Integrative Examination of Neurobehavioral Mechanisms in Tic Suppression

描述(申请人提供)：K23职业发展奖旨在为PI提供所需的培训，以实现她的长期职业目标，即对与皮质-纹状体-丘脑-皮质(CSTC)回路功能障碍相关的抽搐和重复行为问题潜在的神经行为机制进行独立的、程序性的研究。与这一目标一致，这项拟议的研究将集中在慢性抽搐青年样本中抑制抽动的神经行为机制。该奖项基于PI在抽动和强迫症谱系障碍方面的新兴专业知识，以及研究影响抽动表达的行为机制的实验精神病理学方法。这一奖项将扩大PI的研究范围，包括对抑制抽动的行为和神经生物学机制的综合研究。额外的指导培训将确保PI获得开发、领导和促进与CSTC回路功能障碍相关的精神障碍的综合、跨学科疾病机制研究所需的技术技能和先进的理论和科学知识。高度结构化的培训计划将使PI能够获得以下领域的技能和知识：1)CSTC神经电路和神经解剖学，2)经颅磁刺激(TMS)方法，3)使用磁共振成像(MRI)数据指导TMS导航，4)在儿童精神病理学研究中合乎道德和安全地使用TMS，以及5)合作强迫症神经科学研究。培训和研究将由一个由精神病学、心理学和神经学领域的领先科学家组成的专家指导团队指导。这个K23奖项的研究计划将使用一种创新的方法来研究辅助运动区(SMA)激活和抽动抑制之间的关系，该方法结合了1赫兹重复TMS(RTMS)和假rTMS与已建立的行为抽动抑制范例。慢性抽搐是一种致残的神经精神症状，也是儿童最常见的运动障碍。抑制抽动的机制目前知之甚少，但被认为涉及生物因素和环境因素之间的相互作用。SMA是CSTC回路中的一个皮质节点，在促进上下文相关的运动输出方面起着关键作用，在抽动症患者中非常活跃。目前的研究将探索SMA活动在使用TMS抑制抽动中的作用，TMS是一种允许暂时调节皮质区域的非侵入性程序。目标1将探讨抑制SMA兴奋性是否会导致基线抽动频率的改变、自愿的抽动抑制以及在存在抑制条件强化的情况下抽动的抑制能力。目的2探讨前兆冲动强度的改变是否伴随着SMA兴奋性的抑制。这将是第一个直接研究SMA功能、抽动抑制和先兆冲动强度之间关系的研究。研究结果将完善我们对抽动抑制所涉及的大脑-背景关系的理解，并可能对更广泛地理解抑制其他不想要的重复行为所涉及的神经行为过程有影响。

DESCRIPTION (provided by applicant): This K23 Career Development Award is designed provide the training needed for the PI to achieve her long-term career goal of conducting independent, programmatic research on the neurobehavioral mechanisms underlying tics and repetitive behavior problems associated with cortico-striatal-thalamo-cortical (CSTC) circuit dysfunction. Consistent with this goal, the proposed study will focus on the neurobehavioral mechanisms underlying tic suppression in a sample of youth with chronic tics. This award builds on the PI's emerging expertise in tic and obsessive-compulsive spectrum disorders and experimental psychopathology methods to study behavioral mechanisms that impact tic expression. This award will extend the PI's research to include integrated study of behavioral and neurobiological mechanisms in tic suppression. Additional mentored training will ensure that the PI acquires the technical skills and advanced theoretical and scientific knowledge needed to develop, lead, and contribute to integrative, interdisciplinary disease mechanism research in mental disorders associated with CSTC circuit dysfunction. The highly structured training plan will enable the PI to obtain skills and knowledge in the following areas: 1) CSTC neurocircuitry and neuroanatomy, 2) transcranial magnetic stimulation (TMS) methodology, 3) use of magnetic resonance imaging (MRI) data to guide TMS navigation, 4) ethical and safe use of TMS in child psychopathology research, and 5) collaborative obsessive- spectrum neuroscience research. Training and research will be guided by an expert mentorship team comprised of leading scientists in the fields of psychiatry, psychology, and neurology. The research plan of this K23 award will examine the relationship between supplementary motor area (SMA) activation and tic suppression using an innovative methodology that combines 1 hz repetitive TMS (rTMS) vs. sham rTMS with an established behavioral tic suppression paradigm. Chronic tics are a disabling neuropsychiatric symptom and the most common movement disorder in children. The mechanisms underlying tic suppression are poorly understood but thought to involve an interaction between biological and contextual factors. SMA is a cortical node of the CSTC circuit that plays a key role in facilitating context-dependent motor output and is hyperactive in those with tics. The current study will probe the role of SMA activity in tic suppression using TMS, a non-invasive procedure that allows for the temporary modulation of cortical regions. Aim 1 will address whether inhibition of SMA excitability leads to changes in baseline tic frequencies, voluntary tic suppression, and tic suppressability in the presence of suppression-contingent reinforcement. Aim 2 will explore whether premonitory urge intensity changes in conjunction with inhibition of SMA excitability. This will be the first study to directly examine the relationsip between SMA functioning, tic suppression, and premonitory urge intensity. Results will refine our understanding of brain-context relationships involved in tic suppression and may have implications for the broader understanding of neurobehavioral processes involved in the suppression of other unwanted repetitive behaviors.