Charles E. Schroeder - US grants

The broad goals of this project are: 1) to define neural systems underlying selective attention and discrimination in monkeys; 2) to develop a direct link between the disparate neurophysiologic approaches to this issue in monkeys and humans. The human - simian link is based on using spatial and feature attention tasks directly adapted from human studies and on using depth recording techniques that integrate a "neural systems" level of analysis with the specificity of single cell recording, and yet, are directly comparable to visual event related potential (ERP) recording in humans. Brain electrical source analysis (BESA) of surface ERP will provide hypotheses concerning the spatiotemporal pattern of attentional modulation of sensory processing throughout the brain as well as the involvement of particular structures in task-specific effects, and in generating the surface ERP distribution. In-vivo MRI will be used to transpose BESA-derived source configurations onto brain structures and will help in targeting structures for depth studies. Depth recordings will provide both an unparalleled direct means of evaluating and extending the predictive capacity of BESA, and a powerful, independent approach to studying attentional modulation of sensory processes. Depth studies use three complementary methods. Recording of the ERP depth profile allows tracing of ERP components from the brain's surface to their depths of maximum amplitude and polarity inversion. With penetrations normal to a structures lamination pattern, one/dimensional current source density (CSD) analysis of the ERP profile delineates the spatiotemporal pattern of transmembrane current flow which is elicited by visual stimuli and which generates the distribution of field potentials (ERP) in the extracellular medium. Recording of the profile of multiunit activity (MUA), concomitant to the ERP, helps to interpret features in the CSD profile (current sources and sinks) as indices of excitatory and inhibitory postsynaptic potentials, and to link these data to those of approaches measuring action potentials alone. Recording these profiles from numerous incremental depths simultaneously with multicontact electrodes yields a sensitive and reliable measure of the real-time sequence and quantitative distribution of activity over the entire depth of a visual structure. Relating these data to known distributions of cell type and connectivity can evaluate the physiology of structures less than 100 mum thick, and can help to identify the neural basis for surface ERP components. Data will be collected from cortical and subcortical structures in the "form and color" parvocellular- inferotemporal, nd "space and movement" magnocellular-parietal pathways in awake monkeys during performance of visual spatial and feature attention tasks. The specific aims are: 1) To delineate the functional neuroanatomy of attention effects in the visual pathways; 2) to define neurophysiologic processes underlying attentional modulation of sensory processes; 3) to examine the dynamics of attention effects, as governed by discriminative difficulty and discriminandum complexity, emphasizing the earliest stages of effect and the timing of activity within and across structures. The studies will supplement the fundamental understanding of sensory processing in the primate. Defining aspects of processing reflected in the surface- ERP will increase our understanding of both normal and pathological visual function in humans.

DESCRIPTION:(adapted from applicant's abstract) The investigators propose to expand upon a preliminary finding that one or more regions of classic auditory association cortex posterior to A1 are sites of multisensory convergence, in that they respond to somatosensory stimuli, as well as sounds. This surprising finding disputes a prevailing view that multisensory integration is confined to specialized, higher order "association" structures. It also bears on the fundamental question of whether auditory and somatosensory systems have "what" and "where" divisions like those proposed for the visual pathways. Anatomical tracer studies, in conjunction with standard multiunit / single unit mapping procedures in anesthetized monkeys and with multielectrode studies in awake monkeys will address 3 specific aims. 1) To delineate the somatosensory map(s) and determine of the relationship of somatosensory representation to previously defined auditory fields. 2) To identify the anatomical source(s) of somatosensory input. 3) To determine the functional significance of auditory-somatosensory co-representation. These experiments will evaluate the hypotheses that the caudal belt and parabelt regions of auditory cortex are involved in auditory localization and that somatosensory-auditory interactions contribute to this function.

[unreadable] DESCRIPTION (provided by applicant): Studies of higher order visual dysfunction in schizophrenia indicate deficits in perceptual grouping/closure and correlated event related brain potential (ERP) abnormalities. Our broad goal is to determine the precise brain locations and neural processes that are indexed by these ERP abnormalities. The "Frame and Fill" Model of visual object processing provides a conceptual framework for this investigation. The model emphasizes a specific signal interaction; gross form/movement (M) information penetrates the brain systems very rapidly and sets-up or "frames" the neural processing of slower moving, (P) information that "fills-in" the fine detail and color of the object. The derivative hypothesis about schizophrenia is that the low level M system dysfunction, in addition to simply removing M mediated detail from the perceptual "picture", also damages a critical, higher-order "framing" operation, leading to failure in many basic aspects of object processing. This project will use the monkey as a model for the human. Our main recording method is to use dual multielectrodes (i.e., "paired recordings") to sample ERPs and action potentials from two brain regions simultaneously. This permits direct localization of ERP generators, definition of underlying physiological mechanisms, and evaluation of dynamic interactions between areas, Novel, single trial analyses will be critical in defining Neural Response Dynamics in each phase of the project. [unreadable] [unreadable] We have 3 SPECIFIC AIMS: 1-To determine how dynamic, dorsal-ventral stream interactions contribute to object processing and how their disruption degrades processing. 2-To define P, M and K contributions to higher order processing, and the consequences of disruption in one or more of these low level systems. 3-To identify cortical regions, and physiological processes generating object-related ERPs shown to be abnormal in schizophrenic patients. [unreadable] [unreadable]

The Parent Grant explores the finding that one or more regions of classic auditory association cortex posterior to A1 are sites of multisensory convergence, in that, they respond to somatosensory stimuli, as well .as sounds. This surprising finding disputes a prevailing view that multisensory integration is confined to specialized, higher order "association" structures. It also bears on the fundamental question of whether auditory and somatosensory systems have "what" and "where" divisions like those proposed for the visual pathways. Anatomical tracer studies, in conjunction with standard multiunit/single unit mapping procedures in anesthetized monkeys and with multielectrode studies in awake monkeys will address 1. the relationship of somatosensory representation to previously defined auditory fields. 2. the anatomical source(s) of somatosensory input. 3. the functional significance of auditory-somatosensory co- representation. This FIRCA Project will conduct an analysis supplementary to number 3 above. We will address 1)the physiological impact of somatosensory input in auditory cortex, targeting somatosensory source sites identified by the parent grant 2) the hierarchial relationships between somato-recipient regions of auditory cortex and the somatosensory input sources and 3) expansion of physiological findings by anatomical reconstruction of the projections between selected somatosensory "input" and auditory "recipient" site pairs identified by Specific Aim 1.

DESCRIPTION (provided by applicant): Functional magnetic resonance imaging (fMRI) promises to provide the ability to pinpoint and track brain activity patterns underlying sensory, motor and cognitive skills, during their normal operation in intact subjects. However, this promise is thwarted by our inadequate understanding of the linkage between neural activity and fMRI signals, and by inherent limitations of current fMRI methods. We will investigate the neural basis of fMRI signals through experiments that combine high field fMRI with neural ensemble electrophysiology and pharmacology in monkeys; fMRI will be conducted with BOLD- and perfusion-sensitive protocols using a high-resolution, high signal-to-noise 7-Tesla system. Electrophysiology will utilize both scalp ERP recordings, and depth recordings with linear array multielectrodes, and will focus on ERP and current source density (CSD) measures as well as action potentials. CSD measures in particular, are essential for linking neural activity and fMRI. Neurochemical manipulation will entail both systemic infusions and intracortical microinfusions. Our specific aims are: 1. To Identify Neural Correlates of BOLD-fMRI: 2. To Optimize the Spatial and Temporal Resolution of fMRI 3. To Determine the Relationship of fMRI to ERPs and to Brain Processes. Initial studies will be conducted in anesthetized macaque monkeys & will focus on the cortical hand representation in Area 3b. Later studies will be implemented in awake monkeys & will be expanded to a few additional cortical regions. These studies will have the useful by-product of accurately describing the spatiotemporal activation pattern of the ascending somatosensory pathways from the hand surface in the macaque, and of doing so with methods that directly compare to those used in humans. This will help to bridge-the-gap between a vast single unit literature in monkeys, and a developing understanding of somatosensory structure and function in humans.

Until recently, it was believed that multisensory integration begins in high-level cortical regions, after protracted hierarchical processing within each unisensory system. Results in the prior project period refute this view. The hypothesis driving our competing renewal application incorporates low-level multisensory processing with that occurring in higher-order multisensory regions. The pervasiveness of low-level integrative operations is staggering. Among recent findings showing direct anatomical connections between A1 and V1, and a wealth of low-level influences on auditory processing, is the remarkable ability of non-auditory inputs to control the pattern of ongoing neuronal activity in auditory cortex. This is fundamentally significant because ongoing neuronal activity sets the context within which incoming sensory inputs are processed. Our preliminary data make several key predictions about the manner in which context is controlled, and about the way that it in turn controls sensory processing. Our long-term goal is to define the mechanisms of multisensory interactions in auditory cortex, and their contributions to the auditory functions of the region. Our specific aims are: 1. To consolidate and extend our understanding of the functional properties, areal distribution and anatomical mechanisms of visual, as well as somatosensory inputs in auditory cortex. 2. To determine how ongoing oscillatory dynamics control the both unisensory (e.g., auditory) and multisensory integration in auditory cortex. 3. To investigate how auditory cortical dynamics are addressed by attention and discrimination. Because of our unique combination of methods we can bridge the gap between incisive findings from in-vitro cellular-level experiments and effects noted by electromagnetic and hemodynamic imaging studies in humans.

SUMMARY ABSTRACT. Neuroelectric oscillations reflect rhythmic fluctuations of neuronal ensembles between high and low excitability states. These fluctuations clearly impact on sensory processing and cognitive operations, but their actual utility is unclear. Our broad goal is to explore the overarching hypothesis that low frequency neuronal oscillations can function as instruments for active selection of task-relevant inputs in visual cortex and for enhancement of their representation across processing stages. A key proposition of this hypothesis is that in dealing adaptively with ever-changing tasks, ranging from rhythmic (e.g., watching a person walking by) to random (e.g., waiting for a traffic light to change), the brain shifts dynamically between rhythmic and continuous modes of operation. This proposition makes specific predictions vis-¿-vis neuronal oscillations, and these will be explored by paired linear array multielectrode recordings from V1 and extrastriate visual cortices in awake- behaving monkeys. We have 3 specific aims. Aim 1: investigate the mechanistic role of neuronal oscillations in inter-modal attention. Expt 1 will build on our earlier studies on intermodal selective attention (b.2.a; c.2.1). Specific new predictions will be tested using behavioral measures, along with laminar current source density and multiunit activity profiles sampled during task performance using linear array multielectrodes positioned in V1, V4 and inferotemporal (IT) cortex. Inter-areal interactions (prediction 4) will be evaluated using dual multielectrode recordings. Aim 2: evaluate the generality of oscillatory involvement in attentional function and dysfunction. Generalization of finding outside of intermodal selection is important to establish because most selective attention investigations focus on effects within one sensory modality. Thus, Expt 2 will use a visual feature- attention task. To maintain comparability, stimulus manipulations, recording methods and tests of predictions will otherwise generally parallel those of Expt 1. The paradigm in Expt 2 is adapted from studies examining the neurophysiology of attentional deficits in schizophrenia. Expt 2 thus has additional translational value, in that it can determine the physiological significance of ERP components and/or oscillatory characteristics that are shown to be abnormal under corresponding conditions in schizophrenia (b.3; b.5; b.6). Aim 3: investigate the relevance of rhythmic mode processing in natural vision. Expt 3 will use a visual search paradigm, along with a match to sample paradigm, to evaluate the hypotheses that: 1) the key feature of rhythmic mode processing, the rhythmic fluctuation of neuronal excitability, is also a dominant feature in natural visual behavior, and 2) that this is due, at least in part, to the rhythmic nature of visual (saccade/fixation) sampling behavior, and the powerful organizing effects of fixation onset on cortical oscillatory activity (c.2.3). Expt 3 will also examine effects of fixation onset on oscillatory synchrony across cortical layers and across cortical areas.

DESCRIPTION (provided by applicant): Cognitive operations like selective attention are thought to involve coordinated activity of neuronal ensembles in multiple brain areas. It is abundantly clear that attention enhances visual responses within local ensembles of neurons throughout the visual system, the corollary idea that attention also facilitates the transmission of visual inputs between neuron ensembles in different cortical layers and in different cortical regions has not been thoroughly investigated. Similarly, while it is generally agreed that attentional modulation of low level visual processing is controlled by a higher order network, the specific circuits and physiological processes by which top-down control is imposed are not well understood. With these two problems in mind the overall goal of this project is to define the magnitude and physiological mechanisms of attention's influence on feedforward communication in low level visual processing. Using a combination of spike correlation, standard coherence and Granger causality analyses, we will analyze data from multielectrode recordings in V1 and V2 in monkeys performing a single, well-studied (intermodal) attention task. We have shown that because of the predictability of stimulus rhythms in this paradigm, attention can use low frequency oscillations as instruments to enhance neuronal responses to task relevant stimuli. This finding has wide ramifications because rhythm and predictability are prominent in many aspects of natural behavior. To follow it up, we will test the hypothesis that attention can use low frequency oscillatory phase synchrony to facilitate feedforward communication between neuronal ensembles in the visual pathways. Our specific aims are: 1) to characterize attention's influence on feedforward transmission between cortical layers, 2) to characterize attention's influence on transmission between V1 and V2, and 3) to define the brain mechanisms underlying attentional modulation of interlaminar and interareal interactions. Concurrent sampling of laminar current source density (CSD) and multiunit activity (MUA) profiles in V1 and V2 will index synaptic activity and firing patterns in neuronal ensembles at key locations in the supragranular, granular and infragranular layers. Laminar profiles of attention effects in V1 and V2, along with Granger causality analyses will help to differentiate between several of the alternative control circuits. Single trial analysis of both pre- stimulus and poststimulus oscillatory dynamics and of related variations in neuronal firing patterns in these locations will help to relate dynamics to underlying physiology. PUBLIC HEALTH RELEVANCE: Our methods allow use of the monkey as a model for understanding the neuronal mechanisms of ERP and EEG generation in humans. This study will also provide a data set that can be used to evaluate new functional connectivity analyses developed for use in humans, particularly those targeting the study of epilepsy.

DESCRIPTION (provided by applicant): Multisensory Integration begins at or before the level of primary auditory cortex (A1) and builds over higher stages. In A1 the effect seems to be mainly a non-auditory modulation of the strength of driving auditory inputs, while in higher areas it may increasingly reflect a higher order integration of auditory and non-auditory information. In A1, auditory/non-auditory interactions use neuronal oscillations as instruments of auditory response amplification, while in higher stages, interactions also entail classic excitatory convergence. Throughout, the impact of inputs' salience (bottom-up), and that of top-down attentional control are believed to crucial. These elements - neuronal oscillations, modulatory-driving interactions, top-down control, and the underlying anatomic circuits - are ubiquitous and crucial to brain operation. Investigating them in the context of multisensory interactions affords a unique unambiguous control over the key inputs since they arise from different receptor surfaces. Our BROAD GOAL is to investigate multisensory interaction across levels of the auditory system as a general model for integrative operations in the brain. We combine anatomical analyses with electrophysiological methods indexing laminar profiles of synaptic activity and concomitant action potentials to differentiate driving auditory inputs and non-auditory modulatory inputs arising from various cortical and subcortical sources, and to determine how these input types interact physiologically during attentive discrimination. SPECIFIC AIM 1 is to characterize the mechanisms and evolution of multisensory representation across processing levels. SPECIFIC AIM 2 is to determine how cross modal cues that predict sound timing and location help auditory processing. SPECIFIC AIM 3 is to characterize the fine structure of driving and modulatory circuits in auditory cortex, emphasizing anatomical correlates of processes examined under Aims 1 and 2. Improved understanding of the critical instrumental functions of neuronal oscillations in processing of driving inputs, their manipulation by modulatory inputs, influences of stimulus salience and attention, and the underlying circuitry, will enhance the mechanistic understanding of normal hearing, as well as those underlying disruptions of hearing that contribute to a number of pathological conditions.

? DESCRIPTION (provided by applicant): Neuroelectric oscillations reflect synchronous excitability fluctuations in ensembles of neurons, ubiquitous in the waking (and sleeping) brain, and are believed to be fundamental instruments in adaptive brain function. Despite recent progress in understanding the physiological underpinnings and functional significance of neuronal oscillations, the cellular physiology of the reset and entrainment processes, that allow the brain to harness oscillations as building blocks of perception and cognition, are unclear. Recent findings suggest that it is possible to manipulate neuronal oscillations using weak transcranial electrical stimulation (TES) both with direct and alternating currents (tDCS and tACS respectively). This raises possibilities for causal manipulations that can help to confirm the role of specific oscillatory dynamics in specific aspects of perception and behavior, as well as the possibility of treating neuropsychiatric disorders in which disruptions of brain dynamics underlie cognitive deficits. We propose to examine effects of tDCS and tACS with a combination of electric field measurements and modelling, electrophysiological and behavioral measurements in awake-behaving macaque monkeys. Our Specific Aims are: 1) Optimize models to target specific brain regions with tDCS and tACS. Widespread. macro-scale intracranial recordings with chronically-implanted, 48 channel stereotactic EEG (s-EEG) arrays will determine how intracranial electric fields are affected by stimulation parameters, e.g., intensity, frequency (tACS) and variations in stimulating electrode nu mber (up to 8) and positions. 2) Define physiological and behavioral effects of tDCS and tACS in active sensory processing. We will use a limited (24 channel) version of the macro-scale network analysis (AIM 1), along with micro-scale measures in monkeys performing auditory discriminations and making manual responses to targets. Micro-scale measures include laminar field potential (FP), current source density (CSD) and multiunit activity (MUA) profiles sampled with multielectrode arrays across the layers of selected neocortical areas. CSD and MUA analyses are used to define the profiles of synaptic activity (indexed by current sinks and sources) and envelope of concomitant neuronal firing across the cortical layers, thus linking stimulation effects to specific cell populations, circuits and physiological processes engaged in oscillatory dynamics. Measuring network and cell-circuit activity patterns during sensory processing, target detection and motor responding will provide robust and sensitive means to gauge electrical stimulation effects on brain dynamics underlying these key processes. Success will support and inform a broader effort to develop a more detailed concrete picture of the properties of neuronal ensembles that create brain rhythms and organize them to perform fundamental cognitive operations. Improved mechanistic understanding of brain stimulation effects may lead to improved brain stimulation protocols, treatments disorders such as schizophrenia, autism and ADHD, in which sensory entrainment at both low and high frequencies is demonstrably or putatively impaired.

Intrinsic ?functional connectivity? (iFC), a measure of correlation between spontaneous fluctuations in the blood oxygen level dependent (BOLD) signal, reliably distinguish networks of cortical and subcortical areas during both rest and active task performance. iFC methods can map the functional architecture of the human brain in both healthy and pathological conditions, in high detail using as little as 5 minutes of data. Striking reproducibility and test-retest reliability of findings across centers have fueled a widespread application of iFC measures in clinical neuroscience, biomarker discovery, and human connectomics. However, the neural circuits and cellular processes underlying BOLD-iFC remain poorly specified. BOLD amplitude itself appears related to neural activity in the high gamma (HG) range (~70-200 Hz), and thus to an extent, with neuronal firing. However, BOLD?s relationship to the lower frequencies is controversial. This is a critical disconnect, as oscillatory activities below 40Hz reflect ongoing cell-circuit excitability fluctuations that control neuronal firing; i.e., the amplitude of neural population firing is ?coupled? to oscillatory phase. In this, the simplest form of such phase-amplitude coupling (PAC), amplitude variations in higher frequency activity (e.g., firing or HG) are coupled to the phase of a lower frequency (e.g., theta). PAC operates both pairwise and recursively over the spectrum, from the range of neuronal firing down to the slow/infraslow (<1Hz) range where BOLD amplitude fluctuations are observed using resting state fMRI (R-fMRI). Thus PAC may provide a key to connecting resting BOLD fluctuations to activity cycles in the underlying cell circuits. In our framework: 1) At a microscopic, cortical cell-circuit level, a complex of excitatory and inhibitory interactions between neurons generate rhythmic excitability fluctuations (oscillations). 2) PAC organizes slow (0.5-12) Hz and mid-range (13-40Hz) oscillations hierarchically, ultimately controlling temporal patterns of neuronal firing. 3) Infraslow (0.01-0.1 Hz) neural activity fluctuations synchronize to form the macroscale intrinsic connectivity networks (ICN) indexed by R- fMRI, and use PAC to orchestrate faster activity within a network. Our broad goal is to use integrated human and monkey studies to investigate the relationship between macroscale BOLD-derived iFC patterns, and their underlying mechanisms at the microscale cell-circuit level. We will study the sensorimotor network, as its ?nodal? organization and other properties are well understood, and it shows good human-simian correspondence. Focusing on key nodes in this network (e.g., face and hand areas), we will recapitulate prior work tying R-FMRI iFC to macroscale scalp EEG and mesoscale stereotactic (S)-EEG, and will use innovative laminar multielectrode methods to establish novel links to the cell circuit level. Established modeling and computational methods will help to construct a comprehensive model that connects macroscale iFC to underlying microscale, cell circuit activity.

ABSTRACT: Neuroelectric oscillations reflect synchronous excitability fluctuations in ensembles of neurons, ubiquitous in the waking (and sleeping) brain, and are believed to be fundamental instruments in adaptive brain function. Through oscillatory phase reset and entrainment, the large delta (1-3 Hz) and theta (4-8 Hz) oscillations that dominate the spontaneous activity spectrum in auditory cortex can be harnessed as tools that allow the brain to parse, select and represent rhythmic event streams ranging from simple pure tones to multiscale patterns like speech. Despite the demonstrable importance of oscillatory entrainment in selective attention and other cognitive brain operations, physiological mechanisms underlying these dynamical processes remain poorly understood. Of fundamental importance, a wide range of findings converge on the idea that established neuronal ensembles operate according to transient activation cycles. While flexible, activation cycles are physiologically constrained to operate within certain dynamic resonance ranges. These cycles both frame transient sensory evoked responses and form the building blocks of brain rhythms. We propose to develop a combination of computational and physiological methods. Our long-term goal is a mechanistic, physiological understanding of the ways that neuronal dynamics generate cognitive abilities. As an initial exploratory step, we will develop an iterative exchange between computational and physiological investigations focusing on primary auditory cortex (A1). We will address the dynamic cellular mechanisms underlying the tendency of A1 ensembles to oscillate near preferred resonance frequencies, and those causing ensembles? entrainment to behaviorally relevant event streams. The more specific goals are: 1) Devise a mechanistic computational model of A1 incorporating key dynamics, 2) Test the model?s starting specifications and iteratively refine them by recordings in primary auditory cortex of monkeys during performance of auditory discriminations, and 3) Evaluate the model?s predictions by manipulation of A1 physiology using nerve stimulation methods that can impact both A1 dynamics and behavior. The proposed merger of computational and ensemble physiology methods is a novel venture, with admittedly high-risk components. However, success in any of our aims will improve the mechanistic understanding of disorders such as schizophrenia, in which sensory entrainment at both low and high frequencies is demonstrably impaired. Findings in these exploratory studies will support and inform a broader effort to develop a more detailed concrete picture of the properties of neuronal ensembles that create brain rhythms and organize them to perform fundamental cognitive operations.

SUMMARY ABSTRACT There have been many recent developments in invasive and non-invasive techniques for modulating brain operations. However, these techniques typically cannot be efficiently used beyond ?proof of concept? experiments since the cellular-network origins of the most basic functions in the brain are not known. Part of the reason for this is that while cognitive neuroscientists have learned a lot about the principles that govern brain operations, and computational modelers have made leaps and bounds in creating models of nearly every brain circuit, these two fields remain only sparsely connected. Our proposed project will bridge the gap between cognitive neuroscience, electrophysiology, and computational modeling by measuring neuronal activity on multiple spatial scales in behavioral experiments, and connecting these data to detailed computational models of the auditory thalamocortical system. This process will provide specific predictions for the neuromodulation of auditory system function and form a solid base for novel therapeutic approaches. Our project focuses on defining the cellular-network underpinnings of three distinct mechanisms of auditory perceptual processes, which are utilized for speech processing. The first is the flexibility of neuronal oscillations in the delta-theta bands that endows them with the capability to dynamically adapt their cycles to the quasi-rhythmic structure of naturalistic auditory stimulus sequences, including species specific vocalizations and speech. The second mechanism that supports efficient auditory processing is oscillatory phase reset, which enables the precise tracking of stimulus sequences by neuronal oscillations supporting, amongst other things the figure-ground segregation of attended auditory streams. The third fundamental mechanism for processing continuous auditory stimulus streams is parsing, which enables the brain to segment and group acoustic elements so that they form units that are interpretable by the brain. These three mechanisms form the basis of the complex computations needed to make sense of the auditory environment. We will perform concurrent thalamus-cortex electrophysiological recordings in macaques to determine the spatiotemporal organization of neuronal activity patterns supporting the above described fundamental auditory processing mechanisms. The data collected during behavioral tasks will inform our detailed thalamocortical computational model, which will in turn provide precise predictions on efficient neuromodulation approaches to induce, or temporarily inhibit the neuronal activity patterns underlying distinct auditory processes like stream segregation or parsing. Besides advanced time-resolved single unit and neuronal ensemble activity analyses, we will be able to verify the effectiveness of neuromodulation based on behavioral biases. The model based, targeted neuromodulation techniques developed by our proposed projects will pave the way for novel therapeutic approaches in the treatment of neuropsychiatric and developmental disorders that are hallmarked by deficits in the dynamical properties of neuronal oscillatory systems.

Summary Genetic technologies have revolutionized the way scientists can dissect out brain circuitry by inserting G protein-coupled receptors that enable selective modulation of neurons in target structures. Amongst them, a promising tool,DREADDS (designer receptors exclusively activated by designer drugs) is used to modulate neural activity pharmacologically in targeted brain regions. Unfortunately, DREADDS also require invasive methods to deliver the genes that express the receptor. Focused Ultrasound (FUS) is a novel approach that focuses an ultrasound beam through the skull and meninges to reach deep brain structures and directly stimulate or inhibit neurons in the targeted region. Combined with lipid microbubbles, focused ultrasound can be used to open the blood-brain barrier (BBB) in targeted brain regions. This method is non-invasive, but spatially precise. Focused ultrasound mediated BBB opening has been used to deliver optogenetic viruses in rodent models. Here, we propose to test if this approach can be used to express DREADDS in targeted brain regions in nonhuman primates (rhesus monkeys). We will open the BBB using FUS with microbubbles. The BBB remains open for 24 to 48 hours. During this time, a viral delivery system will be used to introduce DREADDS by intravenous injection. The DREADDS should circulate through the bloodstream and enter the brain only in the region where the BBB has been opened. This entire procedure is completely noninvasive. We will test the functional effects of DREADDS using a fMRI and electrophysiology. We will then confirm DREADD expression using post-mortem histology. The development of FUS-based DREADD delivery could make deep brain neuromodulation available for patients who are not candidates for surgical approaches. The proposed experiments are essential for establishing the efficacy of focused ultrasound mediated DREADD delivery to treat psychiatric illnesses that affect cognition and motivation. FUS-based chemogenetic therapy could become a non-surgical alternative for patients with psychiatric disorders who would benefit from DBS