John E. Desmond - US grants

Introduction: The development of Open MR Scanners, such as the Signa-SP facility at Stanford has opened the door for MR-imaging during minimally invasive procedures. The goals of this project are to develop techniques for MR-guidance and monitoring of therapeutic thermal and cryogenic lesions. MR is ideally suited to image guidance during minimally invasive procedures because the inherent multi-planar capabilities allow precise positioning of ablative devices at desired targets in the body. However the real potential of MR is its ability to monitor the effects of ablative processes while they are being performed. Specifically, we are developing methods to image the heat, and ice formed during thermal, and cryogenic lesions, respectively. Methods: MR-compatible RF ablation devices are being developed through a collaboration with Radiotherapeutics corporation. An MR-compatible RF ablation system which can ablate lesions up to 3.5 cm in diameter via a percutaneous approach is under development. Phantom and animal testing has been performed to evaluate device performance. Thermocouple validated trials are underway to test the accuracy of phase-difference MR thermal maps during heating with the device in phantoms and animals. MR-compatible cryoablation systems are being developed through a collaboration with Cordis corporation. With prostate carcinoma as the initial target, device testing in tissue phantoms and a dog prostate model has been implemented to test system performance, and develop MR-guided methods for percutaneous prostate ablation. Results: Successful RF ablation has been demonstrated during MR imaging in electrolyte-doped agar phantom and animal models. Phase difference images clearly show the pattern of head deposited by the probe, and correlate well with gross lesion size and shape. Phase difference imaging has proven accurate within 3 degrees C, within 4 mm of the probe, an a agar phantom. Conclusions: Magnetic resonance imaging with the Signa-SP systems holds great promise for image guidance and monitoring during minimally invasive thermal and cryo therapies. Future research will focus on refining the accuracy of MR-based temperature measurements, and ice ball imaging.

DESCRIPTION (provided by applicant): The overall goal of this research is to better understand the contribution of the cerebellum and cerebrocerebellar networks to cognitive function by combining functional MRI (fMRI) and transcranial magnetic stimulation (TMS) techniques with tasks of verbal working memory. The Sternberg verbal working memory task, with three temporally distinct phases of encoding, maintenance, and retrieval, is an ideal model system for studying cerebro-cerebellar contributions to cognition. Our studies to date have supported a cerebrocerebellar verbal working memory model that emphasizes a functional link between neocortical articulatory control regions, such as Broca's Area, to the superior cerebellum, and a second network that links neocortical substrates of phonological storage, located in inferior parietal regions, to the inferior cerebellum. We propose to further test and extend this model in three specific aims. The first will emphasize the encoding phase and will test the hypothesis that the superior cerebellum and posterior frontal regions participate in the initial preparation of the articulatory trajectory independent of stimulus modality. The second aim will emphasize the maintenance phase. We will test the hypothesis that the right inferior cerebellum is functionally linked to the left inferior parietal region and that activation in these regions will be modulated in tandem when phonological storage demands are systematically manipulated. In addition, we will test the hypothesis that a transient phonological storage deficit syndrome, similar to that observed in left temporal-parietal lesioned patients, can be reproduced in the TMS lab using stimulation to left inferior parietal and right inferior cerebellar regions. The third aim will emphasize the retrieval phase. The retrieval phase of the Sternberg task, which requires utilization of the stored information, has elicited the least amount of cerebellar activation in our event-related investigations. We hypothesize that by increasing the executive demands of the task - by imposing additional processing requirements - we will observe increases in retrieval-phase-related cerebellar activation. We further hypothesize that the amount of behavioral disruption produced by TMS in the retrieval phase will be correlated with the amount of retrieval-phase related cerebellar activation.

DESCRIPTION (provided by applicant): The overall goal of this research is to elucidate, using functional magnetic resonance imaging (fMRI), how aging in humans affects neural systems critical for eyeblink conditioning, including the cerebellum and the medial temporal lobe (MTL). While the cerebellum is essential for conditioned eyeblink responses, the MTL is also necessary for a specific type of learning referred to as "trace" conditioning, in which there is a gap in time between the offset of the conditioned stimulus (CS) and the onset of the unconditioned stimulus (US). Trace conditioning is also impaired in older subjects, and in both older and younger subjects who do not acquire awareness of the stimulus contingencies during the conditioning training. Our hypothesis is that in trace conditioning differences in MTL activation, along with differences in patterns of functional connectivity among neocortical and subcortical structures, will account for differences in trace conditioning behavioral performance in both older and unaware subjects. We predict that when the gap in time is absent (i.e., "delay" conditioning), awareness will have less effect on either performance or cerebellar activations, age group differences in cerebellar activation will account for more of the age differences in conditioned eyeblink performance than will MTL activation differences, and age group differences in patterns of functional connectivity will differ from those observed in trace conditioning. We plan to first characterize age-related changes in CS and US pathways using unpaired CS and US presentations, and hypothesize that any age differences will be observed in the cerebellum for short CSs and in the MTL during the trace period. We will investigate age-related changes in brain activation during delay and trace conditioning protocols, and hypothesize differential importance of cerebellar and MTL activations, respectively, for age-related changes in performance of delay and trace conditioning. Finally, we will investigate the role of awareness in age-related changes in brain activation underlying eyeblink conditioning by (a) disrupting the acquisition of awareness and observing its effect on conditioning and brain activation and (b) measuring the concurrent development of awareness, eyeblink conditioning, and brain activation. We predict that in trace conditioning, subjects that acquire awareness will condition better and exhibit greater MTL activation than unaware subjects, age differences in conditioning and MTL activation will be reduced or eliminated after equating for awareness, age-related changes in functional connectivity will differ between delay and trace conditioning, patterns of functional connectivity will change as a function of awareness for trace conditioning, and left prefrontal cortex will be a critical node in awareness-related functional circuits. Finally, we will examine the link between age-related differences in trace conditioning and other types of age-related cognitive decline, and we will test a model of MTL/neocortical involvement in trace conditioning and awareness using transcranial magnetic stimulation.

Abstract Not Provided.

DESCRIPTION (provided by applicant): The goal of this project is to better understand the changes in cerebro-cerebellar brain function that occur after chronic alcoholism. Using verbal and spatial working memory as model paradigms for investigating cognitive- related cerebro-cerebellar function, our preliminary investigations have suggested that alcoholism can produce either decreases in activation or increases that may be compensatory in nature. We propose to further investigate alcohol-related changes in activation using event-related functional magnetic resonance imaging (fMRI) methods designed to shed more light on the nature of alcohol-induced neuropsychological deficits. Our working memory paradigm is comprised of 3 distinct task phases of encoding, maintenance, and retrieval of information. It has not been determined whether changes in brain activation observed thus far in alcoholics are derived from one or more of the cognitive demands occurring during these task phases. Specifically, differences in activation we have observed could be due to differences in the ability to acquire sensory input and encode verbal information (encoding), differences in rehearsal of information (maintenance), differences in the executive utilization of the maintained information (retrieval), or a combination of these three. We will use event-related fMRI to examine phase specific differences caused by alcoholism, and we will introduce phase- specific challenges to further examine process-specific changes in regional cerebro-cerebellar activation that differ between alcoholic and non-alcoholic subjects. We will also investigate possible dissociations of verbal and spatial working memory on alcohol-related changes in cerebro-cerebellar activation. Whereas spatial working memory in alcoholic subjects has revealed decreases in frontal lobe activation, verbal working memory has elicited left frontal and right cerebellar increases in activation. We propose to investigate whether these different patterns reflect differences in tasks across studies, differences in alcoholic populations, or differences in the effect of alcohol on neural substrates underlying verbal and spatial working memory. Finally, scans designed to measure blood flow, blood volume, and blood oxygenation will be used to determine to what extent BOLD signal differences in the populations are influenced by vascular and/or metabolic changes. These investigations will provide a better understanding of how chronic alcoholism changes brain function underlying cognition. PUBLIC HEALTH RELEVANCE: Chronic alcoholism is known to cause structural changes in the brain, but little is known about the effects of alcoholism on brain function underlying cognitive performance. The experiments in this proposal are designed to characterize, using functional MRI and tasks of verbal and spatial working memory, differences between alcoholics and non-alcoholics in brain function underlying these fundamental cognitive processes.

? DESCRIPTION (provided by applicant): The overall goal of this research is to investigate the nature of cerebellar involvement in cognitive function, using functional MRI (fMRI), transcranial magnetic stimulation (TMS), and concurrent TMS/fMRI. Cerebellar activation has been found in a wide variety of cognitive tasks, including verbal fluency, conceptual reasoning, planning, and theory of mind. Although a number of theories of cerebellar involvement in cognition have been proposed, there is no consensus to date on a specific operation that is provided by the cerebellum that contributes to cognitive function. In addition some cerebellar researchers question whether cognitive-related cerebellar activations are contaminated by incidental motor movements, e.g., movements of the eyes, or movements of articulation. In this project we address these issues using verbal working memory, which reliably and robustly elicits cerebellar activation, as a model cognitive system. Verbal working memory is a fundamental cognitive function with a strong theoretical framework. We propose that the cerebellum can be integrated into this framework: Our studies to date have supported a cerebro-cerebellar verbal working memory model that emphasizes a functional link between neocortical articulatory control regions, such as premotor cortex/Broca's Area, to the superior cerebellum, and a second network that links neocortical substrates of phonological storage, located in inferior parietal regions, to the inferior cerebellum. Our first specific aim is to test these circuitry assumptions using novel concurrent TMS/fMRI investigations that employ our newly developed and published methods for precisely identifying in the scanner the stimulation site and TMS trajectory in the brain. Our second specific aim is to assess the contribution of incidental motor function to cerebellar activation during verbal working memory by systematically varying the eye movement, articulatory movement, and finger movement requirements during verbal working memory to determine if these motor functions can explain working memory-load-dependent activations in the cerebellum. Our third aim is to evaluate alternative theoretical explanations of the fundamental computation underlying cerebellar cognitive activations, using verbal working memory as our model system. Our verbal working memory protocol, the Sternberg Task, contains a number of components that have been theorized by different researchers to be fundamental to cerebellar function. These components include sensory acquisition, timing, sequence deviation detection, and forward modeling/error correction. The experiments in this project will examine the contribution of these different components to verbal working memory elicited cerebellar activations. The impact of this project is that the results will help us understand the fundamental functions(s) that the cerebellum provides in cognition. This understanding is essential for interpreting both the numerous functional neuroimaging studies that show cerebellar activation in well controlled cognitive tasks, as well as the patterns of cognitive deficits observed in cerebellar patients.