 3 would be to test whether changes in neural coordination patterns in rodent models of relevant phenotypes predict similar intervention-induced changes in patients’ EEG signals, during an equivalent behavioral task. The interventions in patients could be noninvasive brain stimulation (e.g., patterned transcranial magnetic or electrical stimulation) or medications. This type of work should also test whether the cognitive/behavioral improvements seen in rodents also predict improvements in patients.
An example of Topic 4 would be to develop a biologically-realistic, computational model for predicting effects of noninvasive brain stimulation on particular frequencies of cortical and subcortical oscillations and how they interact across trial time and across brain areas.
Another example of Topic 4 might be to model and experimentally test the effects of interneuron signaling on systems-level temporal dynamics.

In addition to addressing at least one of the four topic areas listed above, all applications under this FOA are also expected to fulfill the following requirements:

All projects should employ active manipulations in awake, behaving vertebrate animals. The manipulations can consist of electrical or magnetic brain stimulation, optogenetics, genome editing, pharmacological compounds including existing or novel medications, or other modalities, but they cannot consist solely of behavioral manipulations. Biological manipulations can be tested in conjunction with behavioral training, such as brain stimulation protocols to augment the effectiveness of applied behavioral analysis therapy in autism. In general, novel interventions are encouraged.
All projects should provide a strong scientific rationale for the specific biological intervention chosen (pharmacological or otherwise), in particular whether the intervention can be expected to selectively alter a well-defined aspect of a systems-level temporal pattern in a particular direction (e.g., increasing the power of a specific oscillatory frequency).
All projects are expected to include in vivo, electrophysiological systems-level measures during behavior in each species. Computational/analytic work in particular is expected to reciprocally and iteratively interact closely with experimental work. The use of any non-mammalian species should be clearly justified, providing strong evidence that electrophysiological patterns during cognition are likely to generalize from animals to humans.
EEG work is expected to include spectral analyses.
All projects are expected to employ recording methods that detect neural activity directly, without relying on blood flow measures. All recording methods are expected to have the appropriate temporal resolution to address temporal dynamics of coordinated neural activity during cognition.

This FOA seeks to generate a mechanistic understanding of what aspects of neural coordination and patterning can be modified to improve cognitive, affective, and social processing. A related goal is the identification of reliable and sensitive electrophysiological signatures that would facilitate screening novel interventions to understand how they affect particular electrophysiological patterns, and what clinical population might have a deficit in particular patterns. Efforts from projects responding to this FOA should eventually support the development of pharmacological, electrical, magnetic, or other types of interventions that can enhance cognitive, affective, or social processing sufficiently to improve real-life functioning for patients. As such, grant applications for clinical trials should not be submitted under this FOA. For a listing of NIMH FOAs that support Clinical Trials, please refer to the Clinical Trials Funding Opportunity Announcements webpage.

All applicants are encouraged to contact Scientific/Research staff at NIMH before submitting a grant application.

Deadlines: November 8, 2017; then standard dates apply

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Filed Under: Funding Opportunities

NIH – Understanding and Modifying Temporal Dynamics of Coordinated Neural Activity (R01, R21)