Daniel Z. Press - US grants

behavioral /social science research tag; bioimaging /biomedical imaging; brain imaging /visualization /scanning; prefrontal lobe /cortex; short term memory

human therapy evaluation; psychotherapy; cognition disorders; Parkinson's disease; brain imaging /visualization /scanning; motor cortex; brain mapping; prefrontal lobe /cortex; neuropathology; short term memory; magnetic field; brain disorder chemotherapy; brain electronic stimulator; dihydroxyphenylalanine; psychomotor reaction time; bioimaging /biomedical imaging; behavioral /social science research tag; human subject; psychological tests; clinical research;

DESCRIPTION: (Verbatim from applicant?s abstract) This is an application for an NIMH Mentored Patient-Oriented Research Career Development Award (K-23) entitled "Imaging Procedural + Working Memory in Parkinson?s Disease." While the main features of Parkinson?s disease (PD) refer to motor symptoms, cognitive function is also affected, particularly in the realms of working memory and procedural learning. Working memory refers to the maintenance of information "on-line" and procedural learning refers to experience-induced changes in performance. Performance on procedural learning tasks may improve after an intervening period of sleep, a process called procedural consolidation. Dopamine plays a crucial modulatory role on both working memory and procedural learning networks, and this may be the basis for cognitive dysfunction in PD. The goal of this project is to investigate the role of dopamine in working memory and procedural learning in PD patients using a combination of sensitive behavioral tasks and functional MRI (fMRI). PD patients in a dopaminergic deficient state and a dopaminergic repleted state will be compared to control subjects to ascertain the role of dopamine in working memory and procedural learning. fMRI studies of working memory and procedural learning will demonstrate the effects of dopamine on the neural systems subserving these tasks. Subjects will then be tested behaviorally at three time points over 24 hours to determine the effect of consolidation on task performance. By comparing the changes in performance at the three time points, the role of sleep in consolidation can be isolated. It is hypothesized that the combination of dopaminergic repletion and consolidation can improve cognitive performance on tasks. A second fMRI will then be acquired after 24 hours to determine the changes in the neural systems that correspond to the behavioral changes of procedural consolidation. The results will have implications not only for the basis of cognitive symptoms in Parkinson?s disease, but also for the fundamental mechanisms of procedural learning and consolidation. The training program supplements the candidate?s background in clinical investigation and behavioral neurology with additional training in functional imaging and cognitive neuroscience. The program capitalizes on the rich resources in the Boston area. It provides specific training in fMRI, advanced statistics, and research ethics. The integrated training and research program will allow the candidate to develop the tools to become an independent investigator of the cognitive deficits in Parkinson?s disease.

[unreadable] DESCRIPTION (provided by applicant): Parkinson's disease affects over 1 million Americans, 15% of whom are under the age of 50. The hallmarks are motor difficulties, but it also impairs cognitive function, particularly in ordering, monitoring and switching among tasks (executive function). Impaired cognitive ability in this domain contributes markedly to occupational problems and impaired quality of life. The goal of the this project is to determine the brain regions involved in these tasks, how function in these regions is altered in Parkinson's disease, and whether a deficiency in the neurotransmitter acetylcholine contributes to deficits in executive function for patients with Parkinson's disease. The proposed experiments use two complementary imaging techniques: functional MRI to determine how the neural system that subserves executive function is disrupted in Parkinson's disease, and perfusion MRI to examine cerebral blood flow changes that correlate with cognitive deficits. We will test the hypothesis that deficits in executive function in PD are related to impairments in the medial frontal areas, since there is greater cell loss in these areas. The lateral frontal cortex is often assumed to be the cause. The second hypothesis is that these specific behavioral and regional deficits are caused, in part, by a deficiency in the neurotransmitter acetylcholine. PD patients who have executive dysfunction and demographically-matched controls will receive either the cholinesterase inhibitor donepezil or placebo in a double-blind, crossover design. They will then undergo behavioral testing, fMRI with phonemic fluency, and perfusion MRI. The fMRI data will determine the neural regions involved in a specific executive function task, phonemic fluency, and test how these regions are affected in PD. The perfusion MRI results will address what changes in cerebral blood flow are associated with this executive impairment. By contrasting the two imaging paradigms after donepezil with those after placebo, we will test the role of a cholinergic deficiency in the executive dysfunction seen in PD. Taken together; the proposed studies will provide insight in the regional and neurochemical basis of cognitive impairments in Parkinson's disease. It will also test whether cholinergic repletion is a potential mechanism for treating these deficits in executive function using a series of behavioral tests, functional brain imaging, and measures of cerebral blood flow with perfusion MRI. Project Narrative The primary goal of this proposal is to determine the regional and neurochemical basis of executive dysfunction in Parkinson's disease. We plan on using specifically designed cognitive measures as well as two complementary brain imaging techniques, functional MRI and perfusion MRI, to determine the regional basis of the deficit. We then propose a cholinergic probe, applied in a double-blind, placebo-controlled manner, to determine the role that a deficiency in acetylcholine may play in both the behavioral deficits and the dysfunction in the neural systems. [unreadable] [unreadable] [unreadable]

PROJECT SUMMARY Deep brain stimulation (DBS) has had great impact, helping patients with disorders such as Parkinson's disease and obsessive?compulsive disorder (OCD), and with great potential for other disorders such as depression and Alzheimer's disease. DBS, being a surgical procedure, bears the potential for complications that limit its deployment and adoption. Transient non-invasive brain stimulation methods, such as transcranial magnetic stimulation (TMS) and transcranial current stimulation (tCS), also show therapeutic potential and have been used in many human clinical and neuroscientific investigations, but they fail to achieve focality at depth. In a paper we recently published in Cell, we reported the initial stages of development of a non-invasive, steerable, 3D focal brain stimulation method that has the potential in the future to transform the risk-benefit ratio for DBS by providing an alternative without the need for surgery, as well as to improve the precision of other non-invasive methods such as TMS or tCS. We showed that by delivering two electric fields at slightly different carrier frequencies, which are themselves too high to recruit effective neural firing but for which the offset frequency is low enough to drive neural activity, we can create an electric field envelope at the offset frequency. We found that this low-frequency modulated electric field can cause neurons to be electrically activated at a deep focus, without driving neighboring, or overlying, brain regions. We now propose to refine this technology for multiple clinically relevant targets and collaboratively deploy them into several relevant settings, including the demonstration of early human translation assessing feasibility, safety, steerability, and depth selectivity. Specifically, we will (Aim 1) optimize TI stimulation for three targets of clinical interest, basal forebrain, central thalamus, and visual cortex, for investigation in humans and mice; (Aim 2) translate TI stimulation to human and demonstrate safety, steerable precision, and depth selectivity; (Aim 3) develop TI implementations of anesthesia, in rodent models. In this way we will deliver to the clinical community a technology ready for clinical trials in a diversity of clinical contexts.