2006 — 2021 |
Constantinidis, Christos |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Neurophysiological Effects of Training in Visual Cognitive Tasks @ Wake Forest University Health Sciences
[unreadable] DESCRIPTION (provided by applicant): The primate prefrontal cortex plays a central role in the perception of sensory information and the planning of intelligent behavior, evidenced by the profound cognitive deficits following prefrontal injury and the mental illnesses associated with prefrontal malfunction. Previous neurophysiological studies in primates have sought to understand the involvement of the prefrontal cortex in cognitive functions and have indeed revealed prefrontal activation during execution of a large variety of behavioral tasks. Much less is known, however, on how the prefrontal cortex operates under more natural conditions, before animals have been heavily conditioned to perform a stereotypical task, and how training itself modifies neuronal responses and neural circuitry. In fact, the fundamental organization of sensory information within the prefrontal cortex has been under debate, as training in different tasks has resulted in quite distinct patterns of prefrontal activation. We have recently initiated a series of experiments examining the principles of prefrontal intrinsic connectivity as well as experiments examining neuronal responses of monkeys naive to behavioral training. Taking advantage of the methodological advancements and preliminary findings of these studies, we propose to test the nature of prefrontal encoding of visual information before and after training. Experiments will first test whether neurons in the dorsolateral and ventrolateral prefrontal cortex encode the spatial locations and features of visual stimuli presented passively and having no significance for the monkeys. The same monkeys will subsequently be trained in cognitive tasks that require them to identify and remember the spatial locations and features of these stimuli, allowing us to test whether single neurons are able to integrate spatial and feature information after training. We will use microelectrode arrays to record neural and to determine changes in the patterns of neuronal activation and in the functional connectivity between neurons. In the last few years, training human patients in similar tasks has emerged as a means of restoring cognitive function compromised after traumatic brain injury or stroke and ameliorating the effects of genetic brain disorders. Our results will shed light on the underlying neural circuit changes following cognitive training and offer insights on the design of better intervention strategies for the remediation of these conditions. [unreadable] [unreadable]
|
1 |
2008 — 2009 |
Constantinidis, Christos |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Cholinergic Influences On Prefrontal Cortical Activity During Cognitive Function @ Wake Forest University Health Sciences
[unreadable] DESCRIPTION (provided by applicant): A decline in core cognitive functions of attention, memory, and learning ability is commonly observed in neurodegenerative conditions such as Alzheimer's disease. These deficits can be partially reversed by cholinergic agents, for example acetylcholine agonists or acetylcholinesterase inhibitors. Cholinergic agents have also shown promise in enhancing recovery of cognitive functions after brain insult or disease, as in the case of Traumatic Brain Injury. Despite the known effectiveness of cholinergic agents, the neuronal mechanisms mediating cognitive performance that are targeted by ACh are poorly understood. The prefrontal cortex is known to be essential for higher cognitive functions, yet it is unknown how prefrontal neuronal activity mediating cognitive performance is affected by ACh levels. Taking advantage of recent technical innovations and experimental findings, we propose to use a non-human primate model to perform neurophysiological recordings from a chronically implanted array of microelectrodes over the prefrontal cortex during the systemic administration of cholinergic agents. The project relies on monitoring neuronal discharges from multiple cortical sites each day, in the same animals, before and after pharmacological intervention. This research will identify the aspects of neuronal activity that co-vary with behavioral performance during execution of cognitive tasks and will determine which of these are degraded by ACh antagonists and improved by ACh enhancers. Successful completion of the project will allow us to understand the effects of cholinergic agents in the prefrontal cortex associated with cognitive performance. Our research will also provide a primate model for the evaluation of new types of drugs that can potentially improve cognitive rehabilitation after neurodegenerative conditions and brain trauma. [unreadable] [unreadable] PUBLIC HEALTH RELEVANCE: Regulation of acetylcholine levels in the brain has been linked to the cognitive impairments associated with ageing, dementia, and schizophrenia. The proposed research will rely on a primate model to determine the effects of acetylcholine levels in a brain area critical for higher cognitive functions, the lateral prefrontal cortex. Successful completion of the project will provide a novel, primate model for the evaluation of different types of drugs as they relate to cognitive performance and rehabilitation. [unreadable] [unreadable] [unreadable]
|
1 |
2008 — 2017 |
Constantinidis, Christos |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Cortical Circuit Basis of Visual Spatial Processing @ Wake Forest University Health Sciences
[unreadable] Description (provided by applicant): Elucidating the biological basis of perception and cognition has been an enduring goal of neuroscience research because it is essential for treating brain disorders that can devastate the ability to think and act. Higher mental processes have traditionally been attributed to the prefrontal cortex, the part of the brain most developed in higher primates and humans. In recent years, however, it has become clear that many neural correlates of mental functions are not exclusive traits of the prefrontal cortex but are already evident in the cortical pathways that project to it, for example, the association areas of the temporal and parietal lobes. Uncovering the unique and cooperative roles of these cortical regions is therefore necessary for understanding the biological basis of higher mental functions. Even less is known about how the circuit organization and nature of neural processing differs between high-order cortical areas, so as to account for their distinct functional roles. We propose to use an integrative methodological framework to elucidate the unique and cooperative roles of areas involved with the processing of visual-spatial information. We will comparatively investigate the physiological responses and neural-circuit organization of the dorsal prefrontal and posterior parietal cortex. Our experiments will make use of neurophysiological recordings with arrays of closely-spaced electrodes in monkeys trained to perform visual-spatial tasks. We will examine the patterns of neural responses during the presentation of multiple visual stimuli, concurrently or in sequence, and analyze the functional interactions between neurons. Experiments will specifically test whether prefrontal cortex is characterized by more robust, more widely distributed or dynamically modulated neuronal connectivity, or functionally specialized cell types. These experiments will help unveil the functional specialization of cortical areas involved in higher cognitive functions and offer insights on normal perceptual processing as well as the consequences of brain injury and mental illness. PUBLIC HEALTH RELEVANCE Understanding the organization and function of cortical areas mediating higher cognitive processes is key to ameliorating the disorders that can devastate one's ability to think and act. The proposed research will rely on a primate model to determine the role and functional specialization of two areas of the cerebral cortex involved in the processing of visual spatial information, the posterior parietal and dorsal prefrontal cortex. [unreadable] [unreadable] [unreadable]
|
1 |
2009 — 2013 |
Constantinidis, Christos Stanford, Terrence R (co-PI) [⬀] |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) R33Activity Code Description: The R33 award is to provide a second phase for the support for innovative exploratory and development research activities initiated under the R21 mechanism. Although only R21 awardees are generally eligible to apply for R33 support, specific program initiatives may establish eligibility criteria under which applications could be accepted from applicants demonstrating progress equivalent to that expected under R33. |
Neurophysiology of Prefrontal Cortical Development @ Wake Forest University Health Sciences
DESCRIPTION (provided by applicant): The size of the prefrontal cortex has increased dramatically in primates compared to other vertebrates and its evolutionary expansion mirrors the development of attention, memory, and executive function in these species. Developmentally, the prefrontal cortex undergoes a long maturation process that extends through puberty and into early adulthood. A number of mental illnesses have onsets linked to the maturation of the prefrontal cortex, most notably schizophrenia, which manifests itself in early adulthood. Impulse control also improves in adulthood, and failure to develop adequately is associated with delinquency, drug abuse, and other conditions of health and social significance. Little is known about the physiological changes that the prefrontal cortex undergoes during puberty and early adulthood so as to mediate increased cognitive control. Taking advantage of recent methodological and conceptual advances, we propose to investigate the changes of prefrontal cortical physiology and functional connectivity that occur after puberty. We propose to use a non-human primate model which will allow us to conduct neurophysiological recordings in the prefrontal cortex of juvenile and adult animals. Our studies will also sample the posterior parietal cortex, an area interconnected with the prefrontal cortex. This will serve as a control area allowing us to determine what is unique about the maturation of the prefrontal cortex, and it will also allow us to study changes of functional connectivity between the prefrontal cortex and posterior parietal cortex. Our study will make use of monkeys trained to perform behavioral tasks that require attention, working memory, and executive control. These experiments will offer insights on how development of the prefrontal cortex alters its physiological responses which will be essential for understanding and treating mental illnesses associated with problems of prefrontal cortical maturation. PUBLIC HEALTH RELEVANCE: The proposed research will determine how the functions of prefrontal cortex neurons change between adolescence and adulthood. Knowledge drawn from these experiments will elucidate the development of higher cognitive processes such as attention and memory, which is necessary for understanding the biological basis of conditions such as Attention Deficit Disorder and mental illnesses such as schizophrenia.
|
1 |
2013 — 2017 |
Blake, David Trumbull Constantinidis, Christos |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Neuromodulator Influences On Prefrontal Cortical Function @ Wake Forest University Health Sciences
DESCRIPTION (provided by applicant): A decline in cognitive functions such as attention, memory, and decision making is observed in a series of neurodegenerative conditions and mental illnesses. Cholinergic drugs (acetylcholine agonists and acetylcholinesterase inhibitors) can reverse these symptoms. Despite the known effectiveness of cholinergic drugs in improving cognitive function, the neuronal mechanisms of action in cortical areas involved in these processes, such as the prefrontal cortex are poorly understood. This project will investigate the effects of cholinergic drugs on prefrontal cortical activity during the execution of cognitive task and the effects of stimulation of the Nucleus Basalis, the main source of endogenous cortical acetylcholine. Neurophysiological recordings will be performed by a chronically implanted array of microelectrodes over the prefrontal cortex during the systemic administration of cholinergic agents and deep brain stimulation in a non- human primate model. The experiments will allow us to understand the effects of cholinergic agents in the prefrontal cortex associated with cognitive performance. They will also evaluate the relative effectiveness of drug administration compared to deep brain stimulation. Our research will also provide a primate model for the evaluation of new types of drugs that can potentially improve cognitive rehabilitation following injury or illness.
|
0.948 |
2018 — 2021 |
Constantinidis, Christos |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Neurophysiology of Cognitive Development and Response Inhibition
PROJECT SUMMARY We will investigate the neural substrates of the maturation of response inhibition between the time of adolescence and adulthood. Response inhibition is thought to be mediated by the prefrontal cortex, a cortical area greatly expanded in primates compared to other vertebrates, which undergoes a long maturation process that mirrors the development of higher cognitive functions after adolescence. A number of mental illnesses have onsets linked to the maturation of the prefrontal cortex, most notably schizophrenia, which manifests itself in early adulthood. Executive function also improves in adulthood, and inadequate development of this capacity is associated with delinquency and other conditions of health and social significance. Little is known about the physiological changes that the prefrontal cortex undergoes in adolescence so as to mediate improved cognitive control. Taking advantage of recent methodological and conceptual advances, we propose to investigate the changes of prefrontal cortical physiology and anatomical connectivity that occur after puberty. We propose to use a non-human primate model that will allow us to conduct behavioral assessments, neurophysiological recordings, and MR imaging in the prefrontal cortex of developing animals and controls. Our study will make use behavioral tasks that test response inhibition. We will rely primarily on the anti-saccade task which requires subjects to make an eye movement in the opposite direction of a visual stimulus, thus resisting the pre-potent stimulus. Experiments will record neuronal activity related to task performance to understand what neural variables maturate after the onset of puberty. These experiments will offer insights on how development of the prefrontal cortex alters its physiological responses, findings that will be essential for understanding and treating mental illnesses thought to be associated with a failure of prefrontal cortical maturation.
|
1 |
2018 — 2021 |
Constantinidis, Christos Whitlow, Christopher T |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Neurophysiology of Working Memory Maturation in Adolescence @ Wake Forest University Health Sciences
PROJECT SUMMARY The goal of this project is to investigate the neural substrates of the maturation process that takes place around puberty and which is associated with the development of a key cognitive ability, working memory. The prefrontal cortex, a part of the brain greatly expanded in primates compared to other vertebrates, undergoes a long maturation process that extends through puberty and into early adulthood. This process mirrors the development of higher cognitive functions. A number of mental illnesses have onsets linked to the maturation of the prefrontal cortex, most notably schizophrenia, which manifests itself in early adulthood. Executive function also improves in adulthood, and inadequate development of this capacity is associated with delinquency and other conditions of health and social significance. Little is known about the physiological changes that the prefrontal cortex undergoes in adolescence so as to mediate increased cognitive control. Taking advantage of recent methodological and conceptual advances, we propose to investigate the changes of prefrontal cortical physiology that occur after puberty. We propose to use a non-human primate model that will allow us to conduct neurophysiological recordings in the prefrontal cortex of peri-pubertal and adult animals. Our study will make use of monkeys trained to perform behavioral tasks that test working memory ability. Experiments will record neuronal activity related to task performance to understand what neural variables maturate after the onset of puberty. These experiments will offer insights on how development of the prefrontal cortex alters its physiological responses, findings that will be essential for understanding and treating mental illnesses thought to be associated with a failure of prefrontal cortical maturation.
|
1 |
2019 |
Blake, David Trumbull Constantinidis, Christos |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Primate Model of Deep Brain Stimulation For Alzheimers and Age-Related Cognitive Decline @ Wake Forest University Health Sciences
PROJECT SUMMARY This project will investigate the potential of deep brain stimulation to improve cognitive abilities in aging, and counteract the effects of Alzheimer's and other types of dementias. We will perform experiments in nonhuman primates, because they experience a similar age-related cognitive decline as humans. Stimulation will be applied in the Nucleus Basalis of Meynert, the sole source of acetylcholine to neocortex. Drawing from recent experiments showing success of this method, intermittent stimulation will be delivered at 60 pulses per second for 20 seconds of each minute in old monkeys. The study design will test the efficacy of stimulation, and the duration of benefits after the intervention. Use of complementary pharmacological agents will determine if short-term effects of stimulation on cognition may be augmented by other agents, and what pharmacological systems they interact with. Partial nicotinic acetylcholine receptor agonists, positive allosteric modulators, serotonergic and noradrenergic agents will be tested, as will other agents that interact with cholinesterase inhibitors. In addition, the project will determine whether deep brain stimulation can ameliorate pathological changes associated with Alzheimer's dementias, as noted by biochemical, metabolic, and brain structural measures.
|
0.948 |
2019 |
Blake, David T Constantinidis, Christos |
RF1Activity Code Description: To support a discrete, specific, circumscribed project to be performed by the named investigator(s) in an area representing specific interest and competencies based on the mission of the agency, using standard peer review criteria. This is the multi-year funded equivalent of the R01 but can be used also for multi-year funding of other research project grants such as R03, R21 as appropriate. |
Primate Model of Deep Brain Stimulation For Alzheimers and Age-Related Cognitivedecline
PROJECT SUMMARY This project will investigate the potential of deep brain stimulation to improve cognitive abilities in aging, and counteract the effects of Alzheimer's and other types of dementias. We will perform experiments in nonhuman primates, because they experience a similar age-related cognitive decline as humans. Stimulation will be applied in the Nucleus Basalis of Meynert, the sole source of acetylcholine to neocortex. Drawing from recent experiments showing success of this method, intermittent stimulation will be delivered at 60 pulses per second for 20 seconds of each minute in old monkeys. The study design will test the efficacy of stimulation, and the duration of benefits after the intervention. Use of complementary pharmacological agents will determine if short-term effects of stimulation on cognition may be augmented by other agents, and what pharmacological systems they interact with. Partial nicotinic acetylcholine receptor agonists, positive allosteric modulators, serotonergic and noradrenergic agents will be tested, as will other agents that interact with cholinesterase inhibitors. In addition, the project will determine whether deep brain stimulation can ameliorate pathological changes associated with Alzheimer's dementias, as noted by biochemical, metabolic, and brain structural measures.
|
1 |
2021 — 2023 |
Constantinidis, Christos |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Crcns Us-Spain Research Proposal: Serial Dependence in Working Memory
Working memory, the ability to retain and manipulate information over a period of seconds, represents a core component of higher cognitive functions, including language, problem solving, reasoning, and abstract thought. Working memory capacity accounts for a great proportion of individual variability in academic performance, and it is impaired in clinical conditions including schizophrenia, stroke, traumatic brain injury, and ADHD. Understanding the neural basis of working memory has been a question in the forefront of scientific research over the past few years. This project relies on an “imperfection” of working memory, serial dependence: the contents of memory in a previous trial often affect what is being recalled in a following one, even though this is no longer useful. Serial dependences can provide insight into cellular mechanisms and neurotransmitter systems. Patients with genetic conditions such as schizophrenia, autism, and encephalitis exhibit different patterns of serial dependence. This project forms a collaborative experimental and theoretical approach to understand the role of different neurotransmitter systems and brain areas in serial dependence, which will reveal fundamental properties of the circuits that mediate working memory. Beyond the immediate goals of the experiments, understanding the neural basis of working memory and developing mechanistic models that capture its properties is expected to have broader impacts on a number of scientific fields, including neuroscience, psychology, cognitive science, computer science, and machine learning. The combined experimental-modeling approach has also direct relevance to understanding and treating these clinical conditions. The approach opens new avenues of model-guided research in neuropsychiatric conditions and enhances the reach of computational psychiatry.
Working memory has been linked to the prefrontal cortex, an area central to cognitive processing, with unique anatomical and cellular organization. NMDA receptors, which are abundant in the prefrontal cortex, are suspected to play a critical role for the maintenance of information in working memory, by virtue of their ability to maintain neurons at an excited state for an extended period of time, and to induce plasticity of synaptic connections. Direct evidence linking their cellular role to working memory behavior has been scant, however. This project will address the circuit mechanisms by which NMDA receptors support working memory function. We will rely on a novel approach, by investigating the mechanisms of history biases, as a manifestation of long-lasting NMDAR-dependent mechanisms in working memory. Serial dependencies are systematically affected in patients with schizophrenia and anti-NMDAR encephalitis, suggesting an underlying NMDAR-dependent mechanism. Experiments will train non-human primates to perform spatial working memory tasks; obtain single neuron neurophysiological recordings and local field potentials from dorsolateral prefrontal and posterior parietal cortex; administer NMDAR antagonists systemically; and use optogenetic cortical stimulation to test behavioral and physiological predictions of a computational model of serial biases. Analysis of neural data and computational modeling will integrate the results of the experiments in a fronto-parietal network model. This will shed light on the role of prefrontal NMDA receptors in shaping history-dependent biases, and the importance of local-circuit (intrinsic) connections and long-range connections. Specifying subunit-specific NMDAR mechanisms, and the role of the fronto-parietal network, will inform a new computational framework with biophysical detail and enhanced predictive power for subsequent experimentation. The project is expected to advance understanding of cognitive processes and the neural networks mediating them.
A companion project is being funded by the National Institute of Health Carlos III, Spain (ISCIII).
This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
|
1 |