Kathryn A. Cross, Ph.D. - US grants

DESCRIPTION (provided by applicant): Imitation often occurs automatically and unconsciously, especially during social interactions. Imitation is thought to rely on a specialized neural system that contains neurons responsive to both action observation and action execution. These so-called mirror neurons provide a parsimonious mechanism to translate visual information about an action into the motor representation necessary to produce the same action, by specifically modulating the excitability of the primary motor representation of the action. This model is able to explain the automatic tendency to imitate, however it is not clear how this automatic tendency is controlled to prevent perpetual imitation. The goal of the current proposal is to elucidate the neural mechanisms that control the automatic tendency to imitate. In light of neurological and psychiatric patients with imitation control deficits, as well as early research suggesting a distinct inhibitory mechanism for control imitation, we predict that control of imitation occurs through a specialized control network and that it may involve modulation of the mirror neuron system. Impaired imitation is a hallmark of autism spectrum disorders. Due to the proposed role of mirror neurons in understanding others'actions and emotions, recent research has examined mirror neuron function in autism. Converging evidence suggests that activity in the human mirror neuron system may be decreased in autism spectrum disorders compared to typically developing children. However, the etiology of this decrease in activity has not been explored. Two possibilities include intrinsic mirror neuron system dysfunction and impaired regulation of the mirror neuron system by distinct neural circuitry. Understanding control of imitation in typical subjects will pave the way for studies in autism that can disentangle these two possibilities as well as provide insight into the neural underpinnings of the imitative deficits. In Aim 1, two functional magnetic resonance imaging studies are planned to compare inhibition of imitation directly with better understood inhibitory mechanisms. Control of imitation will be compared with response inhibition, as measured by the stop-signal paradigm. In addition, imitation control and resolution of interference in a spatial compatibility task will be compared, since interference resolution has been argued to rely on distinct cognitive control processes. In Aim 2, transcranial magnetic stimulation will be used to evaluate the causal roles of commonly studied control mechanisms in control of imitation. Improved understanding of control of imitation at a basic level in normal populations will provide a platform to explore deficits in imitation and the mirror neuron system in psychiatric illnesses such as autism spectrum disorders. PUBLIC HEALTH RELEVANCE: Deficits in social abilities and imitation are seen in psychiatric conditions such as autism spectrum disorder. Recent work suggests that these impairments may result from decreased activity in a specialized neural system that is important for both the observation of actions and the execution of actions. Understanding how other brain areas control this specialized "mirror neuron system" through the study of imitation control will contribute to our understanding of the social and imitative deficits that are fundamental to these disorders.

PROJECT SUMMARY A promising strategy to improve neuromodulation therapies (e.g. deep brain stimulation) in Parkinson?s Disease (PD) is to develop stimulation paradigms that target specific neural signals. Most previous work has aimed to identify and reduce pathologic signals. An unexplored alternative approach is to identify and enhance neural signals that promote movement. Several scenarios known to improve movement in PD patients are the presence of visual movement targets, rhythmic auditory stimuli, and motivational incentives. The goal of this proposal is to capitalize on these scenarios to identify biomarkers of movement facilitation that may serve as targets for future neuromodulation therapies. This approach has potential to provide novel therapies for symptoms refractory to current treatments, such as freezing of gait. Previous work examining neural mechanisms of movement facilitation in PD have yielded inconsistent results. This may be due to a failure to account for well-known heterogeneity in behavioral benefits across PD patients and the assumption that different cueing phenomena exert motor benefits through a single neural mechanism. The studies proposed here test the overarching hypothesis that 3 different types of cues (visual targets, rhythmic auditory stimuli and reward incentives) facilitate movement through distinct neuroanatomic circuits and electrophysiological mechanisms, by leveraging known variability in behavioral cueing benefits across patients. Aim 1 is to demonstrate behavioral dissociations between the 3 forms of movement facilitation within patients and relate variability in cueing benefits to integrity of dissociable neuroanatomic circuits as measured by resting state and diffusion tensor magnetic resonance imaging (MRI). Aim 2 is to characterize the electrophysiological correlates of behavioral benefits for the different cue types using electroencephalography (EEG) and intraoperative electrophysiological recordings obtained during implantation of deep brain stimulator in the globus pallidus internus. This work will augment my prior skills in task fMRI, transcranial magnetic stimulation (TMS) and electrophysiology by extending training in multiple modalities (high density EEG, resting state fMRI, DTI); build my analytic skills in advanced multivariate statistics; and advance my expertise in PD motor physiology. My mentorship team comprises experts in PD neurophysiology and neuromodulation therapies, and non-invasive studies of inter-individual differences in motor neurophysiology. Coursework in multivariate statistics and seminars in advanced EEG and neuroimaging applications will further my development. The environment at UCLA has a rich interdisciplinary neuroimaging community, state-of-the-art image acquisition facilities including Ahmanson-Lovelace Brian Mapping Center and Staglin Center for Cognitive Neuroscience and a renowned clinical Movement Disorders Division. The career development plan forges a path to become an independent physician-scientist, using multiple modalities to characterize neurophysiologic biomarkers of heterogeneous disease features in Parkinson?s disease to improve therapy development and delivery.