Eric A. Moulton - US grants

DESCRIPTION (provided by applicant): This K01 application is designed to prepare the applicant with the skills necessary to establish an independent research program on pain-related processing in the cerebellum. Although pain studies using functional imaging in humans consistently find cerebellar activation, the role of this structure during pain is unknown. In such studies, speculation regarding the cerebellum's function during a painful event is often influenced by its reputation as a coordinator of motor function, though animal studies have indicated that it may also modulate the neural encoding of noxious stimuli. The candidate has published work that indicates a functional dichotomy in the way the cerebellum responds to experimental pain in healthy subjects and neuropathic pain patients. This suggests that the cerebellum has been overlooked as a potential pain processing area, and research into this area could lend invaluable insight into the basic physiological circuitry involved with pain and its modulation. The hypothesis of this project is that the cerebellum serves as an integrator of aversive stimuli and adaptive motor behavior, and may modulate the emotional and cognitive experience that distinguishes the perception of pain from the appreciation of innocuous sensory stimulation. A human trigeminal model of experimental pain will be used, as all the pain-related circuitry involved can be imaged along with the cerebellum at the same time. The specific aims are (1) to map cerebellar activations related to sensory coding of noxious stimuli and to correlate functional activity with anatomical connectivity using functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI);(2) to distinguish between pain and its anticipation based on cerebellar responses and connectivity;and (3) to determine whether physical pain and aversive images engage similar circuitry in the cerebellum. To accomplish these aims, the candidate will need to expand his background in fMRI of cortical and brainstem pain processing to encompass cerebellar physiology, become proficient in DTI analysis, and learn the white matter connectivity to and from the cerebellum. The research environment at McLean Hospital and the other affiliates of the Harvard Medical School system will provide the candidate with the resources to reach his aims within 4 years. Enhanced understanding of cerebellar pain processing may lead to new treatments for chronic neuropathic pain conditions, which can have altered cerebellar functionality.

DESCRIPTION (provided by applicant): This R21 application is designed to determine the impact of cerebellar damage on pain sensation and pain processing in the brain. Pain is a subjective experience comprised of sensory, affective, and cognitive dimensions. Human functional imaging studies investigating experimental and clinical pain consistently find cerebellar activation, though its functional implications are unclear. Initially thought to reflecta motor circuit response to pain, the characterization of cognitive and affective deficits following cerebellar damage in children and adults suggest a fundamental role in pain processing. We have also published work that suggests that the cerebellum may serve as a multimodal modulator of negative affect, a significant component in pain processing. However, as far as we know, a thorough investigation of changes in pain sensation following cerebellar tumor resection has never been reported. The hypothesis of this project is that the posterior cerebellum modulates affective brain circuits to down-regulate pain perception in response to noxious stimuli. The specific aims are (1) to define the consequences of cerebellar tumor resection on pain perception with sensory testing, and (2) define the consequences of resection on pain processing in the brain with functional magnetic resonance imaging. Boston Children's Hospital will provide an ideal clinical research environment to efficiently recruit patients, and to evaluat them with sensory testing and neuroimaging. The long-term goal is to identify the role of the cerebellum in pain processing.