Joel L. Voss - US grants

DESCRIPTION (provided by applicant): A career development plan is proposed for Dr. Joel Voss, a cognitive neuroscientist committed to a research career studying the brain substrates of memory and memory decline due to various pathological states. Dr. Neal Cohen at the Beckman Institute for Advanced Science and Technology at the University of Illinois Urbana-Champaign will mentor the applicant. Dr. Cohen is an eminent scholar of the neural basis of memory and has a long record of training successful researchers, and the Beckman Institute provides a rich environment for cognitive neuroscience training. Furthermore, two renowned memory researchers will contribute to the scientific development of the applicant, including Dr. Mark D'Esposito at the University of California at Berkeley and Dr. Daniel Tranel at the University of Iowa College of Medicine. Dr. Voss'training will include developing expertise with multi-methods approaches to identifying the brain substrates of cognition and behavior. Training will involve noninvasive methods for measuring brain activity as well as the study of cognitive impairments in patients with focal brain damage and the effects of temporary disruption of neural processing in healthy individuals. Training will also involve studying the effects of aging on memory and using computer-simulated environments to study cognition in realistic circumstances. The proposed research program aims to discover how coordinated neural systems optimize learning and memory by strategically allocating resources in order to meet the demands of a particular learning situation. This process depends upon the confluence of executive function, attention, and memory, and is disrupted by pathological events that target the brain substrates of these three cognitive domains, such as Alzheimer's disease, Schizophrenia, ADD/ADHD, and autism. The research also seeks to develop optimal strategies that can be used by older individuals to combat the pervasive challenge of age-related memory decline, which affects almost every individual as a result of normal aging. The proposed research has transparent clinical relevance with regard to remediation of the memory deficits of older individuals and broad relevance with regard to understanding the mechanisms of pathological effects on executive function, attention, and memory. PUBLIC HEALTH RELEVANCE: This research is intended to discover how the brain enables individuals to strategically control how they interface with the environment in order to optimize learning and retain as much information as possible. In addition, this learning process will be studied in older adults in order to develop interventions to guard against the pervasive problem of memory decline due to normal aging. The knowledge that will be gained is relevant to understanding the mechanisms by which many disease states interfere with the neural machinery of memory, including Alzheimer's disease, Schizophrenia, ADD/ADHD, and autism, and in developing treatments for these ailments.

? DESCRIPTION (provided by applicant): Memory impairment occurs in a variety of neuropsychiatric conditions (e.g., depression and schizophrenia) and in many neurologic disorders (e.g., neurodegenerative disease and brain injury). Unfortunately, memory impairments have devastating consequences for life quality and there are no current treatments that reliably improve memory function. The goal of this project is to better understand a new procedure for the noninvasive enhancement of human hippocampal-cortical brain networks that are thought to critically support memory. This noninvasive brain-stimulation procedure can produce robust and lasting (at least ~24 hours) enhancement of hippocampal-cortical networks and concomitant improvement in long-term associative memory. However, relevant brain mechanisms must be more fully specified before this procedure can be more broadly applied to better understand and treat memory impairments. We therefore propose a collection of experiments that aim to answer three standing mechanistic questions. First, we aim to test whether distinct hippocampal-cortical brain networks can be selectively enhanced, which would determine whether stimulation acts on discrete targeted memory networks. Second, we aim to determine the timecourse and duration of these enhancements, which is essential for evaluation of putative neural mechanisms and of potential for clinical utility. Finally, we aim to test whethe the hippocampus is the key site of stimulation-induced enhancement of hippocampal-cortical networks by targeting intact versus surgically removed hippocampal tissue in individuals with unilateral medial temporalobectomy performed for treatment of refractory epilepsy. Impairments in stimulation-induced enhancement of hippocampal-cortical networks and memory when missing hippocampal tissue is targeted would confirm the necessary/causal role of hippocampus in the effects of stimulation. All proposed experiments involve sophisticated assessments of hippocampal-dependent memory function and of hippocampal-cortical brain networks. Findings will thus deeply inform understanding of stimulation effects while at the same time producing important information on the role of hippocampal-cortical networks in memory. Insights from this research could propel understanding of memory impairment and its treatment by noninvasive stimulation.

DESCRIPTION (provided by applicant): Memory impairment is a major challenge for healthy older adults as well as those with age-related neurodegenerative diseases such as Alzheimer's disease and Mild Cognitive Impairment (MCI). Unfortunately there are no current treatments that reliably and robustly improve memory abilities for older adults. The goal of this project is to better understand and to improve a new potential treatment for memory impairment developed by the investigative team. This procedure involves noninvasive stimulation of the hippocampal brain network necessary for memory, and is called Hipp-Stim. We have previously shown that Hipp-Stim can produce robust and lasting enhancement of the hippocampal network and associative (hippocampal-dependent) memory in young healthy individuals. The current proposal is to test efficacy and mechanisms of action in healthy elderly adults and in MCI patients. The effects of stimulation will be observed on tests of hippocampal- dependent memory and on brain imaging measures of hippocampal network function obtained in relation to memory capabilities. Sham-controlled, double-blind experiment designs will be used to ensure that treatment effects are specific to stimulation. Furthermore, comprehensive cognitive assessments will test selectivity of stimulation effects to memory, and neuroimaging analyses will test selectivity of stimulation effects to hippocampal brain networks. Improvements in memory performance will be assessed in relation to changes in individual's ability to perform and satisfaction with activities of daily living, in order to identify ramifications of improved memory for life quality. By performing Hipp-Stim experiments using a variety of hypothesis-driven stimulation intensities, frequencies, and delivery locations, we will determine optimal parameters for producing the greatest positive effects on memory ability, hippocampal network function, and life quality. A group of individuals with MCI will receive treatment using the optima stimulation parameters in order to determine if Hipp-Stim is effective for this condition. All experiments involve sophisticated assessments of hippocampal- dependent memory performance and hippocampal brain network function. The findings will thus deeply inform knowledge of stimulation effects and therefore foster better understanding of relevant mechanisms of action on memory-related brain regions in older adults. Insights from this research could propel understanding of age- related memory impairment and its treatment by noninvasive stimulation, while also producing new methods to combat age-related and neurodegenerative loss of memory abilities.

? DESCRIPTION (provided by applicant): Prefrontal cortex has been implicated in the formation of long-term episodic memories, although its contributions have not been fully specified. The primary goal of this project is to evaluate the utility of noninvasive brain stimulation for selectve modulation of specific prefrontal processes that contribute to episodic memory. Our approach is based on the notion that hippocampal-dependent relational binding builds episodic memories by linking the various sights, sounds, thoughts, and other content that occur with unique context and timing during events. We hypothesize that specific prefrontal cortical regions contribute critically to this binding process by selecting and organizing the various episode components into a coherent structure for binding by hippocampus. We propose to temporarily modulate the function of these regions in healthy adults using transcranial magnetic stimulation. The effects of this modulation on memory will be assessed using sophisticated cognitive neuroscience paradigms to identify behavioral and neural correlates of prefrontal selection/organization processes that contribute to episodic memory as distinct from other concurrent prefrontal processes that contribute to episodic memory. These paradigms blend manipulations of active versus passive learning with sensitive behavioral and eye-movement tracking measures to provide high specificity to distinct prefrontal processes during episodic memory formation. This will allow thorough evaluation of the ability to modulate specific prefrontal processes contributin to memory formation using transcranial magnetic stimulation. Functional neuroimaging will be used to assess mechanisms for effects of noninvasive stimulation on memory. Validation of noninvasive brain stimulation for the selective modulation of specific prefrontal contributions to episodic memory would open the door for strong causal tests of prefrontal contributions to memory and other cognitive functions and could motivate new stimulation-based interventions for neuropsychiatric and neurological disorders of prefrontal cortex.

Project Summary/Abstract Memory impairment occurs in a variety of neuropsychiatric conditions (e.g., depression and schizophrenia) and in many neurologic disorders (e.g., neurodegenerative disease and brain injury), often with devastating consequences for life quality. The goal of this project is to determine optimal dosing parameters for a new procedure involving the noninvasive enhancement of human hippocampal-cortical brain networks that critically support memory. This noninvasive brain-stimulation procedure, ?HFN-Stim?, can produce robust and lasting enhancement of hippocampal-cortical networks and concomitant improvement in long-term memory for up to 15 days after stimulation. However, stimulation parameters have not been optimized. It is yet unknown whether HFN-Stim could be tailored to have greater effects on hippocampal-cortical networks and memory. We therefore propose a collection of experiments that will determine optimal duration, frequency, and context of stimulation by establishing dose-response relationships for each of these three parameters. First, we will determine whether increasing consecutive, daily HFN-Stim sessions (5, 10, and 20 days) produces greater and/or longer- lasting effects on hippocampal-cortical networks and memory. Second, we will determine whether stimulation frequencies matching endogenous oscillatory activity of the hippocampal-cortical network (i.e., theta rhythm) produce greater and/or longer-lasting effects on hippocampal-cortical networks and memory, relative to existing frequencies that have been used for HFN-Stim. Finally, we will determine whether delivery of HFN-Stim while subjects perform a demanding memory task designed to engage the hippocampal- cortical network produces greater and/or longer-lasting effects on hippocampal-cortical networks and memory, relative to performance of a control task that does not robustly engage the hippocampal-cortical network. These research objectives are in close alignment with the focus of RFA-MH-16-815 on establishing dose/response relationships for existing neuromodulation devices to promote neuroscience applications and clinical interventions, specifically RFA Topics 1, 3, and 4 on the duration, frequency, and contextual aspects of stimulation. All proposed experiments involve sophisticated assessments of hippocampal-dependent memory and of hippocampal-cortical brain networks, obtained through simultaneous fMRI/EEG and detailed memory testing. Findings will deeply inform efforts to optimize noninvasive stimulation for the enhancement of hippocampal-cortical networks and memory. This research could propel understanding of memory impairment and its treatment by noninvasive stimulation.

Project Summary/Abstract The distributed brain network of the hippocampus supports memory and related cognitive abilities. Disruptions of this network occur in many neurological disorders such as epilepsy, brain injury, and neurodegenerative disease. Brain stimulation targeting the human hippocampal network can produce long-lasting improvements of memory ability, with corresponding increases in brain-activity markers of network function. However, mechanisms for this beneficial network-level neuroplasticity caused by brain stimulation remain unknown. Mechanistic knowledge is essential to optimize how and where to stimulate the hippocampal network in order to maximize the resulting memory benefits. This project will investigate the cellular mechanisms for the effects of brain stimulation on the hippocampal network. We will capitalize on the property that activity of regions of the hippocampal network synchronize in the theta frequency band (5-8Hz) to test for mechanistic homology in the effects of stimulation on human versus rodent hippocampal networks. In humans undergoing neurosurgery for intractable epilepsy and in awake, behaving rodents, we predict that electrical stimulation will have greater effects on hippocampal network function when it is delivered with increasing levels of synchronization to the ongoing hippocampal theta activity rhythm. Thus, we will test whether the effects of manipulating the synchrony between brain stimulation and hippocampal theta activity are comparable in humans and rodents. The effects of stimulation will be assessed using measures of hippocampal network functional connectivity and paired-associate memory performance that can be performed similarly in both species. We will then conduct in vitro electrophysiology experiments in rodent brain slices obtained after stimulation in order to identify cellular mechanisms for the effects of stimulation. We predict that stimulation parameters that increase hippocampal network function will increase cellular excitability, as measured via the postburst afterhyperpolarization, of dorsal hippocampal CA1 pyramidal neurons. Viral manipulation of CREB expression, which is necessary for changes in excitability, will be used to causally test the role of dorsal hippocampal CA1 excitability in the effects of stimulation on hippocampal network function. These research objectives are in close alignment with the focus of RFA-NS-18-018 on establishing cellular mechanisms for the effects of brain stimulation on neuronal circuits. Findings will uniquely uncover cellular mechanisms by which brain stimulation beneficially impacts distributed brain networks and corresponding cognitive abilities. These mechanistic insights could propel brain-stimulation treatments for memory impairments caused by disruption of the hippocampal network.

Supplement Project Summary/Abstract The purpose of this administrative supplement for our ongoing grant ?Cellular mechanisms of hippocampal network neuroplasticity generated by brain stimulation? (R01-NS11380) is to use the innovative translational brain stimulation methods developed under the ongoing parent grant to test whether and how they rescue memory impairments in the next-generation rodent model of Alzheimer?s disease (AD), TgF344-AD. AD produces memory impairment by affecting the function of the distributed network of the hippocampus. Our ongoing project investigates the mechanisms whereby electrical brain stimulation targeting the hippocampal network can improve its function. By performing companion in vivo electrophysiological experiments in healthy young adult rodents and in human neurosurgical cases with depth electrodes in regions homologous to those implanted in the rodents, the ongoing project takes a highly translational approach to identify similarities across species in how the hippocampal network responds to brain stimulation. This approach thereby enhances the relevance to human function of the mechanistic insights offered by rodent in vivo and in vitro electrophysiology experiments performed for the ongoing project. This administrative supplement will expand our translational model of hippocampal network brain stimulation to address memory impairment due to AD. We first will behaviorally characterize young (5-6 mo.) and aged (20-23 mo.) F344 wild-type and aged TgF344-AD rats (a rodent model of AD) using the spatial Morris water maze task. Aged F344 rats will be categorized based on performance of this task into age-unimpaired (AU) and age-impaired (AI) subgroups, such that comparisons among the four groups (young, AU, and AI F344 rats and aged TgF344-AD rats) will be able to differentiate variation in stimulation efficacy based on aging, on typical aging-related memory impairment, and on AD pathology. In each of these groups, we will then compare the effects of locking stimulation to the ongoing phase of the hippocampal theta rhythm (versus non-phase-locked control conditions) on hippocampal network in vivo electrophysiology and on performance on the paired associate learning (PAL) touchscreen task, which is hippocampal dependent in both rodents and humans. Across-group comparisons will be used to determine whether phase-locked stimulation is maximally beneficial for hippocampal network electrophysiology and PAL performance in TgF344-AD rats relative to AI rats, with comparisons between AI and AU groups and between AU and young groups used to differentiate the effects of AD from those of aging with versus without memory impairment. Notably, although brain stimulation has shown moderate efficacy for memory impairment in aging and AD, very little data are available regarding mechanisms. These experiments will thus yield important and highly novel data on how brain stimulation targeting the hippocampal network influences its function in animals with AD. Results will be useful in tailoring brain stimulation for memory rescue in human AD patients owing to the highly translational nature of the experimental animal brain stimulation model that we have developed.