Geoffrey Ghose - US grants

DESCRIPTION (provided by applicant): Behavior relies on the reliable interpretation of sensory information and the flexible association of that information with actions. It therefore depends on the both the accurate encoding of information by sensory neurons and the appropriate decoding of these sensory signals according to task constraints. In circumstances involving rapid changes in the sensory environment, the speed of these processes can be of paramount importance: an inability to quickly respond to a looming threat can be fatal. Evidence acquired in the previous grant submission demonstrates that the activity of single neurons over tens of milliseconds can accurately and precisely encode motion information. The same brief periods of activity were also strongly predictive of behavioral choice when animals were engaged in a natural foveation task, and therefore potentially play a pivotal role in rapid decision making. The proposed experiments will explore how such precision is distributed among neural populations and how it is altered by training or task demands. Animals will be trained in tasks requiring the rapid analysis of motion information. Simultaneous recording of neuronal activity and behavior will be analyzed to infer the precision and reliability of sensory signals and their influence on behavioral choice. In the first specific aim, the distribution of reliable sensory information over a cortical population will be investigated. In the first experiment, nearby neurons will be simultaneously activated by a motion stimulus in order to examine how activity correlations might improve or degrade sensory information and its association with behavioral outcome. In the second experiment, the stimulus dependence of precision and reliability will be used to infer how these factors vary across a broad population of activated neurons. In the second specific aim, recordings of individual neurons will be made during the acquisition of proficiency in rapid motion detection to study the extent to which this precision is learned. In the third specific aim, stimulus and probability manipulations will be used to reveal the specific task parameters responsible for such precise neuronal activity. Because all of these tasks are highly challenging, they will help reveal the underlying constraints on the accuracy and speed of decision making. By simultaneously addressing the reliability and precision of sensory encoding and decoding within the brain, these studies could also provide valuable information for the development of effective neural interfaces for prosthetics. PUBLIC HEALTH RELEVANCE: Decisions based on small epochs of perceptual information are often of life-or-death importance not only in nature but every time we cross a busy intersection or navigate a busy highway. However, no existing model is able to explain how our brains are able to rapidly and reliably process brief amounts of information and subsequently plan and execute appropriate actions on the basis on that information. This goal of this proposal is to reveal the physiological basis of such capabilities by investigating how neural activity in a specific brain area is able to precisely represent visual information and influence behaviors during the course of rapid decision making.

DESCRIPTION (provided by applicant): Especially since the introduction of functional magnetic resonance imaging (fMRI), a plethora of magnetic resonance (MR) techniques, such as neurochemical spectroscopy, perfusion imaging, imaging of vascular anatomy, diffusion imaging and functional imaging etc., have come to play an indispensable role in neurosciences. Furthermore, many of these methodologies, even at ultrahigh fields such as 7 Tesla, are rapidly moving from the domain of technique development carried out by MR physicist to become an indispensable tool employed routinely by a community of neuroscience researchers without expertise in MR physics. Contemporary use of such MR methodologies in neuroscience research requires immense auxiliary support that includes complex animal surgery, invasive infusions in humans and animal model studies, large scale data and image processing, and complementary non-MR measurements (e.g. electrophysiology, optical imaging, histology etc.). The aim of this proposal is to establish Neuroscience CORE facilities that will augment the existing state-of-the art and unique MR instrumentation resources located in the Center for Magnetic Resonance Research (CMRR) at the University of Minnesota, so as to enable access and utilization of CMRR,A6s resources by a large community of neuroscience researchers, and maximize the impact of modern MR techniques in neuroscience discovery.

Although MR techniques offer enormous potential for non-invasive in-vivo whole brain measurements, the interpretation of the measurements can be greatly enhanced when combined with classical neuroscience techniques. For example, although MR is particularly well suited for population level studies of neuronal chemistry or activity, its temporal resolution is often limited by hemodynamic factors. By combining high temporal resolution electrophysiology, such as provided by extracellular or EEG electrodes, with MR measurements, a more complete picture of brain metabolism and function is possible. One traditional challenge for such multimodal investigations is the high barrier to entry that neuroscience investigators face in trying to state-of-the-art MR techniques. The purpose of this core is to reduce this barrier to entry by encouraging and supporting the integration of the cutting-edge MR methods available at the CMRR with traditional neuroscience methodologies. This methodologies include behavioral measurements, electrophysiology, histochemistry, optical imaging, and tract tracing. Because of the success of the core in supporting a variety of such projects, as is documented in our Usage Tables, we propose to continue our efforts through human and equipment resources to promote the incorporation of MR techniques, and to assist in the design and implementation of multimodal

Abstract While functional magnetic resonance (fMRI) has proved invaluable for identifying where in the brain activation is occurring during a particular task, it has had less to say about how the dynamics of that activation actually contribute to task performance. Indeed, because of the belief that fMRI signals are sluggish and temporally imprecise, fMRI experimental paradigms traditionally have used sustained block designs which deliberately preclude measuring the rapid changes in sensory and motor signals that underlie everyday actions. Recent evidence, however, suggests that there is considerable temporal information present in the BOLD signal, opening the possibility that fast neuronal dynamics can be revealed by fMRI. In this proposal, we will examine this possibility with a series of multimodal experiments in which a consistent experimental paradigm is applied across spatial and temporal scales to quantify responses to transient inputs. In the first specific aim, we will characterize the relationship between cellular level population activity,mesoscopic activity, and metabolic patterns across variations in input strength, network state, and behavioral state using simultaneous 2-photon and 1-photon imaging in ferret visual cortex. In the second specific aim, we will extend these results to awake behaving primates using 1-photon imaging to resolve and compare metabolic and hemodynamic responses. In the third specific aim, we will extend these results to fast whole brain fMRI in both monkeys and humans. We will integrate the results aims 1 and 2, in which forward spatiotemporal filters describing the evolution of impulses of activity to metabolism and consequently to hemodynamics are measured, to construct an inverse filter that allows temporally precise inferences regarding neuronal activity from fast fMRI measurements. The same manipulations of local and network inputs used in the aims 1 and 2 will also be used to relate the variability of local event-driven signals to more global fluctuations such as are seen in resting state studies. These innovations will transform fMRI into a non-invasive systems neuroscience paradigm that can reveal not only spatial aspects of neural activity but also measure the temporal dynamics of neural activity that underlie cognitive processes and behavior.

Project Summary Synchronous low-frequency brain activity, as measured by human EEG, has been implicated in both normal cognition and in disease states such schizophrenia. However, we still do not know whether changes in such rhythms directly alter neuronal information processing, or are merely epiphenomenal. To address this issue, we will measure how single and multi unit activity linked to task performance in non-human primates is altered by endogenous alpha rhythms, and how that activity is changed when alpha rhythms are directly modulated via closed-loop electrical stimulation. The proposal will offer a mechanistic explanation for the relationship between alpha rhythms, attention, and perceptual decision making and validate the potential of direct modulation of alpha rhythms as a therapeutic approach to attentional pathologies.

Project Summary Non-human primates offer a unique opportunity, because of their strong physiological and behavioral homologies to humans, to both advance our understanding of fundamental issues of neuroscience and test therapies and strategies with direct clinical implications for addressing a spectrum of mental health issues. A ?missing link? in such efforts has been the inability to use the primary techniques of human neuroscience, including non-invasive magnetic resonance imaging (MRI), on monkeys. Without such capabilities, a direct comparison of the signals we measure in humans, and those that only available more invasively, such as through electrophysiological, histo- logical, and optical methodologies, is impossible. To avoid potentially speculative modeling, the most informative multi-modal measurements require comparable spatial and temporal scales of study. Accordingly, the impor- tance of such high resolution multi-modal imaging has been recognized by the NIMH: it is a vital component of a number of current projects, including several sponsored by the BRAIN initiative. At the Center for Magnetic Reso- nance Research, we have demonstrated that a unique resource, a 10.5 Telsa MR scanner, can push MRI spatial and temporal resolution to unparalleled levels in non-human primates which are directly comparable to invasive measurements. To maximize the scienti?c impact of this unique resource, we seek the shared instrumentation necessary to obtain high-resolution electrophysiological and optical data from non-human primates in the 10.5 T scanner. The center has a long tradition of making its unique technical and personnel resources available to the broader community through core grants including a P41 and a P30. In this proposal, we leverage this tradition to ensure that the requested equipment supports a broad spectrum of NIMH projects aimed at understanding the signals and circuitry underlying human brain function.