Vincent P. Ferrera, Phd - US grants

[unreadable] DESCRIPTION (provided by applicant): The ability to make decisions based on abstract categories is a fundamental component of higher-order cognition and is essential for survival. In the past decade, much progress in understanding categorical decision-making has been made through the combination of visual psychophysics and single-unit neurophysiology in awake, behaving monkeys. This work has led to a clearer understanding of decision networks in parietal, frontal and inferotemporal cortex. However, two very basic questions remain unresolved. First, how does activity in specific brain regions targeted by single unit studies relate to the overall pattern of brain activation when monkeys are engaged in decision-making tasks? What additional regions also are involved in processing such decisions, and what role do such regions play? Second, are results from non-human primates applicable to humans? Specifically, given identical psychophysical tasks, can we establish functional homology between human and non-human primate brains? To answer these questions, we propose to use functional magnetic resonance imaging in awake behaving monkeys to map brain regions that are activated during a perceptual categorization task, using a paradigm identical to one used with human subjects. The proposed experiments will open up a new avenue of research into cognitive processes that are dramatically impaired in schizophrenia, attention-deficit disorder, Parkinson's disease, and Alzheimer's disease. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): This project investigates the interaction between reward and cognition. There is evidence that the prefrontal cortex and basal ganglia work together to support reinforcement-based decision-making, and that psychoses may result from dysregulation of this circuitry. However, we know little about the physiological mechanisms through which brainstem reward systems might contribute to abstract thought. We plan to address this by recording activity in prefrontal cortex and striatum during a categorical decision-making task. The central question addressed by this proposal is How does knowledge about reward affect the representation of sensory evidence and decision criteria in the brain? One process that contributes to flexible decision-making is stimulus categorization. Categorization affords a flexible linkage between sensory stimuli and motor responses. Categorization improves the efficiency of decision-making because responses that are appropriate for one member of a class often generalize to other stimuli in the same category. Categorization requires that attention be directed to critical stimulus features that identify stimuli as being in the same or different classes. Some categories are innate or overlearned. But in many cases category boundaries must shift on the fly to adapt to changes in the environment. We will present preliminary evidence that a fronto-striatal network is involved in categorical decision-making. In this project, we will investigate how reinforcement modulates activity in this network during categorical decision-making and category learning. This work is highly relevant to many Psychiatric and Neurological disorders including Schizophrenia, Depression, Autism, Drug Addiction, Obsessive-Compulsive disorders, and Attention-deficit disorders (ADD and ADHD). PUBLIC HEALTH RELEVANCE: To function adaptively in the real world, animals and humans must constantly make choices that affect survival, reproduction, and the overall health and well-being of the organism. In this project, we will investigate how decision-outcomes modulate activity in fronto-striatal networks during categorical decision-making and category learning. This work is highly relevant to many Psychiatric and Neurological disorders including Schizophrenia, Depression, Autism, Drug Addiction, Obsessive-Compulsive disorders, and Attention-deficit disorders (ADD and ADHD).

DESCRIPTION (provided by applicant): We propose a new approach to the study of inferential learning by investigating how monkeys and humans infer implicit serial relationships during training on a Transitive Inference (TI) paradigm. TI implies the ability to conclude that A C if A > B and B > C. This logic can be extended to any number of items as long as their relationships obey transitivity. TI has been shown to exist in species as diverse as pigeons, monkeys, and humans and is thought to be essential for understanding complex social relationships such as dominance hierarchies. TI is also critical for understanding ordinal relationships, which, by definition, obey transitivity. Linear spatial relationships also obey transitivity (if A is to the left of B, and B is to the left of C, then A is to the left of C). Hene, it has been proposed that TI may be related to spatial representations that inhabit a virtual workspace. The idea is that one can imagine adjacent items in an ordered list as occupying neighboring positions on an imaginary line. Thus, ordinal relationships that seem abstract may in fact be mapped onto existing spatial representations. To test this, we plan to investigate the learning and representation of ordinal relationships among novel stimuli in regions of parietal and prefrontal cortex that are believed to be involved in representing spatial information, especially relative spatial position. These are the first experiments to investigate the acquisition of implict inference at the behavioral level that is synchronized to simultaneous measurement of the activity of individual brain cells throughout TI learning (including acquisition). Ours are signifiant because they provide the first neurological investigation of implicit serial learning in a non-human primate that is not confounded by spatial or temporal cues. From a physiologist's perspective, areas LIP and SEF have been shown to encode both spatial and abstract qualities of visual stimuli. There is, however, no theoretical framework that integrates these different representations. We propose to test the idea that a virtual workspace may account for both spatial and non-spatial coding in LIP and SEF. Health Relatedness: These experiments are relevant to Schizophrenia, Autism, Alzheimer's disease, and other conditions whose patient populations have deficits in their performance of TI problems.

We propose to develop focused ultrasound (FUS) for deep brain stimulation (DBS.) DBS is a proven therapy for movement disorders and holds considerable promise for psychiatric conditions such as medically intractable depression. The main drawback of electrical DBS is that it is highly invasive. Non-invasive methods, such as transcranial magnetic or direct current stimulation (TMS and TDCS) have limited penetrability to reach deep brain structures. Is a novel approach that uses focused ultrasound (FUS) to reach any brain structure and directly stimulate or inhibit neurons in the targeted region. The method is non-invasive, but spatially and temporally precise. It has been hypothesized that FUS interacts with ion-channel coupled mechanoreceptors that occur naturally in the targeted brain region. We have recently shown that FUS can improve performance on a decision-making task in monkeys. Here, we propose to study the mechanism underlying this effect by varying FUS frequency and pressure in awake monkeys trained to make evidence and reward based decisions, and in anesthetized monkeys undergoing fMRI. We will also test whether FUS enhances the efficacy of neuroactive drugs. FUS could provide a new research tool for establishing causal brain-behavior relationships and mapping neural circuits in healthy humans. It also provides a novel method for introducing neuroactive drugs that do no cross the intact BBB, or enhancing the effect of drugs that do cross the BBB. The development of sonogenetics could make deep brain stimulation available for patients who are not candidates for surgical approaches. Our approach incorporates safety controls to demonstrate that neural and behavioral effects of FUS or FUS+microbubbles are not due to edema, hemorrhage, lesions or thermal effects.The proposed experiments are essential for establishing the efficacy of focused ultrasound deep brain stimulation to treat psychiatric illnesses that affect cognition and motivation. To reap these benefits, it is necessary to determine the behavioral effects of FUS alone or in combination with other factors such as microbubbles. We are currently the only group currently developing this approach in the basal ganglia of awake, behaving monkeys as well as examining the FUS technique with and without microbubbles in order to exploit its full scope.

Project Summary One of the oldest questions in psychology and neuroscience is whether associations of stimuli and responses are sufficient to explain learning. Or, in addition, are there conditions that require knowledge of rules and representations? We propose a new approach to the study of serial learning by investigating how humans and monkeys infer ordinal knowledge implicitly during training on a Transitive Inference (TI) task. In its simplest form, TI is the ability to conclude that A > C, if A > B and B > C, but here we extend the same logic to longer series composed of 7 items. TI has been shown to exist in species as diverse as pigeons, monkeys, and humans and has been used to explain complex social relationships such as dominance hierarchies. TI is critical for understanding ordinal knowledge, which, by definition, obeys transitivity, and which is believed to give rise to an internal representation of serial order. To investigate this theory, we plan to study learning and representation of ordinal knowledge during and following TI training in monkeys and human subjects. The logic of our experiments is to show (1) how manipulations of expected value do not alter the representation of ordinal knowledge in studies on overtraining of particular pairs during TI acquisition and in studies in which there is a reversal of reward magnitude during TI training, (2) overtraining of a particular stimulus-response contingency does not impair learning, and (3) the inability of association theory to account for accurate performance on derived lists on which knowledge of associations learned on the original list are irrelevant. Our monkey experiments are the first to investigate implicit inference at the behavioral level that is synchronized to simultaneous measurement of the activity of individual neurons in prefrontal cortex (PFC) and posterior parietal cortex (PPC) throughout TI learning (including acquisition). Our experiments aim to show that 1) TI training leads to a representation of serial order of novel stimulus pairs and 2) ordinal position and symbolic distance are represented in PFC and LIP and that those representations arise de novo each time an animal learns a new list. Health Relatedness: These experiments are relevant to Schizophrenia, Autism, Alzheimer?s disease, and other conditions whose patient populations have deficits in learning and reasoning that manifest in the performance of TI problems.