Michael A. Silver - US grants

DESCRIPTION (provided by applicant): The proposed experiments will investigate how prior knowledge and expectations affect the control of visual attention and processing of visual inputs. Specifically, activity in the cholinergic nuclei of the basal forebrain is hypothesized to signal the level of uncertainty subjects have about upcoming events. Under conditions of low uncertainty, top-down attention-related signals representing subjects' expectations should be emphasized in the analysis of visual information in early cortical areas. On the other hand, when uncertainty is high, there is little useful information in these top-down inputs, and bottom-up stimulus-related signals should be facilitated. The technique of functional magnetic resonance imaging (fMRI) will be employed to measure brain activity in different brain areas while subjects are making visual judgments under conditions of low or high uncertainty. These studies will also identify candidate areas in the parietal and frontal lobes that mediate attention to a location in space versus attention to specific features of visual objects. Finally, the interactions between bottom-up sensory inputs and their modulation by top-down attentional signals will be measured in early visual cortex and correlated with performance on psychophysical tasks. In addition to providing information about how attention is represented in the brain and how it affects processing of visual stimuli, the present experiments should also shed light on the function of the cholinergic projection from the basal forebrain to the cerebral cortex. As this projection is thought to be selectively impaired in Alzheimer's disease, knowledge concerning its function in the healthy brain may be useful for understanding the etiology of this disease and for development of appropriate therapies.

[unreadable] DESCRIPTION (provided by applicant): The long-term objectives of this project are 1) to identify functional networks of cortical areas in the human brain that subserve visual spatial attention, and 2) to determine the effects of manipulation of synaptic levels of acetylcholine on the physiology of these functional networks. Humans employ spatial attention to select portions of the visual field that are most relevant for their current behavioral goals. If a visual stimulus appears in an attended location, observers perceive the stimulus more accurately than if the same stimulus is presented to an unattended location. This improvement in perception is thought to be due to attention signals that are transmitted by parietal cortex to early visual cortical areas. However, the neural pathways that carry these attention signals to visual cortex are largely unknown. Acetylcholine is a neurotransmitter that plays an important role in attention networks in the brain. Drugs that prolong the synaptic actions of endogenous acetylcholine (cholinesterase inhibitors) improve performance on attention tasks in human subjects. However, very little is known regarding the physiological effects of acetylcholine on attention signals. The fundamental importance of attention for behavior is demonstrated by the many brain disorders characterized by compromised attention networks. Attention abnormalities are the central symptom in Attention Deficit Disorder. Additionally, many of the mental impairments that have been associated with Alzheimer's disease can be traced to a failure of attention. We will use neuroimaging (functional magnetic resonance imaging, or fMRI) to measure the activity in defined brain areas while subjects are performing attention-demanding tasks. Changes in activity in these areas during task performance will be compared across the identified brain areas, using coherency and partial coherency methods recently developed by our group, to characterize attention pathways and flow of attention signals to visual cortex. In addition, subjects will be administered donepezil (trade name: Aricept), a cholinesterase inhibitor and Alzheimer's medication that enhances attention. The effects of this drug on the functional networks underlying attention will be measured. PUBLIC HEALTH RELEVANCE We will use magnetic resonance imaging (MRI) to measure brain activity in healthy human subjects while they are maintaining attention at a defined visual location. The activity in many brain areas will be compared to identify the network of brain regions that is responsible for visual attention. In addition, the subjects will be administered donepezil, an Alzheimer's medication known to improve attention, and we will measure the effects of this drug on brain activity and the communication between brain areas during sustained attention. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): The long-term objective of this project is to characterize neural correlates of perceptual learning in the human visual system. Perceptual learning can be defined as a specific improvement in the performance of a perceptual discrimination through training. Humans are capable of learning new and intricate skills throughout the lifespan, and perceptual learning experimental paradigms provide model systems for studying these processes. In addition, training procedures involving perceptual learning have been used to treat learning disorders like dyslexia and developmental disorders such as amblyopia. Therefore, understanding the neural mechanisms underlying perceptual learning has consequences for basic science as well as public health implications. Two perceptual learning tasks will be employed in these studies: a motion direction discrimination task and a texture orientation discrimination task. These tasks differentially involve two different visual processing streams in the human brain. One of these specialized for perception of motion and spatial location, and the other is specialized for perception of visual form. Human subjects will be trained on these tasks, and the improvements in behavioral performance resulting from this training will be measured. To study neural correlates of this enhancement in behavioral performance, functional magnetic resonance imaging (fMRI) will be used to measure the activity in defined brain areas before and after perceptual learning occurs. The fMRI experiments will include measurements of the amplitude of responses evoked by visual stimuli and estimates of selectivity of populations of neurons in a number of cortical areas. [Changes in functional connectivity among these areas following perceptual learning will also be measured.] Selectivity will be defined in the spatial domain and in the featural domain (selectivity for stimulus orientation or direction of motion). Acetylcholine is a neurotransmitter that plays an important role in attention networks in the brain. Drugs that prolong the synaptic actions of endogenous acetylcholine (cholinesterase inhibitors) are the most common treatment of Alzheimer's disease. Although the actions of these drugs at the biochemical level are well characterized, their cognitive effects and neural correlates of these effects are poorly understood. The cholinesterase inhibitor donepezil (trade name: Aricept) will be administered during the perceptual learning training procedures to shed light on the role of acetylcholine on learning neural plasticity and to better understand the mechanisms by which these drugs improve cognitive function in patients with Alzheimer's disease. PUBLIC HEALTH RELEVANCE: We will use magnetic resonance imaging (MRI) to measure brain activity in healthy human subjects before and after they undergo a training procedure that improves their ability to make visual discriminations. A variety of MRI measurements will be made to characterize the changes that take place in the brains of subjects as a result of this learning. In addition, the subjects will be administered donepezil, an Alzheimer's medication known to enhance cognition, and the effects of this drug on the perceptual and brain correlates of learning will be determined.

The ability to learn and remember facts, experiences, and skills is critical for a wide range of human activities. Although how experience is encoded into memory, how such memory is then consolidated and later retrived have been extensively studied by psychologists and neuroscientists, a critical context in which memory processing taking place has been understudied. That is the natural rise and fall of the neurochemicals that are known to influence a wide range of brain functions through the sleep and wake cycles. Here Dr. Sara Mednick of the University of California, Riverside (UCR) and Dr. Michael Silver of the University of California, Berkeley (UCB) and their colleagues will investigate how acetylcholine (Ach), a major neuromodulator known to play a critical role in learning and memory, might differentially affect neural processing at the stages of encoding, consolidation, and retrieval. Rivastigmine a drug for treating Alzheimer's Disease, will be given to human subjects to increase Ach just before training (encoding), just after training (consolidation in the waking state), just before bedtime (sleep-dependent consolidation), and just before testing (retrieval). Brain electrical activity will be monitored using high-density electroencephalography (EEG) to characterize how different cortical regions are affected by both natural variations in ACH associated with sleep-wake cycles and by pharmacological treatment. Together, these experiments will provide the critical empirical data to test theories of learning and memory that take into consideration of dynamic changes in neuromodulation

Acetylcholine has been associated with Alzheimer's disease, a neurodegenerative disease that affects over 5 million Americans. Better understanding of ACh's role in mechanisms of memory will help treat patients with the disease and also develop tools for enhancing healthy memory as well. A better understanding of neurochemical mechanisms of learning and memory will also help improve educational practice and applied training regimes, and investigations of the role of sleep in this project will help emphasize the importance of sleep in a society that has record low levels of sleep and impaired functioning due to poor sleep habits. Dr. Mednick and Dr. Silver will develop teaching modules and courses on the roles of sleep and acetylcholine and learning and memory as well as a course on sleep methods that will help train students to conduct research in this area. Finally, Dr. Mednick will present public lectures on the health benefits of sleep at local Hispanic-serving public hospitals and will work with the UCR Health Center to promote napping and healthy sleep habits in college students through Nap-Ins and other university-wide events.

DESCRIPTION (provided by applicant): The goal of this project is to investigate two fundamental visual processing streams in the human brain, the magnocellular and parvocellular pathways. These pathways are physically segregated in subdivisions of the lateral geniculate nucleus (LGN) of the thalamus, a subcortical visual structure that connects the retina to the visual cortex. The magnocellular and parvocellular subdivisions of the LGN have different and complementary visual functions but have been difficult to study in humans due to their small size and subcortical location deep within the brain. A better understanding of the functional specialization of these pathways is important for public health, because deficits in specific subdivisions have been associated with human disorders such as dyslexia and schizophrenia. Further, it has been proposed that the magnocellular and parvocellular subdivisions preferentially provide input to large-scale visual pathways in dorsal and ventral cortex, respectively, but the precise relationships between subcortical and cortical pathway organization in the human brain remain unknown. We propose to use functional magnetic resonance imaging (fMRI) with high spatial and temporal resolution to noninvasively characterize responses to visual stimulation in human LGN. By presenting visual stimuli known to preferentially drive activity within a single subdivision, we will localize the magnocellular and parvocellular subdivisions within the LGN in each participant based on their patterns of visual responses. The localization technique we will develop may be used in the future to characterize the functional properties of the magnocellular and parvocellular subdivisions in both healthy and diseased brains. We will then investigate the functional relationships among large-scale visual cortical networks and the magnocellular and parvocellular LGN subdivisions. To do this, we will employ recent advances in imaging technology for fMRI to obtain measures of connectivity between each subdivision and each of many objectively defined cortical areas, based on correlated fMRI activity in pairs of brain regions. This investigation will help to precisely characterize relationships between subcortical and cortical visual pathways and will assess an influential but incompletely tested theory about the relative contributions of magnocellular and parvocellular pathways to visual processing in dorsal and ventral cortex. A more complete understanding of the normal functional organization of subcortical and cortical visual pathways is critical for developing treatments for multiple diseases, disorders, and injuries that affect visual areas of the brain.

Project Summary/Abstract The long-term objective of this project is to characterize how attention and acetylcholine affect visual perception and the brain's representation of the visual environment. Acetylcholine is a naturally occurring neurotransmitter, and acetylcholine release is elevated during periods of sustained attention. Both acetylcholine and attention enhance aspects of visual perception, but the underlying brain mechanisms are poorly understood. The proposed work will address these questions in healthy human subjects by using functional magnetic resonance imaging (fMRI) to measure the brain's responses to visual stimuli, Our previous studies have shown that increasing levels of acetylcholine in the brain enhances the spatial resolution of the brain's representation of the visual environment. The proposed research will document exactly which brain areas mediate this effect of acetylcholine and will also characterize the effects of attention on these measures of spatial resolution in the brain. The consequences of enhanced spatial resolution for visual perception will also be investigated. This work may have particular significance for the treatment of macular degeneration, a disease characterized by loss of central vision. Patients suffering from macular degeneration must rely exclusively on peripheral vision, and the low spatial resolution of peripheral vision severely impairs their ability to read and to recognize faces and other visual objects. We will also examine the effects of acetylcholine and attention on the reliability of the brain's representations of the visual environment. Our preliminary studies show that increasing acetylcholine levels reduces the variability of the brain's response to repeated presentations of a visual stimulus. In other work, we have shown that increasing acetylcholine dramatically boosts perceptual learning (the improvement in visual ability following practice of particular tasks). The enhanced stability of brain representations following increases in acetylcholine may be responsible for the improvement in perceptual learning. In addition, we have found that acetylcholine can facilitate the beneficial effects of attention on perception. The proposed research will directly examine the relationships among attention, acetylcholine, brain activity, and visual perception. Drugs that enhance the effects of acetylcholine (cholinesterase inhibitors) are used to treat cognitive deficits in Alzheimer's disease. Although the biochemical actions of these drugs are well characterized, their perceptual and cognitive effects and the neural correlates of these effects are less well understood. We will use the cholinesterase inhibitor donepezil (trade name: Aricept) to manipulate brain acetylcholine levels in order to shed light on the role of acetylcholine in attention and perception and to better understand the mechanisms by which these drugs improve cognitive function. In addition, a better understanding of the neural substrates of attention is important for the development of more effective treatments of diseases that affect attention, including attention deficit disorder, schizophrenia, and Alzheimer's disease.

Age-related decline in central auditory function significantly affects quality of life in the elderly, with impaired speech perception leading to increased risk for depression, social isolation and cognitive decline. A 2017 Lancet Commission report cites hearing loss as the largest modifiable risk factor for developing cognitive decline, exceeding smoking, high blood pressure, lack of exercise and social isolation. Remarkably, a 2019 large-scale study found that even mild hearing loss, i.e., still within the normal range, produced an even closer association with cognitive decline. Currently, there is no effective therapy for age-related central auditory decline?hearing aids only address audibility?and no drug treatment. Ideally, a combination of drug treatment with hearing aids and behavioral training could restore auditory function, but the development of pharmacological treatments requires a better understanding of the mechanisms by which candidate drugs improve hearing. The goals of this proposal are to develop biomarkers of altered auditory processing in aging mice and humans, and using these biomarkers, to test the hypothesis that nicotine can normalize these age-related central auditory deficits. Because nicotine enhances cortical and cognitive function, pharmaceutical companies are developing nicotine-like drugs to target cognitive deficits in aging. These drugs are non-addictive (unlike nicotine in tobacco), yet nicotine also is non-addictive when given topically or orally. However, its clinical benefits have not been exploited except as an aid to stop smoking. We hypothesize that: 1) acute nicotine compensates for the age-related decline in inhibition by exciting the remaining inhibitory neurons; 2) chronic nicotine exposure (CNE) upregulates nicotinic acetylcholine receptors (nAChRs); and, as a result, 3) acute nicotine and/or CNE will reduce or reverse the age-related auditory decline. We will test these hypotheses in both mouse and human at the level of cells (mouse in vitro brain slice), neural systems (mouse in vivo physiology; human brain imaging and EEG) and behavior (human psychoacoustics). Aim 1 will determine in mouse whether age-related decline in auditory spectrotemporal processing is reversed by acute nicotine or CNE, and characterize the associated cellular mechanisms. Aim 2 will identify, in humans, age-related changes in receptive field properties in auditory cortex using novel fMRI techniques and determine if nicotine reverses these changes using psychoacoustics, fMRI and EEG. This project features a multifaceted, parallel approach in mouse and human. Each Aim will: 1) examine auditory processing at multiple adult ages; 2) use similar acoustic stimuli in both species, accounting for species differences in hearing, to target common mechanisms; 3) test the effects of nicotine. A successful outcome will promote an integrated understanding across levels, from cellular mechanisms to perception, and facilitate translation of nicotine-based therapeutic treatments to clinical populations.